Eur J Cardiothorac Surg 2008;34:798-804. doi:10.1016/j.ejcts.2008.07.010
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Sivelestat attenuates postoperative pulmonary dysfunction after total arch replacement under deep hypothermia
Naoto Morimoto*,
Keisuke Morimoto,
Yoshihisa Morimoto,
Hiroaki Takahashi,
Mitsuru Asano,
Masamichi Matsumori,
Kenji Okada,
Yutaka Okita
Division of Cardiovascular Surgery, Kobe University, Graduate School of Medicine, Kobe, Hyogo, Japan
Received 17 November 2007;
received in revised form 22 May 2008;
accepted 2 July 2008.
* Corresponding author. 7-5-1 Kusunoki-cho, Chuuo-ku, Kobe, Hyogo, 650-0017, Japan. Tel.: +81 78 382 5942; fax: +81 78 382 5959. (Email: naotom{at}med.kobe-u.ac.jp).
 |
Abstract
|
|---|
Background: Total arch replacement necessitating deep hypothermia with circulatory arrest has a greater effect on pulmonary function than other cardiac surgery using cardiopulmonary bypass (CPB). Since April 2004, 100 mg of sivelestat sodium hydrate was administrated by bolus injection into pulp circuit at the initiation of CPB in every case performed total arch replacement. We investigated the hypothesis that prophylactic use of the drug attenuates post-pump pulmonary dysfunction. Methods: A retrospective analysis of 120 consecutive patients who underwent total arch replacement from August 2001 to December 2006 was conducted. Patients were divided into two groups according to the date of surgery, April 2004, when we started sivelestat administration. Group A (n
= 60), operated after April 2004, was administrated sivelestat at the initiation of CPB. Group B (n
= 60), before April 2004, was not administrated. Time courses of hemodynamic variables were evaluated until 24 h after surgery and those of respiratory variables and inflammatory markers until 48 h after surgery. Results: There were no significant differences in patient age, sex, prevalence of chronic obstructive lung disease, preoperative lung function, time of operation and CPB, minimum temperature, and aprotinin usage. Hospital mortality occurred in two patients in the group B (3.3%) and no patient in group A (0%). Postoperative hemodynamic variables were not different between the two groups. Respiratory index, oxygenation index were significantly better in patients pretreated with sivelestat (respiratory index; p
< 0.001, oxygenation index; p
< 0.001, respectively). CRP was significantly lower in patients pretreated with sivelestat (p
= 0.022). Except for patients who required tracheostomy or re-exploration for bleeding, patients pretreated with sivelestat were extubated significantly shorter (group A: 12.6 ± 10.8 h, group B: 25.5 ± 12.9 h, p
= 0.033). No patient with postoperative respiratory failure requiring tracheostomy was noted in sivelestat group. Conclusion: Prophylactic administration of sivelestat at the initiation of CPB results in better postoperative pulmonary function, leading to earlier extubation time. Our study suggests that sivelestat was effective in facilitating postoperative respiratory management in total arch replacement.
Key Words: Cardiopulmonary bypass • Total arch replacement • Postperfusion pulmonary dysfunction
|
1. Introduction
|
|---|
In 1977 Pennock et al. [1] wrote that ‘pulmonary problems remain the most significant cause of morbidity following cardiopulmonary bypass (CPB) today’. Although this statement may no longer hold true, the impact of CPB on lung function sometimes brings physiologic and pathologic consequences. CPB induces inflammatory response by contact activation of blood that affects organs including the lung. Although the impact of deep hypothermia on respiratory function is still controversial, the interruption of pulmonary circulation associated with circulatory arrest of the lower body impairs pulmonary function by reperfusion injury [2]. Postoperative pulmonary dysfunction after aortic arch surgery under deep hypothermic circulatory arrest remains an unresolved problem and we have often encountered difficult respiratory problems in managing patients who undergo aortic arch replacement.
