Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) on Oxygenation in Patients with Sepsis Induced Acute Respiratory Distress Syndrome

doi:10.21203/rs.3.rs-4918271/v1

Download PDF

Research Article

Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) on Oxygenation in Patients with Sepsis Induced Acute Respiratory Distress Syndrome

https://doi.org/10.21203/rs.3.rs-4918271/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objectives

Neutrophil elastase (NE) plays an important role in the development of acute respiratory distress syndrome (ARDS). As a selective NE inhibitor, Sivelestat may improve the outcomes of patients with sepsis-induced ARDS in previous studies, but there is a lack of solid evidence. This trial aimed to evaluate the effect of sivelestat sodium on oxygenation in patients with sepsis-induced ARDS.

Methods

We conducted a multicenter, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with sepsis-induced ARDS admitted within 48 hours of the advent of symptoms. Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administrated as a 24-hour continuous intravenous infusion for a minimum duration of 5 days and a maximum duration of 14 days. The primary outcome was the proportion of PaO₂/FiO₂ ratio improvement on Day5 after randomization, defined by a greater than 50% improvement in PaO₂/FiO₂ compared with that on ICU admission or PaO₂/FiO₂ reached over 300 mmHg on Day5.

Results

The study was stopped midway due to a potential between-group difference in mortality observed during the interim analysis. Overall, a total of 70 patients were randomized, of whom 34 were assigned to receive sivelastat sodium and 36 placebo. On day5, 19/34 (55.9%) patients in the sivelastat group had PaO₂/FiO₂ ratio improvement compared with 7/36 (19.4%) patients in the placebo group (risk difference, 0.36; 95% CI, 0.14 to 0.56, p < 0.001). The Kaplan-Meier curves showed a significantly improved 28-day survival rate in patients receiving sivelestat than those not (hazard ratio, 0.32; 95% CI, 0.11 to 0.95; p = 0.041).

Conclusion

In patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first five days and may be associated with decreased 28-day mortality.

sepsis

acute respiratory distress syndrome

neutrophil elastase

sivelestat

oxygenation

Sepsis is an aberrant immune response to an infection and a syndrome characterized by organ dysfunction[1]. Lung injury is common in sepsis and acute respiratory distress syndrome (ARDS) is a devastating complication of sepsis[2]. Sepsis is the leading cause of ARDS, accounting for approximately 75% of patients with ARDS[3], and the outcomes of patients with sepsis-induced ARDs is worse than those with ARDS from other causes[4, 5]. However, therapies to prevent or treat sepsis-induced ARDS remain elusive[2].

During the pathogenesis of sepsis-induced ARDS, multiple circulating immune cells are activated and inflammatory mediators are massively released into the circulation, which leads to capillary endothelium injury in the lungs[6, 7]. Following lung injury, immune cells such as neutrophils are recruited to the alveolar space and release large amounts of toxic mediators, including neutrophil elastase(NE)[8, 9]. Previous studies found that systemic inflammatory response syndrome (SIRS) patients with high NE levels were prone to developing ARDS[10] and elevated NE activity was also observed in the bronchoalveolar lavage fluid (BALF) of patients with ARDS[11].

Sivelestat sodium, a small molecule weight, selective and reversible NE inhibitor, was discovered in 1990s[12] and may confer protective effects on pulmonary endothelial injury in sepsis animal models[13–15]. Several clinical studies showed that sivelestat sodium could improve oxygenation, ameliorate lung injury, and reduce the duration of mechanical ventilation in patients with sepsis-induced ARDS[16–18]. However, no causal relationship can be implicated due to the observational nature. Therefore, we conducted a multi-center, randomized controlled study to evaluate the role of sivelestat sodium on oxygenation in patients with sepsis-induced ARDS.

Trial design and oversight

We conducted an investigator-initiated, multi-center, double-blind, randomized, placebo-controlled trial at 12 hospitals across China. The human research ethics committee at each hospital approved the protocol. Patients or their surrogates provided written informed consent before enrollment. This trial was designed by the authors, who collected and analyzed the data, vouched for the accuracy and completeness of the data and the adherence of the trial to the protocol, wrote and agreed on the submission of the manuscript. Shanghai Huilun (Jiangsu) Pharmaceutical Co., Ltd. supplied the trial drugs but had no role in designing or conducting the trial, or analysing the data and did not have access to the data before publication. The trial was registered on the Chinese Clinical Trial Registry (ChiCTR2200056892) on February 22, 2022.

