Effect of Sivelestat Sodium Hydrate in Three Patients with Septic ARDS

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1 Crit Care & Shock (2003) 6: Effect of Sivelestat Sodium Hydrate in Three Patients with Septic ARDS Michihiko Kitamura, Shigeatsu Endo, Nobuhiro Sato, Yasuhiko Yamada, Hideyuki Makabe, Hajimu Abe, Satoko Imai, Nobuyoshi Shioya, Gaku Takahashi, Kiyofumi Mori, Hirohisa Inoue, Michiko Miyata, Yoriko Ito Abstract phil elastase inhibitor improved the PaO 2 /FiO 2 ratio in all the three patients, which allowed earlier weaning of these patients from artificial ventilation. These findings suggest that sivelestat may be effective in the treatment of septic ARDS. Introduction In 1996, Garber et al. reviewed the risk factors of acute respiratory distress syndrome (ARDS) through a meta-analysis of 83 studies on ARDS [1]. They concluded that the most significant risk factor that consistently contributed to the development and progression of ARDS was the systemic inflammatory response syndrome (SIRS) associated with sepsis [2]. Underlying SIRS is a complex network of proinflammatory cytokines, such as the tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and interleukin 8 (IL-8), which cause activation of neutrophils, and subsequently, when uncontrolled, multiple organ failure [3-7]. Polymorphonuclear leukocyte elastase (PMNE) released from activated neutrophils degrades connective tissue proteins of the lung, such as elastin, collagen, fibronectin and proteoglycans. PMNE also increases vascular permeability and induces the production of leukocyte chemotactic factors (e.g., C5a, IL-8). These molecular events have been demonstrated to be associated with pulmonary injury in ARDS patients. Elevated PMNE levels in the bronchoalveolar lavage (BAL) fluid have been demonstrated in ARDS patients. A significant correlation has been reported to exist between increases From the Department of Surgery, Iwate Prefectual Isawa Hospital (Dr. Michihiko Kitamura) and Department of Critical Care Medicine, Iwate Medical University (Drs. Shigeatsu Endo, Nobuhiro Sato, Yasuhiko Yamada, Hideyuki Makabe, Hajimu Abe, Satoko Imai, Nobuyoshi Shioya, Gaku Takahashi, Kiyofumi Mori, Hirohisa Inoue, Michiko Miyata and Yoriko Ito). Address requests for reprints to: Shigeatsu Endo, Department of Critical Care Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka , Japan. Tel & Fax: We administered sivelestat sodium hydrate, a selective polymorphonuclear leukocyte elastase (PMNE) inhibitor, to three patients with septic ARDS. While causing a decrease in the serum PMNE and surfactant protein D levels, the neutroin the serum and BAL PMNE levels and reduced pulmonary function. In the context of these findings, we had previously suggested that surfactant protein D (SP- D) might also be involved in the pathogenesis of ARDS, because we had observed high values of this protein in ARDS patients [8,9]. Sivelestat sodium hydrate (sivelestat) is a selective PMNE inhibitor. It has been shown in experimental studies to attenuate pulmonary injury and improve respiratory function. The PMNE inhibitor has also been shown to be effective in the treatment of patients with pulmonary injury associated with SIRS [10-13]. Sivelestat was the first drug to be approved in Japan for the treatment of acute lung injury (ALI) associated with SIRS. In this study, we administered sivelestat to 3 patients with septic ARDS and evaluated the drug s efficacy in these patients by determining the serum PMNE and SP- D levels, as well as the PaO 2 /FiO 2 (P/F) ratio. Subjects and Methods Table 1 shows the patient characteristics, including the primary cause of sepsis and the SIRS parameters. All the three patients were receiving antimicrobial drugs to which the isolated bacteria were sensitive. Intravenous infusion of sivelestat (Elaspol; Ono Pharmaceutical Co., Ltd., Osaka, Japan), started at the dose of 0.2 mg/kg/h within 2 hours of the diagnosis of septic ARDS, was continued for 14 days. Sepsis was diagnosed according to SCCM/ACCP 172