Neutrophil activation and sequestration is one of the most important initiating events of pulmonary dysfunction induced by CPB [3]. Neutrophil sequestration in microvessels is due to loss of deformability and changes of qualities between neutrophil and endothelial cells. Neutrophils also secrete toxic oxygen species and proteolytic enzymes, including neutrophil elastase [3]. Neutrophil elastase is an extremely cytotoxic enzyme. This enzyme degrades connective tissue components such as elastin, proteoglycan, fibronectin, and collagen, and potentially causes severe tissue injury and subsequent multiple organ dysfunction.
Sivelestat sodium hydrate is a synthetic, specific and low-molecular weight neutrophil elastase inhibitor. It inhibits neutrophil elastase activity competitively but does not affect other serine protease, such as plasmin, thrombin, kallikrein, cathepsin B, or collagenase I, released by polymorphonuclear neutrophils [4]. The eliminating phase of the drug is biphasic, and the half-life of the first and second phases are constant at about 2 and 3 h, respectively. Intrinsic macromolecular antiprotease, which inhibit neutrophil elastase in an ordinary state, are immediately inactivated by superoxide radicals and blocked from close contact with neutrophil during the onset of inflammatory state. A low-molecular weight antiprotease, such as sivelestat, achieves close contact with neutrophils without rapid inactivation by superoxide and is therefore advantageous [5]. The efficacy of sivelestat on postperfusion lung, ischemia-reperfusion and endothelial injuries has been demonstrated in several investigations. A recent report showed the protective effects of this drug on pulmonary function after CPB in dog experiments [4]. The use of the drug in humans has been approved in Japan for cases of acute lung injury.
We hypothesized that pretreatment with sivelestat before CPB can prevent pulmonary function impairment after CPB. Since April 2004, we have used it routinely in every patient who has undergone cardiac surgery with CPB. The purpose of the present study was to assess the affect of sivelestat on perioperative respiratory and oxygenation indices 48 h after deep hypothermic CPB. Patients who underwent total arch replacement under hypothermic circulatory arrest were selected for this study.
|
2. Patients and methods
|
|---|
2.1 Patient characteristics
From August 2001 to December 2006, 166 patients had a total arch replacement in our institution. One hundred and twenty consecutive patients undergoing total arch replacement under deep hypothermia via mid-sternotomy were enrolled to this retrospective study. From this study we excluded 31 patients who underwent emergent surgery for acute aortic dissection and (impending) rupture of thoracic aorta and one patient who performed simultaneous lobectomy for lung carcinoma. Fourteen patients who had a total arch replacement via a left thoracotomy were also excluded from the analysis. The indication for total arch replacement was transverse or distal arch aneurysm which did not extend below the level of the carina. Since April 2004, 100 mg of sivelestat has been administrated by bolus injection into pump circuit prophylactically at the initiation of CPB. The administration of the drug was approved by an ethics committee and informed consent was obtained from every patient. Patients were divided into two groups according the date of surgery, April 2004, when we started sivelestat administration. Group A (n
= 60), operated after April 2004, was administrated sivelestat. Group B (n
= 60), operated before April 2004, was not administrated. Preoperative patient demographics were essentially similar in two groups (Table 1
). Chronic obstructive pulmonary disease (COPD) was diagnosed using the criteria of the global initiative for chronic obstructive lung disease. Seven patients had COPD in group B and five had it in group A (p
= 0.082).
2.2 Anesthetic protocol
Anesthesia was induced using midazolam, vecuronium, and fentanyl, and was maintained using intravenous propofol and fentanyl. Ventilation strategy during the procedure was intended to prevent alveolar collapse and overdistension. The tidal volume was maintained at a level of 6–8 ml/kg. The PEEP level was set between 5 and 8 cm of water. During total cardiopulmonary bypass, mechanical ventilation was discontinued but lung inflation was maintained by delivery of an oxygen-air mixture administrated at 2 l/min (FiO2: 0.25) with continuous airway pressure. Continuous pulmonary airway pressure was established via a circle system with airway pressure maintained at 10 cm H2O by adjusting the ventilator pop-off valve. In the present study all patients received 4 mg/kg of methylprednisolone at the initiation of CPB. Aprotinin was administrated when intraoperative large blood boss or prolonged cardiopulmonary bypass time was expected. Loading dose of aprotinin (2 million units) was administrated in the CPB priming solution. Additionally, 0.5 million IU/h CPB-time were applied.