Study population

Patients diagnosed with sepsis aged between 18 to 75 years old and with ARDS admitted to any of the participating sites within 48 hours of sepsis-induced ARDS onset were eligible for inclusion. The diagnosis of sepsis was according to sepsis 3.0 criteria[19] and diagnosis of ARDS was based on Berlin criteria[20]. The inclusion criteria were: (1) diagnosed with sepsis-induced ARDS; (2) diagnosed with mild to moderate ARDS; (3) age between 18 to 75 years old; (4) less than 48 hours from ARDS onset; (5) written informed consent obtained. The exclusion criteria were: (1) patients with an PaO2/FiO2 ratio < 100 mmHg (PEEP ≥ 5 cm H2O); (2) pregnant or lactating women or women who may be in the midst of pregnancy; (3) diagnosed with neutropenia; (4) patients receiving chemotherapeutic agents or other immunomodulatory drugs or high-dose corticosteroid therapy for more than 5 days; (5) had a history of severe cardiovascular, respiratory, renal, or hepatic diseases; (6) post-transplant patients, or patients with disseminated intravascular coagulation, end-stage malignancy, mental illness, etc. Detailed inclusion and exclusion criteria were provided in the Supplementary Protocol.

Randomization, blinding and interventions

Each eligible participant was assigned randomly from a computer-generated sequence to either the sivelestat sodium or placebo group in a 1:1 ratio, using a block size of 4 stratified by site. The random allocation sequence was generated by a third party independent of the study. Allocation concealment was achieved using blinded medication packs. Participants, data collectors, and investigators assessing outcome data will be blinded to the treatment allocation.

After randomization, treatment administration were started within 1 hour of randomization. Patients were assigned to receive a 24-hour continuous intravenous infusion of sivelastat sodium at a rate of 0.2 mg/kg/h, for a minimum duration of 5 days and a maximum duration of 14 days or a placebo during the same study period. All other treatments were administered at the discretion of the treating clinicians.

Trial outcomes

The primary outcome was the proportion of PaO₂/FiO₂ ratio improvement on Day5 after randomization. PaO₂/FiO₂ ratio improvement on Day5 was defined as a greater than 50% improvement in PaO₂/FiO₂ compared with that on ICU admission or PaO₂/FiO₂ reached over 300 mmHg on Day5. Secondary outcomes included PaO₂/FiO₂ ratio on Day3, 5, 7 and 28-day mortality, ventilator free days (28-VFDs) with 28 days, ICU and hospital free days within 28 days.

Sample size estimation

Based on previous studies[16, 17], it is estimated that 35% of the study patients in the control group would reach the primary endpoint (oxygenation index improvement on Day5). We estimated that a sample size of 122 participants could provide 80% power at a two-sided alpha level of 0.05 to detect an absolute 25% elevation in the primary endpoint from the sivelestat sodium intervention. The calculation was implemented using the PASS 11.0 software (PASS, NCSS software, Kaysville, USA). In this trial, we plan to randomize 142 patients in total (71 per group) after allowing for a less than 15% withdrawal. This study employed one planned interim analysis that was conducted by an independent Data and Safety Monitoring Board (DSMB) after the first 70 participants enrolled. The DSMB will review the results of the interim analysis and regular safety report, and can recommend that a trial should be stopped early because of concerns about participant safety. The DSMB will review the safety report every six months.

Statistical analysis

Continuous data were reported as means and standard deviations (SD) when normally distributed or as medians and interquartile ranges (IQR) when not normally distributed. The normality of continuous variables will be examined using the Shapiro–Wilk test. Categorical data will be expressed as numbers and percentages.

