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Anesth Analg 2004;99:872-877
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000129996.22368.85

CRITICAL CARE AND TRAUMA

Pilot Study of the Effects of ONO-5046 in Patients with Acute Respiratory Distress Syndrome

Yuji Kadoi, MD*, Hiroshi Hinohara, MD*, Fumio Kunimoto, MD*, Shigeru Saito, MD{dagger}, Fumio Goto, MD{dagger}, Takayuki Kosaka, MD{ddagger}, and Keisuke Ieta, MD{ddagger}

*Department of Intensive Care, {dagger}Department of Anesthesiology, and {ddagger}First Department of Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan

Address correspondence and reprint requests to Yuji Kadoi, MD, Department of Intensive Care, Gunma University, Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Address e-mail to kadoi{at}med.gunma-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Evidence has linked neutrophil elastase to acute respiratory distress syndrome (ARDS), suggesting that inhibiting the activity of this enzyme could prevent the development and progression of ARDS. However, few clinical trials have examined this notion. We therefore examined the effects of ONO-5046 (sivelestat, a specific inhibitor of neutrophil elastase; sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylaminobenzoyl]amino-acetate tetrahydrate]) in a randomized, double-blinded trial in patients with ARDS. We randomly assigned 24 patients with ARDS to groups that received conventional therapy without or with sivelestat (0.2 mg · kg–1 · h–1) for 14 days. The variables of interest associated with clinical outcome were the duration of mechanical ventilation; changes in oxygenation from baseline; changes in cytokine levels from baseline; number of patients alive at 30 days who did not need mechanical ventilation; and mortality rate. The length of intensive care unit stay, number of ventilation days, and mortality rates did not statistically differ between groups. ARDS was more persistent in the control than in the sivelestat group (control, 19.5 ± 7.4 days; sivelestat, 13.5 ± 5.9 days; P = 0.039). Neutrophil elastase activity significantly differed between groups at 72 h after treatment. Levels of interleukin-6 were lower in the sivelestat group than in the controls at 24, 48, and 72 h after treatment. ONO-5046 apparently did not affect survival or the duration of mechanical ventilation.

IMPLICATIONS: ONO-5046 decreased cytokine levels more rapidly in acute respiratory distress syndrome patients treated with sivelestat than in those who received placebo. However, these decreases did not appear to affect other clinical variables, such as the duration of mechanical ventilation or survival rates.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Acute respiratory distress syndrome (ARDS) is characterized by acute inflammation that develops after a latent period of hours or days after various predisposing conditions, such as sepsis and trauma (1). Inflammatory mediators generated because of the predisposing condition might induce inflammatory cells abnormally sequestered in the pulmonary microvasculature to secrete proinflammatory mediators that damage the microvascular endothelium (1,2). Many of the manifestations of an acute inflammatory response are attributable to neutrophil actions (3–5). Neutrophils accumulate in the lung microvasculature during early ARDS and release cytokines and cytotoxic products, including reactive oxygen species and proteases. Among these proteases, neutrophil elastase plays a role in the pathogenesis and progression of ARDS (6). Excessive neutrophil elastase activity results in cell and tissue injury and indirectly potentiates the inflammatory response by increasing interleukin (IL)-8 expression and release (7–9). Increased IL-8 concentrations in the serum and bronchoalveolar lavage fluid (BALF) of ARDS patients correlate with the extent of lung injury (8). Evidence linking neutrophil elastase to ARDS suggests that inhibiting neutrophil elastase activity could prevent the development and progression of ARDS (10).