2.3 Operative technique
The cannulation site for arterial return was selected meticulously by preoperative CT scan and by an intraoperative epiaortic sonography or transesophageal echocardiography. When moderate to severe atheromatous plaque or ulceration was detected in the ascending aorta or when the ascending aorta was dissected, femoral cannulation or additional cannulation into the right axillary artery with femoral cannulation was employed. The whole aortic arch was replaced using a quadrifurcated collagen or a gelatin-impregnated woven Dacron graft. In order to avoid injury to the esophagus and left recurrent nerve, open distal anastomosis was performed consistently with complete transaction of descending aorta distally to the left subclavian artery. Reperfusion and rewarming were always achieved in an antegrade manner through the side branch of the graft. The surgical technique was not changed during the study period. Concomitant operative procedures performed in group A were coronary bypass graft in 21 patients, aortic root replacement with valve sparing in 3, cardiac valve replacement or repair in 2, radiofrequency pulmonary vein isolation in 2 and replacement of abdominal aortic aneurysm in 1 patient. In group B, simultaneous surgery consisted of CABG in 25, aortic root replacement in 3 (Bentall in 2 and valve sparing in 1), cardiac valve replacement or repair in 2, and replacement of abdominal aortic aneurysm in 1. Internal mammary artery was harvested in 18 patients in group A and 19 patients in group B (p
= 0.687).
2.4 Brain protection
Our principle in selective cerebral perfusion (SCP) included arterial cannulation performed with an ordinary arterial cannula in the right axillary artery or with a balloon-tipped cannula inserted directly in brachiocephalic artery from inside the aortic arch in the left common carotid artery, and the left subclavian artery. Cerebral perfusion flow was maintained at 12–15 ml/kg min; mean pressure in the right and left radial artery ranged from 40 to 60 mmHg, and regional saturation of bilateral frontal cortex maintained more than the value at the initiation of CPB. Monitoring of regional saturation was performed using INVOS 4100 (Somanetics Corp, MI). After anastomosing the ascending aorta to the graft, coronary circulation was started and the arch vessels, the left subclavian artery, the left common carotid artery, and the brachiocephalic artery were anastomosed in that order.
Extubation criteria were as follows: patient awake and cooperative, mediastinal drainage less than 200 ml in the last hour, respiratory rate <30/min, PaCO2 <50 mmHg (except patients with COPD), and PaCO2 >70 mmHg with FiO2 <0.5 if possible. These criteria were not changed in the study period. If a blood transfusion was required, leukocyte depleted blood products were routinely used.
2.5 Measurements
Arterial blood samples were collected for gas analysis at before and 0, 3, 5, 8, 12, 18, 24, and 48 h after CPB. Alveolar-arterial oxygen difference (AaDO2), respiratory index (RI) and ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) (PF ratio) were calculated with the following equations:
where PACO2 is alveolar carbon dioxide tension, R the respiratory exchange ratio, and PaO2 is arterial oxygen tension. It was assumed that R
= 0.85 and PACO2 was the same as arterial carbon dioxide tension. FiO2 is fraction of inspired oxygen. Normal values of these parameters are as follows; AaDO2 <10 mmHg, respiratory index <0.25, and oxygenation index >350 mmHg.
Systolic systemic and pulmonary artery pressure, systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), cardiac index, and the mean-systemic-arterial-pressure-to-mean-pulmonary-artery pressure ratio (Pp/Ps) were measured at before and 0, 3, 5, 8, and 12 h after CPB because a pulmonary artery catheter was routinely inserted at least 12 h after CPB. White blood cell (WBC) counts and serum levels of C reactive protein (CRP) were measured at before and 0, 1, and 2 days after the operation.
2.6 Side effect of sivelestat
To investigate the side effect of sivelestat, serum creatinine, blood urea nitrogen, aspartate amino transferase and alanine amino transferase were measured before and at the maximum value 1 week after surgery.