The primary analysis was based on the intention-to-treat (ITT) population, defined as all enrolled patients from the participating sites. We used generalized linear model (GLM) to compare the difference in the primary outcome (the proportion of PaO₂/FiO₂ ratio improvement on Day5) between groups. In the GLM model, the proportion of oxygenation index improvement on trial day-5 will be treated as the response variable following a binomial distribution and the sivelestat sodium intervention as fixed effect, and the identity and log link function will be used. In the adjusted GLM model, we introduced several baseline characteristics (including diabetes, history of covid-19 infection, lung compliance and PaO2/Fio2 ratio) as covariates. However, the above log-binomial and identity-binomial regression model do not converge, and logit link function was used. We analyzed secondary outcomes also using GLM. Risk differences and its 95% confidence interval (CI) were calculated for categorical variables, and mean differences (95% CI) for continuous variables. Kaplan–Meier curves were used to compare the 28-day survival curves after randomization. The difference between two-groups was calculated by tested by log-rank test and its hazard ratio (HR) and 95%CIs was calculated by Mantel-Cox regression model.

Four pre-defined subgroup analyses were conducted for the primary endpoint according to (1) age (dichotomized at 50 years old), (2) APACHE II score at enrollment (dichotomized at 15), (3) septic shock at enrollment, and (4) PaO₂/FiO₂ ratio at enrollment (dichotomized at 200). Adverse event analyses were reported for all the participants who received the study treatment. Analyses were conducted using R 4.2.3 software. Statistical tests were two-sided, and p values < 0.05 were considered statistically significant.

Recruitment and baseline characteristics

During the study period, 282 patients with sepsis combined with ARDS were assessed for eligibility, of whom 70 were enrolled in the trial from nine hospitals across China. The trial recruitment was halted by the DSMB after the interim analysis owing to observed between-group difference in mortality, and the DSMB requested to unblind the data. After reviewing the unblinded data, the DSMB concluded that the trial should be stopped midway due to the analysis result that sivelestat group showed improved survival compared with the placebo group, and the trial was then formally stopped. The numbers of cases from each site were shown in online Supplemental table 1. Among those 70 randomized patients, 34 were assigned to receive sivelastat sodium and 36 placebo. All randomized participants completed follow-up and were included in the primary analysis (Fig. 1).

The characteristics of the participants at baseline were evenly distributed between the two trial groups (Table 1). The majority of the trial participants required mechanical ventilation (52/70, 74.3%) at admission. The median (IQR) PaO₂/FiO₂ ratio was 136.0 (104.2–163.0) mmHg in the sivelastat group and 161.0 (144.0-195.0) mmHg in the placebo group.

Table 1

Baseline characteristics of the study subjects.
Characteristics	Sivelestat group	Placebo group
Characteristics	(N = 34)	(N = 36)
Mean Age ± SD, yr	61.2 ± 11.4	56.5 ± 17.6
Gender, n (%)
Women	12 (35.3)	13 (36.1)
Men	22 (64.7)	23 (63.9)
Mean BMI ± SD, kg/m²	25.0 ± 4.4	25.5 ± 3.6
Median Charlson score (IQR)	4.0 (2.5-5.0)	5.0 (2.5–5.5)
Comorbidities, no. (%)
Hypertension	15 (44.1)	11 (30.6)
Diabetes mellitus	11 (32.4)	4 (11.1)
Coronary heart disease	6 (17.6)	4 (11.1)
History of covid-19 infection, n (%)	4 (11.8)	8 (22.2)
Use of mechanical ventilation, n (%)	25 (73.5)	27 (75.0)
Interval between randomization and ICU admission, d, median (IQR)	0.4 (0.2–2.2)	1.0 (0.2, 5.6)
Ventilator related parameters, median (IQR)
Lung compliance, ml/cmH₂O	51.0 (30.8–58.5)	39.3 (33.2–48.4)
Positive end-expiratory pressure at randomization, cmH₂O	5 (5–8)	5 (5–8)
Clinical parameters
Presence of sepsis, no. (%)	34 (100.0)	35 (97.2)
Presence of septic shock, no. (%)	16 (47.1)	15 (41.7)
Median APACHE II score (IQR)	20.5 (12.0–25.0)	17.5 (11.3–24.0)
Median SOFA score (IQR)	7.0 (4.8–10.0)	6.0 (4.3–9.8)
Median lac (IQR), mmol/L	1.2 (1.0-2.8)	1.4 (1.0-1.8)
Median PaO₂/FiO₂ ratio (IQR)	136.0 (104.2–163.0)	161.0 (144.0-195.0)
Laboratory parameters, median (IQR)
Serum NE concentration, pg/ml, ×10⁴	31.0 (7.8–35.5)	32.7 (15.6–37.7)

Primary and secondary outcomes

On day5 after randomization, 19/34 (55.9%) patients in the sivelastat group had PaO₂/FiO₂ ratio improvement compared with 7/36 (19.4%) patients in the placebo group (risk difference, 0.36; 95% CI, 0.14 to 0.56, p < 0.001). In addition, the PaO₂/FiO₂ ratio constantly differ between groups on day3, day5 and day7 (Table 2).