ONO-5046 (sivelestat; sodium N-[2-[4-(2,2-dimethyl-propionyloxy) phenylsulfonylaminobenzoyl]amino-acetate tetrahydrate]) is a specific inhibitor of neutrophil elastase (10–12). Kawabata et al. (11) have reported that sivelestat prevents the development of lung injury induced by endotoxin inhalation in hamsters. Tamakura et al.1 compared the effect of large and small doses of sivelestat in Japanese patients whose lung injury was associated with systemic inflammatory response syndrome (SIRS). They found that although the time of discharge from the intensive care unit (ICU) (30 days) was significantly better for the large-dose (0.2 mg · kg–1 · h–1) than for the small-dose (0.004 mg · kg–1 · h–1) group, rates of removal from mechanical ventilation, remission of SIRS, PaO2/fraction of inspired oxygen (FIO2), and lung injury scores did not significantly differ. However, their study did not contain a control group or patients with ARDS. Zeiher et al. (10) suggested that additional clinical and preclinical studies of sivelestat were needed, not only to clarify the clinical potential of this intervention strategy, but also to define the activities of neutrophil elastase in inflammatory disorders such as acute lung injury (ALI) and multiple organ failure. Few clinical trials have examined the effectiveness of neutrophil elastase inhibitors for ARDS (2,10).1 This study examined the effects of a neutrophil elastase inhibitor (sivelestat) on plasma cytokine levels and oxygenation in patients with ARDS.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
From October 2002 to May 2003, 24 patients fulfilling the American-European Consensus Conference definition for ARDS from the ICU at the University of Gunma Hospital were entered into a randomized, controlled clinical trial to compare the effects of conventional and sivelestat therapies on plasma cytokine levels and oxygenation. The university IRB approved the study protocol, and the families of the patients provided written, informed consent to examine their records. Patients with head trauma were excluded because improved lung function probably could not alter the incidence of death or the duration of mechanical ventilation.

Patients randomized within 12 h of meeting all inclusion or exclusion criteria (Table 1) received either a continuous infusion of sivelestat (Ono Pharmaceutical Co., Ltd., Osaka, Japan; 0.2 mg · kg–1 · h–1) or a placebo (same dose of saline) for 14 days in a double-blinded fashion according to a blocked randomization algorithm. To maintain the blind, the study drug was prepared for IV infusion by dilution to a total volume of 100 mL with normal saline. Neither the patients nor the medical personnel responsible for their care were aware of which treatment was being administered.


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  		Table 1. Study Selection Criteria
 
All patients received mechanical ventilation with a Siemens Servo 300 ventilator (Siemens, Danvers, MA) in volume-controlled ventilation mode and with a positive end-expiratory pressure of 5–10 cm H2O. We maintained peak airway pressure less than 35 cm H2O and applied tidal volumes of 8–10 mL/kg. Target oxygenation variables were PaO2 more than 60 mm Hg and arterial oxygen saturation more than 90%. We adjusted the ventilatory rate to a maximum of 30 breaths/min to adequately remove CO2 and considered levels of PaCO2 less than 50 mm Hg as satisfactory. All patients were sedated with propofol infusions, and vecuronium induced muscle relaxation when necessary.

Blood collected in sterile EDTA-treated tubes was immediately centrifuged at 1500g for 15 min at 4°C, and plasma was stored at –70°C. Neutrophil elastase activity was measured with an enzyme-linked immunosorbent assay kit (Diagnostica Merck, Darmstadt, Germany) as described by Fujita et al. (13), and IL-6 was measured by using commercially available enzyme-linked immunosorbent assay kits (R&D Systems, Tokyo, Japan). Neutrophil elastase activity and IL-6 were measured before and 24, 48, and 72 h after the administration of sivelestat or placebo.

SIRS was defined as the presence of 2 or more of the following: temperature ≥38°C or ≤36°C; heart rate ≥90 bpm; respiratory rate ≥20 breaths/min; PaCO2 ≤32 mm Hg or requiring mechanical ventilation; white blood cell count ≥12,000/mm3 or ≤4,000/mm3; or ≥10% band forms. The primary end-point was the prevalence of ARDS occurring at any time during the 30 days after sivelestat or placebo administration. We considered that ARDS was reversed when the patient no longer met the criteria for ARDS on the basis of either arterial blood gas measurement or chest radiography and when the reversal lasted for at least 24 h.