2.7 Statistics
Mean values were expressed as average ± standard deviation. Statistical significance was determined using the non-paired Student's t-test, Wilcoxon rank sum test, chi squared test and repeated analysis of variance (ANOVA). Student's t-test was used to compare the distributions of normally distributed variables and Wilcoxon rank sum test was used to compare the distributions of non-normally distributed variables determined by the Shapiro–Wilk test for normality p value. Categorical data were compared with the chi squared test. A p value of less than 0.05 was considered significant in all hypothesis testing. The p value inscribed in the figures shows probability of difference between two groups by repeated ANOVA. Statistical computations were done using SPSS (SPSS version 11.0, Chicago, IL).
|
3. Results
|
|---|
Total duration of the operation, of extracorporeal circulation, of myocardial ischemia, of circulatory arrest of the lower body, minimum rectal and tympanic temperatures and the frequency of aprotinin administration showed no statistical significance in the two groups (Table 2
).
3.1 Respiratory data
Respiratory index (Fig. 1a) were significantly improved in group A for 48 h after CPB (repeated ANOVA, p
< 0.001, respectively). Oxygenation index (Fig. 1b) were preserved significantly better in group A (repeated ANOVA, p
< 0.001). In group B, the values of respiratory index and oxygenation index were deteriorating between 0 and 3 h after CPB, followed by a gradual recovery toward normal level. In contrast, in group B the deterioration of these values after CPB was not accompanied with any recovery during the study period.
View larger version (19K):
[in this window]
[in a new window]
|
Fig. 1. Changes in respiratory index (a) and oxygenation index (b). Values are expressed as mean ± standard error of the mean. The p value shows probability of difference between groups by repeated ANOVA.
|
|
3.2 Hemodynamics
Although there was no significant difference in hemodynamic variables including systemic systolic blood pressure, systolic pulmonary artery pressure, cardiac index, mean-arterial-pressure-to-mean-pulmonary-artery pressure, systemic vascular resistance index, and pulmonary vascular resistance index (Fig. 2
), group A had a tendency of showing a lower level of PVRI from 3 to 8 h after the termination of CPB (Fig. 2f).
View larger version (14K):
[in this window]
[in a new window]
|
Fig. 2. Changes in systemic systolic blood pressure (a), systolic pulmonary artery pressure (b), cardiac index (c), mean-arterial-pressure-to-mean-pulmonary-artery pressure (Pp/Ps; d), systemic vascular resistance index (SVRI; e), pulmonary vascular resistance index (PVRI; f), and CRP (g). Values are expressed as the mean ± standard error of the mean. The p value shows probability of difference between groups by repeated ANOVA.
|
|
3.3 Inflammatory reactions
There was no significant difference in WBC counts between two groups (repeated ANOVA, p
= 0.678). Group A had significantly lower level of CRP after the operation (repeated ANOVA, p
= 0.022).
3.4 Side effect of sivelestat
There were no differences in preoperative and postoperative changes in serum creatinine, blood urea nitrogen, aspartate amino transferase and alanine amino transferase (Table 4
).
Hospital mortality was noted in two patients in group B (3.3%). No patient died in group A. The causes of death were mediastinitis and pneumonia. Respiratory failure requiring tracheostomy occurred in three patients of group B. No patient suffered from respiratory failure in group A. The causes of respiratory failure were pre-existing COPD in two patients and pulmonary artery perforation with Swan-Ganz catheter in 1. None of the patients in this series suffered from major side effects of sivelestat.
Among survivors, the stay in the ICU showed no statistically significant difference between the two groups (group A: 2.7 ± 1.1 days vs group B: 2.8 ± 1.1 days, p
= 0.793, Table 3). Excepting the patients requiring re-exploration for bleeding, group A had significantly shorter extubation time (A: 10.4 ± 1.1 h vs B: 25.5 ± 12.9 h, p
= 0.037, Table 3).