Table 2

Trial outcomes. CI denotes confidence interval. SD denotes standard deviation. IQR denotes interquartile range. ICU denotes intensive care unit. # calculated in patients undergoing mechanical ventilation at randomization; * calculated in patients admitted in ICU at randomization. ^§Difference was shown for continuous and catergorical variables, risk ratio (RR) was shown for catergorical variables, odd ratio (OR) will was shown when the above log-binomial regression model does not converge. ¶ adjusted for sex, Age, AP etiology, organ failure, acute kidney injury (AKI) at enrollment, APACHE II score, and referral or not.
	Sivelestat group (N = 34)	Placebo group (N = 36)	Difference/ Risk ratio/Odd ratio^§ (95%CI)	P value
Primary outcome
PaO₂/FiO₂ ratio improvement on day5, n (%)	19 (55.9)	7 (19.4)	Difference: 0.36 (0.14, 0.56) RR: 2.87 (1.48, 6.58)	< 0.001
Adjusted^¶			OR: 6.12 (1.93, 22.10)	0.003
Secondary outcomes
PaO₂/FiO₂ ratio
Day 3, mean ± SD	252.1 ± 78.5	169.4 ± 64.6	Difference: 82.7 (49.1, 116.3)
Day 5, mean ± SD	261.8 ± 68.4	173.7 ± 69.2	Difference: 88.1 (54.6, 121.6)
Day 7, mean ± SD	270.1 ± 82.6	201.3 ± 85.0	Difference: 68.8 (16.8, 120.7)
Ventilator free days within 28 days, d, median (IQR)^#	21.0 (6.5, 24.5)	20.0 (0, 23.0)	Difference: 3.9 (-1.9, 9.7)	0.20
28-day ICU free days, d, median (IQR)*	17.0 (0, 20.5)	10.0 (0, 21.3)	Difference: 2.2 (-3.4, 7.7)	0.45
28-day hospital free days, d, median (IQR)	9.0 (0, 15.3)	9.5 (0, 17.8)	Difference: -1.3 (-5.2, 2.6)	0.52
28-day mortality, n (%)	3 (8.8)	10 (27.8)	Difference: -0.19 (-0.37, -0.01) RR: 0.32 (0.08, 0.93)	0.03
Adverse events
Hematological Abnormalities, no.	2	2
Abnormal liver function, no.	1	2
Hyperuricaemia, no.	0	1
Hyperlactacidemia, no.	0	1

Patients in the sivelastat group had a median of 21.0 VFDs (IQR, 6.5–24.5) within the first 28 days compared with 20.0 VFDs (IQR, 0–23.0) for those receiving placebo. The mean difference in VFDs between groups was 3.9 days (95% CI, -1.9 to 9.7, p = 0.20). No significant difference in cumulative event of weaning from mechanical ventilation between treatment groups was observed (hazard ratio, 1.70; 95% CI, 0.87 to 3.31, p = 0.12, supplementary Fig. 1). The 28-day mortality was 3/34 (8.8%) in patients receiving sivelastat and 10/36 (27.8%) in those receiving placebo (risk difference, -0.19; 95% CI, -0.37 to -0.01, p = 0.03). The Kaplan-Meier curves showed a significantly improved survival rate in patients receiving sivelestat than those not (HR, 0.32; 95% CI, 0.11 to 0.95; log-rank p = 0.041) (Fig. 2). The ICU and hospital free days within 28 days were both comparable between two groups (Table 2).

Subgroup analysis

Subgroup analysis suggested the treatment effect of sivelestat on the primary outcome had trends toward more significant in patients with APACHE II score < 15 (p for interaction = 0.042) (Fig. 3).

Adverse events

The number of adverse events did not differ meaningfully between the trial groups. Details regarding adverse events are provided in Table 2.