The clinical outcome variable of secondary interest concerned the duration of mechanical ventilation, changes in oxygenation (PaO2/FIO2) from baseline, changes in cytokine levels (neutrophil elastase activity and IL-6) from baseline, number of patients alive at 30 days who did not need mechanical ventilation, and mortality rate at 30 days. Discontinuing mechanical ventilation was defined as extubation. The time to oxygenation criteria for extubation was defined as the first time that the patient maintained a PaO2 value of 60 mm Hg on an FIO2 ≤0.4 with a positive end-expiratory pressure of ≤5 cm H2O.

All data are expressed as means ± SD. An unpaired Student’s t-test or Fisher’s exact test was used to analyze demographics and continuous variables between groups. After the confirmation of equal variance among groups by the Bartlett test, two-way repeated-measures analysis of variance was used to perform multiple comparisons. When the F value was significant, the Bonferroni method was used to perform multiple comparisons. To eliminate a Type II error, each individual P value was adjusted. The Kaplan-Meier product-limit estimation compared ventilator-free days between treatment groups. The duration of mechanical ventilation was written down, and the duration was set to 30 days for patients who died during the study.

Statistical significance was established at P < 0.05. All calculations were performed by using a Macintosh computer with SPSS (SPSS Inc., Chicago, IL) and StatView 5.0 (Abacus Concepts, Inc., Berkeley, CA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Table 2 shows the primary causes of ARDS and baseline characteristics in the treatment groups. The groups were well balanced with respect to the primary cause of ARDS and baseline respiratory dysfunction. There was no significant difference in baseline PaO2/FIO2 between groups (baseline PaO2/FIO2: control—142 ± 56 mm Hg; range, 73–199 mm Hg; sivelestat—155 ± 46 mm Hg; range, 72–198 mm Hg). None of the patients receiving sivelestat developed adverse effects such as increased hepatobiliary or renal enzymes during the study.


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  		Table 2. Patient Data
 
Ventilation days and ICU stay and mortality did not statistically differ between groups (Table 2). The total duration of ARDS was longer in the control than in the sivelestat group (control, 13.8 ± 8.4 days; sivelestat, 7.3 ± 3.8 days; P = 0.025). Total ALI duration was longer in the control than in the sivelestat group (control, 19.5 ± 7.4 days; sivelestat, 13.5 ± 5.9 days; P = 0.025) (Table 2).

Table 3 shows the time course of changes in PaO2/FIO2 ratio, neutrophil elastase activity, and IL-6 levels. Neutrophil elastase activity significantly differed between groups at 72 h after treatment. Levels of IL-6 were lower in the sivelestat than in the control group at 48 h after treatment.


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  		Table 3. Time Course of Changes in PaO2/FIO2 Ratio, Neutrophil Elastase Activity, and Interleukin (IL)-1, IL-6, and IL-8 Levels
 
Serum laboratory values were evaluated by comparing the pre- and postinfusion values of individual patients. Abnormalities in renal, hepatic, or hematological variables did not differ regardless of treatment, and the rates of development of new infections and bacterial superinfections and of recovery from superinfections were essentially identical between groups.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We describe a randomized, controlled, double-blinded trial of patients with ARDS treated with sivelestat. Cytokine levels decreased more rapidly in ARDS patients treated with sivelestat than in those who received a placebo. However, these decreases did not appear to affect other clinical variables, such as duration of mechanical ventilation or survival rate. Some evidence suggests that neutrophil elastase plays an important role in the pathogenesis and development of ARDS. Donnelly et al. (6) discovered that plasma neutrophil elastase levels were significantly increased in patients who progressed to ARDS. They also found a significant correlation between initial elastase values and subsequent requirements for mechanical ventilation or organ failure scores. They emphasized the importance of neutrophils and their secretory products in early ARDS pathogenesis. Worthen et al. (3) showed that trace amounts of lipopolysaccharide, together with neutrophil chemotactic factors, significantly increased lung vascular permeability in a neutrophil-dependent fashion and produced lung endothelial injury. In contrast, others have questioned the role of neutrophils in ARDS, suggesting that neutrophilic inflammation is a result rather than a cause of lung injury (1). This view is supported by findings of ARDS in neutropenic patients (14). However, substantial evidence from humans and other animals supports a causative role for neutrophil elastase in lung injury (2,10).