|
4. Discussion
|
|---|
Pulmonary dysfunction after CPB, one of most serious inflammatory reactions induced by CPB, has been called postperfusion lung syndrome. Although its mechanism has not been elucidated, neutrophil activation and sequestration is one of the most important initiating events of this phenomenon. An imbalance between neutrophil elastase and its endogenous protease inhibitors has been considered to be a possible mechanism by which neutrophil elastase causes lung tissue destruction [3]. In aortic arch surgery under hypothermic circulatory arrest, the impact on respiratory function is a more serious and important problem. The cause of pulmonary dysfunction depends on two interactive mechanisms; one is the blood-foreign body surface reaction induced by CPB, and another is the ischemia-reperfusion injury [3]. Stopping ventilation during CPB induces a certain degree of pulmonary ischemia by lack of lung tissue oxygenation via gas diffusion. Especially in aortic arch surgery the interruption of pulmonary circulation during circulatory arrest of the lower body deteriorates pulmonary ischemia. Furthermore hypoventilation during CPB is associated with the development of microatelectasis. The commonly scrutinized pharmacological agents with which to treat pulmonary dysfunction are corticosteroids and aprotinin. The administration of these drugs has been demonstrated to reduce the release of proinflammatory mediators or to inhibit the complement activation. However clinical efficiency of these drugs is insufficient to prevent pulmonary dysfunction after CPB dramatically [3].
It is well known that CPB primes and activates neutrophils through mechanical shear stress and contact with the artificial surface of the CPB circuit. Activated neutrophil can further release a number of proteolytic enzymes and oxidative chemicals both into the systemic circulation and into local lung tissue. These enzymes are instrumental in the development of post-CPB lung injury by breaking down the pulmonary ultrastructure, which results in increased pulmonary alveolar-endothelial permeability, thereby affecting gas exchange and lung mechanics [7]. Neutrophil elastase is the most injurious protease produced by activated neutrophils. It has been reported to have a major influence on lung injury in adult respiratory distress syndrome [8] and to induce pulmonary edema by increasing endothelial permeability [9]. The clinical study reported a close relationship between blood concentrations of neutrophil elastase and interleukin (IL)-6 or IL-8 after CPB [10]. The IL-6, IL-8, and neutrophil elastase level were significantly higher in patients with respiratory distress syndrome after CPB [11]. Therefore, the inhibition of neutrophil elastase or inflammatory cytokines such as IL-6 or IL-8 could contribute to attenuate pulmonary dysfunction after CPB.
Sivelestat sodium hydrate is a synthetic, specific and low-molecular weight neutrophil elastase inhibitor. Sivelestat is not inactivated by superoxide radicals, while intrinsic alpha-1-protease inhibitor or alpha-2-macrogloblin, which inhibits elastase in an ordinary state, are immediately inactivated [6]. Its molecular weight of 529 Da is small enough to achieve close contacts in microenvironment between neutrophil and substrates, even where alpha-1-protease inhibitor does not reach. In the experimental study using stimulated extracorporeal circulation model, sivelestat had been reported to reduce both neutrophil elastase level and IL-8 production [12] and to prevent pulmonary edema and pulmonary dysfunction after partial CPB [4]. Recently a small clinical series in patients who underwent coronary artery bypass or valve surgery showed a protective effect of sivelestat on lung injury after CPB. However there was no clinical study about sivelestat administration among the patients who employed CPB with deep hypothermic circulatory arrest.
Our method of administration of sivelestat was bolus injection into pump reservoir at the initiation of CPB. According to a phase I clinical study [13], when sivelestat was given for 5 min at a dose of 1.0 mg/kg, plasma concentration of uncharged form of sivelestat reached maximal drug concentration of 10 µg/ml immediately after the end of administration and stayed above a minimum effective concentration of 6 µg/ml about 2 h. This fact shows that bolus injection was suitable to exhibit its effect immediately after the administration and that the dose of 100 mg is sufficient to keep above minimum effective concentration for more than 2 h. To inhibit elastase activity during cardiopulmonary bypass, we decided the bolus injection of sivelestat at the dose of 100 mg soon after initiation of cardiopulmonary bypass because bypass time seldom reaches over 3 h.