In this multicenter, double-blind, randomized, placebo-controlled trial, the use of sivelestat sodium could improve oxygenation within the first week in patients with sepsis-induced ARDS. Moreover, it was associated with decreased 28-day mortality, though there is no difference in ventilator-free days or other outcomes. Subgroup analysis showed that age, the baseline respiratory function, disease severity and septic status may affect the efficacy of sivelestat sodium, favouring sivelestat use in patients with APACHE II score < 15.

Meta analysis showed that sivelestat can not only reduce the mortality, shorten the mechanical ventilation time, increase ventilation free days, but also improve the oxygenation in ARDS patients[21]. However, two recent large clinical trials demonstrated discordant effects of sivelestat sodium in patients with acute lung injury (ALI)[22, 23]. The phase III Japanese study by Tamakuma et al. included 230 ALI/ARDS patients combined with SIRS, and sivelestat was shown to increase pulmonary function, reduce duration of mechanical ventilation, and shorten ICU stay[22]. An international multicenter double-blind, placebo-controlled Phase II study (STRIVE study) randomized 492 mechanically ventilated patients with ALI/ARDS[23], and the results showed that sivelestat did not change 28-day mortality or VFDs. Furthermore, a negative trend in long-term 180-day mortality rate was noted, and the trial was then stopped midway per the recommendation from the DSMB.

The discrepancy between the two studies may be due to differences in the characteristics of study patients, such as age, baseline respiratory function, disease severity and septic status. The patients enrolled in the phase III Japanese study had a narrower age distribution and better respiratory function than those in the STRIVE study. In addition, clinical studies reporting positive results with sivelestat therapy had mainly enrolled ARDS patients with a Lung Injury Score < 2.5, whereas the majority of the patients in the STRIVE study had a Lung Injury Score > 2.5[24, 25]. A post-hoc analysis of the STRIVE patients involving those who had a mean Lung Injury Score ≤ 2.5, revealed favourable trends in mortality and VFDs in patients receiving sivelestat[23]. On the other hand, it is suggested that the different proportions of septic patients may have contributed to the discordant results among these studies (58% vs. 69%). Our results were consistent with the above findings, showing that sivelestat may confer larger treatment effects in patients with sepsis-induced ARDS, especially in patients with APACHE II score < 15. Taken together, our study suggests that sivelestat could be effective in patients with mild sepsis-induced ARDS, and may be associated with survival benefits in this popualtion. In addition, the mortality rate in our placebo group was 27.8%, which was in the acceptable range compared with previous studies [26, 27], implying the generalizability of our results.

The above results can also be explained from a pathophysiological point of view. Neutrophil activation and NE release are very early biological events in the pathogenesis of ARDS[28]. Previous research showed a significant increase in blood NE in patients with sepsis-induced ARDS[29] and a decrease in blood NE after sivelestat administration[30, 31], suggesting that the therapeutic effect of sivelestat is related to the inhibition of NE. Recent studies have shown that damage to the endothelial glycocalyx is a critical factor in the development and progression of ARDS[32, 33]. In addition, our preclinical research has shown that sivelestat can reduce endothelial glycocalyx damage by inhibiting the production of neutrophil trapping nets (NETs), improve endothelial cell permeability, attenuate lung histopathological injury and ultimately improve survival in sepsis-induced ALI model mice. Further molecular docking and visualisation analysis showed that sivelestat could bind with high affinity to the key ferroptosis protein glutathione peroxidase (GPX4), increase the expression of GPX4 and thus interfere with the process of ferroptosis[29]. Therefore, sivelestat may have pleiotropic effects on ARDS and may not be limited to interfering with NE.

The trial had several limitations. First, the current sample size was not powered to detect mortality difference, and stopping the trial midway further weaken the robustness of the results. Thus, the results of this trial should be interpreted cautiously. Second, subjective factors contribute to the decision to wean patients from mechanical ventilation, which may bias the VFDs. The fact that approximately 25% of patients did not receive mechanical ventilation at randomization and the prematurely stopped trial wihout adequate statistical power may explain the non-significant difference in VFD. Third, the results could be strengthened had more inflammatory mediators and other surrogate measurements, including IL-6, IL-8, IL-10, TNF-α been measured. Last, we did not observe the effects of sivelestat on long-term outcomes, like pulmonary function after hospital discharge.

In patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first week, and was associated with decreased 28-day mortality, particualrly in patients with less severe disease, including those with APACHE II score < 15 or with PaO₂/FiO₂ ratio ≥ 200 or without septic shock. Further large-scale RCTs are needed to confirm the effects of sivelestat on mortality in this population. These data also support the conduct of a large confirmatory trial with a hard clinical endpoint.

Ethics and approval statement

The protocol and the informed consent document have been reviewed and approved by the Institutional Ethics Committee of all participating centers. Study investigators will provide potential participants with verbal and written information prior to inclusion in the study. Informed consent will be provided from participants or their authorized representatives. The study was registered in the Clinical Trials Register (ChiCTR2200056892).

Authorship contribution statement

Wu TJ, Wang T and Wang XZ: drafting of the manuscript; material or technique support; critical revision of the manuscript. Jiang JJ, Tang Y, Zhang LN, Jiang ZM, Liu F, Kong GQ, Zhou TF, Liu RJ, Guo HP, Xiao J, Sun WQ, Li YY, Zhu YY, Liu Q, Xie WF, Qu Y: Patient screening and data collection. Wang XZ: analysis and interpretation of data. Wu TJ and Wang T: conceived, designed and supervised the study; analysis and interpretation of data; critical revision of the manuscript; obtained funding. All authors have read the manuscript and approved its submission.

Consent for Publication

The authors have declared that no competing interest exists, and we have obtained the informed consent of all authors for publication.

Funding

This study is supported by Shanghai Huilun (Jiangsu) Pharmaceutical Co., Ltd., which is also responsible for the supply of the study drug andplacebo as well as distribution to the participating centers. Funding agencyhad no input into the design, conduct, data collection, statistical analysis, orwriting of the manuscript.