Neutrophil elastase can also potentiate the inflammatory response by increasing IL-8 expression and release (7). In addition, Donnelly et al. (8) reported that the early appearance of IL-8 in BALF from patients at risk for ARDS might be an important prognostic indicator for its development. Nakamura et al. (7) found that neutrophil elastase released by neutrophils induces the bronchial epithelium to secrete IL-8, which in turn recruits additional neutrophils to the bronchial surface. These reports imply that early inhibition of increased plasma neutrophil elastase levels could prevent an increase in cytokine levels and thus hinder the development of ARDS. Therefore, the effects of neutrophil elastase inhibitors should be understood in patients with ARDS.

ONO-5046 (sivelestat) is a novel, specific neutrophil elastase inhibitor with a 50% inhibiting concentration of 0.044 ± 0.003 µM (Ki, 0.20 ± 0.02 µM; suc-Ala-Pro-Ala pNa substrate) (11,15) that inhibits leukocyte elastase obtained from rabbits, rats, hamsters, and mice. The inhibition is competitive, as determined by Lineweaver-Burk analyses. The binding of ONO-5046 to neutrophil elastase is highly specific. Sivelestat acts in the microenvironment between neutrophils and tissues, whereas {alpha}1-protease inhibitor incompletely blocks neutrophil-mediated tissue destruction. The inhibition of neutrophil elastase is useful in models of lung injury (16).

Results of animal studies support the notion that the neutrophil elastase inhibitor ONO-5046 (sivelestat) can improve an animal’s condition after lung injury (10,12,16,17). Miyazaki et al. (17) examined the effect of ONO-5046 in a model of ALI induced by tumor necrosis factor-{alpha} in isolated perfused rabbit lungs. ONO-5046 attenuated ALI by inhibiting the alveolar epithelial and vascular endothelial damage triggered by activated neutrophils. Kawabata et al. (11) examined the relationship between the progression of ALI and neutrophil elastase activity in BALF and the effects of sivelestat on ALI in hamsters caused by endotoxin inhalation. They concluded that delayed inhibition of neutrophil activity with sivelestat prevents the subsequent progression of ALI in hamsters. Kaneko et al. (16) reported that ONO-5046 attenuates the increased permeability of the endothelium induced by acid instillation. Nishina et al. (12) reported that IV ONO-5046 attenuated subsequent endotoxin-induced lung injury in rabbits by reducing the levels of the mediators that activate neutrophils. These findings from animal studies indicate that ONO-5046 (sivelestat) can prevent the progression of ALI in humans. However, few clinical trials have examined the effect of neutrophil elastase inhibitors on patients with ARDS (2,10). Tamakura et al.1 examined the effect of sivelestat on 230 Japanese patients with lung injury associated with SIRS in a multicenter double-blinded Phase III clinical study compared with a small-dose group. The patients were randomized to either large (0.2 mg · kg–1 · h–1) or small (0.004 mg · kg–1 · h–1) doses of sivelestat for up to 14 days.

Of the 230 enrolled patients, 221 were considered assessable according to the primary end-point of the investigator’s assessment of global improvement on Day 14. The assessment showed that 71.7% (81 of 113 patients) were moderately or significantly improved in the large-dose group, compared with 55.5% (60 of 108 patients) in the small-dose group. The survival rates did not differ between groups, but the large-dose group was discharged from the ICU sooner than the small-dose group. The large-dose group tended toward a reduced duration of mechanical ventilation compared with the small-dose group (P = 0.0636). However, the study did not compare the group given sivelestat with a control group or with ARDS patients.