The influence of circulatory arrest on the lung is still unclear. However its mechanism was considered to be similar to ischemia-reperfusion injury. Bimodal blood supply from the bronchial and pulmonary arteries makes the lung tolerable for ischemia during CPB. Although the bronchial arteries contribute about 1–3% of the total blood flow to the lungs under normal physiologic conditions, the lungs are purely dependent on the bronchial arteries during total CPB to provide the 5% of whole-body oxygen uptake that is necessary even under hypothermic condition [14]. Experimental and clinical studies in lung transplantation demonstrated that donor neutrophils activated by ischemia during cold storage can induce reperfusion lung injury after transplantation [15]. Therefore, the employment of circulatory arrest could cause neutrophil-derived ischemia-reperfusion lung injury, promoting pulmonary dysfunction that was initiated by the mechanism of pump circuit-blood surface reaction. Ischemia-reperfusion injury is induced by a sudden oxygen overload at the reperfusion. Cytokines derived from neutrophils are related to superoxide production. Among the protease released from activated neutrophils, neutrophil elastase is one of the most important enzymes associated with the onset and progression of ischemia-reperfusion injury. Recently sivelestat administration was reported to reduce the reperfusion lung injury after lung transplantation in rats [16]. It is expected that sivelestat administration ameliorates also ischemia-reperfusion lung injury induced by circulatory arrest.
Pulmonary vascular resistance increased after CPB regardless of the administration of sivelestat. Although there was no statistically significant difference, pulmonary vascular resistance was lower in patients receiving sivelestat 3–8 h after CPB. Although the effect of inotropes should be taken into consideration, dosage of inotropes and other hemodynamic parameters, including blood pressure, pulmonary artery pressure, systemic vascular index, and cardiac index, were not significantly different between group A and B. Pulmonary vascular resistance was increased after ischemia-reperfusion injury. According to the lung ischemia-reperfusion injury model [17] in rabbits, it is caused by the swelling of endothelial cells, adhesion to endothelial cells and aggregation of neutrophils. Increased pulmonary vascular resistance is associated with endothelial dysfunction and significantly reduced by continuous intravenous administration of sivelestat. In this study sivelestat was administrated only by bolus injection and keeps plasma effective concentration for only 2 or 3 h. If we applied subsequent continuous intravenous administration, sivelestat could probably reduce the elevation of pulmonary vascular resistance.
This study shows that the deterioration of the respiratory index and oxygenation index continued for 48 h after the termination of CPB in patients not receiving sivelestat. Impairment of gas exchange in the lung after CPB was usually progressive and reached a maximum about 48 h after operation. Sometimes it was detectable 2 weeks after the operation [18]. However in patients receiving sivelestat deterioration of oxygenation index and respiratory index reached a maximum 3 h after CPB and then gradually recovered. The sivelestat administration reduced pulmonary dysfunction after CPB, leading to better recovery with a shorter extubation time.
In the present study no patient suffered from this side effect. The degrees of elevations in transaminase, serum creatinine and blood urea nitrogen were not significantly different between two groups. A phase III clinical study in 230 patients with systemic inflammatory response syndrome reported that there were abnormal results of liver function test only in 2% of patients who were administrated sivelestat at a dose of 0.20 mg/kg h for 14 days [19].
The limitation of this study is that it is a retrospective study, and the absence of data of chemical mediators such as IL-6, IL-8, and TNF-
. Further prospective study would be necessary including the measurement of chemical mediators. Although it is not significantly different, an imbalanced use of aprotinin, a protease inhibitor with anti-inflammatory effect, between two groups is the limitation. This serine protease inhibitor might have affected neutrophil activation by inhibiting tumor necrosis factor-alpha release and CD11b up-regulation. Therefore, it might have affected some of the results in both groups. Internal mammary artery harvesting is also a limitation. It might reduce the force of respiration by decreasing the blood supply to intercostal muscle.