2 Table 1. Characteristics of three patients item of SIRS case age sex primary BT pulse respirator WBC disease rate rate 1 69 M panperitonitis , F ileus , M pneumonia ,800 (yrs) (0C) (/min) (/min) (/µl) M: male, F: female, BT: body temperature, WBC: white blood cell Consensus Conference definitions for sepsis [2], and AECC criteria [14] were employed for the diagnosis of ARDS. The serum PMNE level was measured by determining the level of the PMNE and a1 plasmin inhibitor complex (NE/a1PI complex) by enzyme-linked immunosorbent assay (ELISA) (Merck, Darmstadt, Germany); the normal range was 55 to 154 ng/ml. Serum SP-D was also quantified by ELISA (Teijin Bio Laboratories, Inc., Tokyo, Japan); the cutoff level for this parameter was ng/ml. Pearson s correlation coefficient was used to analyze the relationships among the variables. P < 0.05 was considered to denote statistical significance. Results Figure 1 shows the clinical course of Patient 1. The time to weaning from mechanical ventilation was 324 hours. Patient 2 required 69 hours before he could be weaned off the ventilator, as shown in Figure 2. The time to weaning from artificial ventilation in Patient 3 was 266 hours, as shown in Figure 3. The relationships between the serum levels of PMNE and SP-D and the P/F ratio at individual time points during the clinical course of the three patients (Figure 1, 2, and 3) are illustrated in Figure 4, 5, and 6. Discussion Sivelestat was demonstrated in a lung of a model of acute lung injury, to attenuate the pathological changes characteristic of acute lung injury, such as intraalveolar bleeding, plasma protein leakage into the alveolar space, and enhanced permeability of pulmonary capillaries by reducing the protein permeability of pulmonary vascular endothelial cells and alveolar epithelial cells and by attenuating disruption of the vascular basement membrane [15, 16]. Pulmonary surfactant is a bioactive substance that is synthesized and Figure 1. Clinical course of Patient 1 after the start of sivelestat infusion 173

3 Figure 2. Clinical course of Patient 2 after the start of sivelestat infusion Figure 3. Clinical course of Patient 3 after the start of sivelestat infusion Figure 4. A significant correlation was observed between the serum PMNE and SP-D levels measured after the start of sivelestat therapy in all the three patients (r = 0.811, p < 0.01) 174

4 Figure 5. A significant negative correlation was observed between the P/ F ratio and the serum PMNE levels in all the three patients after the start of sivelestat therapy (r = , p < 0.01) Figure 6. A significant negative correlation was observed between the P/F ratio and the serum SP-D levels in all the three patients after the start of sivelestat therapy (r = , p < 0.01) secreted by alveolar type II epithelial cells, that helps to prevent lung collapse at the end of expiration by reducing the surface tension at the air-water interface in the alveoli [17]. The surfactant is composed of a phospholipid component (90%), primarily consisting of saturated phospholipids and specific apoproteins (10%) containing surfactant proteins (SP)-A, SP-B, SP- C and SP-D. SP-A and SP-D were once believed to exist only in the surfactant monolayer at the alveolar interface, and not to be released into the blood. Their clinical significance, however, has drawn increasing attention since SP-A was reported to be detected in the serum of patients with idiopathic pulmonary fibrosis and alveolar proteinosis [18,19]. We previously reported that the serum SP-D and PMNE levels were increased in ARDS patients [20]. This study further revealed a significant correlation between the serum SP-D and PMNE levels. Elevation of the serum SP-D level was attributed to possible alveolar epithelial damage by PMNE and resultant SP- D leakage into the blood. These findings indicate that PMNE not only causes direct damage of the pulmonary tissue, but also affects the metabolism and surface activities of the pulmonary surfactant, with resultant exacerbation of ARDS. Although this study included only three ARDS patients, the results suggest that sivelestat might di- 175