Author Contribution

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10.
Beitler JR, Thompson BT, Baron RM, Bastarache JA, Denlinger LC, Esserman L, Gong MN, LaVange LM, Lewis RJ, Marshall JC, et al. Advancing precision medicine for acute respiratory distress syndrome. Lancet Respir Med. 2022;10(1):107–20.
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016;315(8):788–800.
Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell ES, Steinberg KP. Causes and timing of death in patients with ARDS. Chest. 2005;128(2):525–32.
Sheu CC, Gong MN, Zhai R, Chen F, Bajwa EK, Clardy PF, Gallagher DC, Thompson BT, Christiani DC. Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS. Chest. 2010;138(3):559–67.
Englert JA, Bobba C, Baron RM. Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome. JCI Insight 2019, 4(2).
Xu H, Sheng S, Luo W, Xu X, Zhang Z. Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup. Front Immunol. 2023;14:1277161.
Zeiher BG, Matsuoka S, Kawabata K, Repine JE. Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med. 2002;30(5 Suppl):S281–287.
Sahebnasagh A, Saghafi F, Safdari M, Khataminia M, Sadremomtaz A, Talaei Z, Rezai Ghaleno H, Bagheri M, Habtemariam S, Avan R. Neutrophil elastase inhibitor (sivelestat) may be a promising therapeutic option for management of acute lung injury/acute respiratory distress syndrome or disseminated intravascular coagulation in COVID-19. J Clin Pharm Ther. 2020;45(6):1515–9.
Kodama T, Yukioka H, Kato T, Kato N, Hato F, Kitagawa S. Neutrophil elastase as a predicting factor for development of acute lung injury. Intern Med. 2007;46(11):699–704.
McGuire WW, Spragg RG, Cohen AB, Cochrane CG. Studies on the pathogenesis of the adult respiratory distress syndrome. J Clin Invest. 1982;69(3):543–53.
Kawabata K, Suzuki M, Sugitani M, Imaki K, Toda M, Miyamoto T. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun. 1991;177(2):814–20.
Suzuki K, Okada H, Takemura G, Takada C, Kuroda A, Yano H, Zaikokuji R, Morishita K, Tomita H, Oda K, et al. Neutrophil Elastase Damages the Pulmonary Endothelial Glycocalyx in Lipopolysaccharide-Induced Experimental Endotoxemia. Am J Pathol. 2019;189(8):1526–35.
Suda K, Takeuchi H, Hagiwara T, Miyasho T, Okamoto M, Kawasako K, Yamada S, Suganuma K, Wada N, Saikawa Y, et al. Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis. Shock. 2010;33(5):526–31.
Hagiwara S, Iwasaka H, Togo K, Noguchi T. A neutrophil elastase inhibitor, sivelestat, reduces lung injury following endotoxin-induced shock in rats by inhibiting HMGB1. Inflammation. 2008;31(4):227–34.
Gao X, Zhang R, Lei Z, Guo X, Yang Y, Tian J, Huang L. Efficacy, safety, and pharmacoeconomics of sivelestat sodium in the treatment of septic acute respiratory distress syndrome: a retrospective cohort study. Ann Palliat Med. 2021;10(11):11910–7.
Hayakawa M, Katabami K, Wada T, Sugano M, Hoshino H, Sawamura A, Gando S. Sivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome and disseminated intravascular coagulation patients. Shock. 2010;33(1):14–8.
Miyoshi S, Hamada H, Ito R, Katayama H, Irifune K, Suwaki T, Nakanishi N, Kanematsu T, Dote K, Aibiki M, et al. Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis. Drug Des Devel Ther. 2013;7:305–16.
Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):775–87.
Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017;377(6):562–72.
Ding Q, Wang Y, Yang C, Tuerxun D, Yu X. Effect of Sivelestat in the Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis. Intensive Care Res 2023:1–10.
Tamakuma S, Ogawa M, Aikawa N, Kubota T, Hirasawa H, Ishizaka A, Taenaka N, Hamada C, Matsuoka S, Abiru T. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther. 2004;17(5):271–9.
Zeiher BG, Artigas A, Vincent JL, Dmitrienko A, Jackson K, Thompson BT, Bernard G. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med. 2004;32(8):1695–702.
Aikawa N, Kawasaki Y. Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome. Ther Clin Risk Manag. 2014;10:621–9.
Mohamed MMA, El-Shimy IA, Hadi MA. Neutrophil Elastase Inhibitors: A potential prophylactic treatment option for SARS-CoV-2-induced respiratory complications? Crit Care. 2020;24(1):311.
Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370(23):2191–200.
Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261–70.
Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in Sepsis. Front Immunol. 2019;10:2536.
Fei Y, Huang X, Ning F, Qian T, Cui J, Wang X, Huang X. NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomed Pharmacother. 2024;175:116621.
Matsuzaki K, Hiramatsu Y, Homma S, Sato S, Shigeta O, Sakakibara Y. Sivelestat reduces inflammatory mediators and preserves neutrophil deformability during simulated extracorporeal circulation. Ann Thorac Surg. 2005;80(2):611–7.
Pan T, Tuoerxun T, Chen X, Yang CJ, Jiang CY, Zhu YF, Li ZS, Jiang XY, Zhang HT, Zhang H, et al. The neutrophil elastase inhibitor, sivelestat, attenuates acute lung injury in patients with cardiopulmonary bypass. Front Immunol. 2023;14:1082830.
Li J, Qi Z, Li D, Huang X, Qi B, Feng J, Qu J, Wang X. Alveolar epithelial glycocalyx shedding aggravates the epithelial barrier and disrupts epithelial tight junctions in acute respiratory distress syndrome. Biomed Pharmacother. 2021;133:111026.
Liu XY, Xu HX, Li JK, Zhang D, Ma XH, Huang LN, Lü JH, Wang XZ. Neferine Protects Endothelial Glycocalyx via Mitochondrial ROS in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome. Front Physiol. 2018;9:102.

No competing interests reported.

FigureS1.docx
Figure S1. Cumulative event of weaning from mechanical ventilation. HR denotes hazard ratio. CI denotes confidence interval.
TableS1.docx
Table S1. Numbers of cases from each site.

Download PDF

Version 1

posted

You are reading this latest preprint version

Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) on Oxygenation in Patients with Sepsis Induced Acute Respiratory Distress Syndrome

Status:

Version 1

Abstract

Objectives

Methods

Results

Conclusion

Figures

Introduction

Materials and methods

Trial design and oversight

Study population

Randomization, blinding and interventions

Trial outcomes

Sample size estimation

Statistical analysis

Results

Recruitment and baseline characteristics

Primary and secondary outcomes

Subgroup analysis

Adverse events

Disscussion

Conclusion

Declarations

Ethics and approval statement

Authorship contribution statement

Consent for Publication

Funding

Author Contribution

References

Additional Declarations

Supplementary Files

Status:

Version 1