We found that sivelestat rapidly decreased neutrophil elastase activity and levels of cytokines such as IL-6 in patients with ARDS. These findings are consistent with those of Nishina et al. (12) and Tamakura et al.1 Because increased levels of proinflammatory cytokines play pivotal roles in the development of ARDS (1,2), a decrease in such levels should be important for improving this condition.

The mechanism through which sivelestat decreased the cytokine levels remains a matter of speculation. Cai and Wright (18) reported that neutrophil elastase is an endogenous ligand for integrin complement receptor-3 and that neutrophil elastase expression on the neutrophil surface allows neutrophil migration by eluting immobilized ligands such as intercellular adhesion molecule-1. Neutrophil elastase might indirectly facilitate the migration of neutrophils via the production of chemotactic factors such as IL-8 (11,19,20).

Some evidence indicates that serine proteases might be inhibited only by multiple inhibitors, because the various types of these enzymes, along with oxidants, might inactivate the inhibitors before they can act (15,21). However, several animal studies have uncovered a direct relationship between decreased neutrophil elastase activity and sivelestat (12,16,17).

We examined the time course of plasma cytokine levels during ARDS. Some reports have suggested that plasma cytokine levels do not reflect lung levels (2,3). Donnelly et al. (6) found that plasma neutrophil elastase levels were significantly increased in patients who progressed to ARDS. Moreover, Chollet-Martin et al. (9) described interactions between neutrophils and cytokines in blood alveolar spaces during ARDS.

We administered a continuous infusion of sivelestat 0.2 mg · kg–1 · h–1 as recommended by the production pharmacy (Ono Pharmaceutical Co.). In addition, Sakura et al. (15) and Kawabata et al. (11) showed that sivelestat 0.2 mg · kg–1 · h–1 could prevent neutrophil elastase activities in animals. In addition, Tamakura et al.1 recommended that sivelestat be administered at 0.2 mg · kg–1 · h–1 for 14 days in the clinical setting.

Why the rapid decrease in neutrophil elastase activity and IL-6 in the sivelestat group did not correlate with either a decreased requirement for ventilation or decreased mortality remains unclear. The small patient cohort, heterogeneous target group, and selection bias might be factors. Further studies are required to clarify the effects of sivelestat in patients with ARDS.

Although neutrophil elastase might be deleterious during the early course of ALI, it may play a crucial immunomodulatory or reparative role thereafter. Neutrophil elastase might also exert a beneficial bacterial effect. The investigations of Belaaouaj et al. (22) in neutrophil elastase knockout mice revealed increased susceptibility to infection with Gram-negative Klebsiella pneumoniae and Escherichia coli, but not to Gram-positive Staphylococcus aureus.

In conclusion, we examined the effects of a neutrophil elastase inhibitor (sivelestat) on plasma cytokine levels and oxygenation in patients with ARDS. The cytokine levels decreased more rapidly in patients treated with sivelestat than in those who received placebo. However, these decreases apparently did not affect cytokine levels or other clinical variables, such as the duration of mechanical ventilation or survival.


   Acknowledgments
 
Supported by Grant 155919914 (YK) from the Japanese Ministry of Science, Education and Culture.

The authors thank Forte Inc. (Tokyo, Japan) for assistance with the manuscript.


   Footnotes
 
1 Tamakura S, Shiba T, Hirasawa H, et al. A phase III clinical study of a neutrophil elastase inhibitor;ONO-5046_Na in SIRS patients. J Clin Ther Med (Jpn) 1998;14:289–318. This article is not registered in PubMed. From the original article from Tamakura et al., patients were randomized to either high (0.2 mg · kg–1 · h–1) or low (0.004 mg · kg–1 · h–1) doses of sivelestat for up to 14 days. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 5, 2004.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press