In conclusion, the findings of this study showed prophylactic administration of sivelestat at the initiation of CPB improved postoperative respiratory function and shortened extubation time in the patients who had a total arch replacement under circulatory arrest. We suggest that sivelestat could be effective in facilitating postoperative respiratory management in aortic arch surgery.
|
References
|
|---|
- Pennock JL, Pierce WS, Waldhausen JA. The management of the lungs during cardiopulmonary bypass. Surg Gynecol Obstet 1977;145:917-927.[Medline]
- Turnbull KW, Miyagishima RT, Gerein AN. Pulmonary complications and cardiopulmonary bypass: a clinical study in adults. Can Anesth Soc J 1974;21:181.[Medline]
- Ng CSH, Wan S, Yim APC, Arifi AA. Pulmonary dysfunction after cardiac surgery. Chest 2002;121:1269-1277.[CrossRef][Medline]
- Yamazaki T, Ooshima H, Usui A, Watanabe T, Yasuura K. Protective effects of ONO-5046-Na, a specific neutrophil elastase inhibitor, on postperfusion lung injury. Ann Thorac Surg 1999;68:2141-2146.[Abstract/Free Full Text]
- Kawabata K, Suzuki M, Sugitani M, Imaki K, Tada M, Miyamoto T. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 1991;177:814-820.[CrossRef][Medline]
- Kawabata K, Moore AR, Willoughby DA. Impaired activity of protease inhibitor towards neutrophil elastase bound to human artificial cartilage. Ann Rheum Dis 1996;55:248-252.[Abstract/Free Full Text]
- Sakamaki F, Ishizaka A, Urano T, Sayama K, Nakamura H, Terashima T, Waki Y, Tasaka S, Hasegawa N, Sato K, Nakagawa N, Obata T, Kanazawa M. Effect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxin-induced acute lung injury. Am J Respir Crit Care Med 1996;153:391-397.[Abstract]
- Weiland JE, Davis WB, Holter JF, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome: clinical and pathologic significance. Am Rev Respir Dis 1986;133:218-225.[Medline]
- Suzuki N, Ishii Y, Kitamura S. Mechanism for the increased permeability in endothelial monolayers induced by elastase. Mediators Inflamm 1994;3:11-16.[CrossRef][Medline]
- Kawamura T, Wakusawa R, Okada K, Inada S. Elevation of cytokines during open heart surgery with cardiopulmonary bypass: participation of interleukin 8 and 6 in reperfusion injury. Can J Anaesth 1993;40:1016-1021.[Medline]
- Ito H, Hamano K, Gohra H, Katoh T, Fujimura Y, Tsuboi H, Esato K. Relationship between respiratory distress and cytokine response after cardiopulmonary bypass. Surg Today 1997;27:220-225.[CrossRef][Medline]
- 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;80:611-617.[Abstract/Free Full Text]
- Nakajima M, Kanemaru M. A phase I clinical study of a neutrophil elastase inhibitor; ONO-5046 Na in healthy volunteers. J Clin Therap Med 1998;14:195-218.
- Loser SA, Scheeren TW, Tarnow J. How much oxygen dose the human lung consume?. Anesthesiology 1997;86:532-537.[CrossRef][Medline]
- de Perrot M, Liu M, Waddel TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 2003;167:490-511.[Abstract/Free Full Text]
- Suzuki S, Sugawara T, Tabata T, Osihi H, Niikawa H, Kondo T. Sivelestat reduces reperfusion injury of lungs harvested from endotoxin-primed rats by inhibition of neutrophil-mediated inflammation. J Heart Lung Transplant 2007;26:370-375.[CrossRef][Medline]
- ishikawa N, Oda M, Kwaguchi M, Tsunezuka Y, Watanabe G. The effects of a specific neutrophil elastase inhibitor (ONO-5046) in pulmonary ischemia-reperfusion injury. Transplant Int 2003;16:341-346.[CrossRef][Medline]
- Geha AS, Sessler AD, Kirklin JW. Alveolar-arterial oxygen gradients after open intracardiac surgery. J Thorac Cardiovasc Surg 1966;51:609-615.[Medline]
- Tamakuma S, Shiba T, Hirasawa H, Ogawa M, Nakajima M. A phase III clinical study of a neutrophil elastase inhibitor. ONO-5046-Na in SIRS patients. J Clin Therap Med 1998;14:289-318.
Top
Abstract
1. Introduction