5 rectly attenuate alveolar damage induced by PMNE and prevent disorder of the SP-D system. Further studies and accumulation of data are required to clarify the effect of sivelestat on ARDS. References 1. Garber BG, Hebert PC, Yelle JD, Hodder RV, McGowan J: Adult respiratory distrress syndrome: a systemic overview of incidence and risk factors. Crit Care Med 1996; 24: Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee: American college of chest physician/society of critical care medicine consensus conference: Definition of innovative and organ failure and guideline for the use of innovative therapies in sepsis. Chest 1992; 101: Crit Care Med 1992; 20: Nakae H, Endo S, Inada K, Kasai T, Yoshida M: Significance of a-tocopherol and interleukin 8 in septic adult respiratory distresss syndrome. Res Commun Chem Pathol Pharmacol 1994; 84: Endo S, Inada K, Inoue Y, Kuwata Y, Suzuki M, Yamashita H, Hoshi S, Yoshida M: Two types of septic shock classified by the plasma levels of cytokines and endotoxin. Circ Shock 1992; 38: Endo S, Inada K, Yamada Y, Kasai T, Nakae H, Kikuchi M, Hoshi S, Suzuki M, Yamashita H, Yoshida M: Plasma tumor necrosis factor-α (TNF-α) levels in patients with burns. Burns 1993; 19: Endo S, Inada K, Yamashita H, Takakuwa T, Nakae H, kasai T, Kikuchi M, Ogawa M: Platelet activating factor (PAF) acetylhydrolase activity, type II phospholipase A2, and cytokine levels in patients with sepsis. Res Commun Chem Pathol Pharmacol 1994; 83: Endo, S., Inada, K., Ceska, M., Takakuwa, T., Yamada, Y., Nakae, H., kasai, T., Yamashita, H, taki, T., Yoshida, M: Plasma interleukin 8 and polymorphonuclear leukocyte elastase concentrations in patients with septic shock. J. Inflamm 1995; 45: Kitamura M, Endo S, SatoN, Yamada Y, Makabe H, Abe H, Imai S, Inada K, Sato S: Study of surfactant D(SP-D) in septic ARDS: a report of three cases. Cri Care & Shock (in press). 9. Endo S, Sato N, Nakae H, Yamada Y, Makabe H, Abe H, Imai S, Wakabayashi G, Inada K, Sato S: Surfactant protein A adn D (SP-D, SP-D) levels in patients with septic ARDS. Res Commun Molecul Phathol Pharmacol (in press) 10. 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: Suzuki N, Ishii Y, Kitamura S: Mechanism for the increasedpermiability in endothelial monolayers induced by elastase. Mediators Inflamm 1994; 3: Kubo K, Kobayashi T, Hayano T, Koizumi T, Honda T, Sekiguchi M, Sakai A: Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheep. J Appl Physiol 1994; 77: Zeiher BG, Matsuoka S, Kawabata K, Repine JE: Neutrophil elastase and acute lung injury: Prospects for sivelestata and other neutrophil elastase inhibitors as therapeutics. Crit care Med 2002; 30:S Bernard GR, Atrigas A, Brigham KL, carlet J, falke K, Hudson L, Lamy M, Legal JR, Morris A, Spragg R, and the Consensus Committee. The American-European consensus conference on ARDS: Definition, mechanism, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: Yasui S, Nagai A, Aoshiba K, Ozawa Y, Kakuta Y, Konno K. A specific neutrophil elastase inhibitor (ONO-5046 ENa) attenuates LPS-induced acute lung inflammation in the hamster. Eur Respir 1995; 8: Kawabata K, Hagio T, Matsumoto S, Nakano S, Orita S, Aze Y, Ohno H. Delayed neutrophil elastase inhibition prevents subsequent progresssion of acute lung injury induced by endotoxin inhalation in hamsters. Am J Respir Crit Care Med 2000; 161: King, R.J. and Clements, J. A. Surfactant active materials from dog. II. Composition and physiological correlations. Am J Physiol 1972; 223: Kuroki Y, Tsutahara S, Shijubo N, Takahashi H, Shiratori, M., Hattori, A., Honda, Y., Abe, S., Akino, T: Elevatedlevels of lung surfactant protein A in sera from patients with idipathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis 1993; 147: Honda Y, Kuriki Y, Matsuura E, Nagase H, Takahashi H, Akino T, Abe S. Pulmonary surfactant protein-d in sera and bronchoalveolara lavage fluids. Am J Respir Crit Care Med 1995; 152: