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Interact CardioVasc Thorac Surg 2009;9:236-240. doi:10.1510/icvts.2009.206193 © 2009 European Association of Cardio-Thoracic Surgery
A pilot randomized study of the neutrophil elastase inhibitor, Sivelestat, in patients undergoing cardiac surgery
a Department of Cardiovascular Surgery, Social Insurance Chukyo Hospital, 1-1-10 Sanjyo, Minami-ku, Nagoya, 457-8510, Japan Received 25 February 2009; received in revised form 24 April 2009; accepted 28 April 2009
*Corresponding author. Tel.: +81-52-691-7151; fax: +81-52-692-5220.
The primary objective of this study was to determine the feasibility and safety of treatment with Sivelestat in humans to attenuate post-cardiopulmonary bypass lung injury. Twenty patients scheduled to undergo on-pump coronary artery bypass surgery were randomized to receive either 0.3 mg/kg/h intravenous Sivelestat sodium (Sivelestat group; n=10) or isotonic sodium chloride solution (placebo group, n=10), peri-operatively. Postoperative adverse events were recorded until hospital discharge. The alveolar–arterial oxygen gradient (A-aDO2), intrapulmonary shunt (Qs/Qt) and dynamic lung compliance were determined four times peri-operatively as secondary exploratory outcomes. All patients completed study protocol without discontinuation of intervention. The number of total adverse clinical outcomes, including atrial fibrillation and superficial wound infection, was nine in seven patients in the placebo group and four in four patients in the Sivelestat group (P=0.37). The mean duration of the postoperative hospital stay was shorter in the Sivelestat group (19.0±3.4 vs. 25.6±9.1, P=0.04). The exploratory analysis of relative changes in lung functions showed trends toward attenuation of lung injury in the Sivelestat group in all three pulmonary parameters, though the inter-group difference could be due to chance (P>0.05). It is feasible to administer Sivelestat as a preventive measure against lung dysfunction after cardiopulmonary bypass.
Key Words: Cardiopulmonary bypass; Inflammatory response; Coronary artery bypass grafts; Pulmonary function; Peri-operative care
Pulmonary dysfunction after a cardiopulmonary bypass (CPB) has been well documented [1]. CPB induces a serial inflammatory response including leukocyte activation [2]. A positive correlation has been reported between the serum neutrophil elastase concentrations and respiratory dysfunction, thus suggesting that elastase might play a role in lung injury [3]. Sivelestat sodium hydrate (Ono Pharma, Osaka, Japan) is a specific inhibitor of neutrophil elastase [4]. The molecular weight is 528.51. The protective effects of Sivelestat from post-CPB lung injury have been demonstrated in a canine model [5]. This prospective, randomized, double-blind, placebo-controlled study including patients undergoing on-pump coronary artery bypass grafting (CABG) was conducted to address two objectives.
After obtaining institutional review board approval, 20 patients scheduled for elective, isolated on-pump coronary artery bypass were enrolled in this pilot study from November 2005 to August 2006. Patients requiring either preoperative intravenous inotropic or vasodilative drugs, intraaortic balloon support, supplemental oxygen, or mechanical ventilation were excluded. All patients gave written consent to the study. The primary end points of this study were completeness of the study protocol, and operative morbidity. Operative morbidity was defined as conditions listed in in-hospital complications in the society of thoracic surgeons adult cardiac surgery database [6] and superficial chest wound infection. Secondary outcomes included the alveolar–arterial oxygen gradient (A-aDO2), intrapulmonary shunt (Qs/Qt), dynamic lung compliance and clinical outcomes such as the lengths of hospital stay, the length of the intensive care unit (ICU) stay and the ventilation time. Before surgery, each patient was randomized to receive either intravenous (IV) Sivelestat sodium (Sivelestat group; n=10) or IV isotonic sodium chloride solution (placebo group, n=10). The randomization codes were concealed in sealed, opaque envelopes. The treatment allocation for a patient was determined by opening the next envelope the evening before the operation. The Sivelestat group patients started to receive 0.3 mg/kg/h IV Sivelestat as soon as a central venous catheter had been inserted. IV Sivelestat was continued until 20 h after surgery. The placebo group patients received similar volumes of IV isotonic sodium chloride solution for the same period of time. A research pharmacologist performed the randomization and prepared the syringes that were administered by the anesthesiologist managing the case. Therefore, all physicians and nursing staff caring for the patients were blinded to the treatment group. The intra-operative anesthetic technique was standardized and included IV fentanyl, midazolam and vecuronium. CABG was performed in a standardized fashion through a median sternotomy. Complete revascularization was always planned. The CPB equipment consisted of a non-occlusive centrifugal pump (Gyro-Pump; Medtronic Inc, Minneapolis, MN), a membrane oxygenator (Affinity; Medtronic Inc, Minneapolis, MN) and an extracorporeal circuit (Medtronic Inc, Minneapolis, MN). The non-pulsatile flow was set at between 2.2 and 2.4 l/min/m2 and the perfusion pressure was maintained between 50 and 70 mmHg. Cardioplegic arrest was maintained with administration of blood/crystalloid mixture every 20 min. The patients were not actively cooled while on CPB. After rewarming to 36.5 °C, the patients were weaned from CPB and systemic anticoagulation was reversed by protamine sulfate administration. The A-aDO2, Qs/Qt and dynamic lung compliance were determined four times peri-operatively: 10 min after intubation (Time A), 10 min after the patient was weaned off CPB (Time B), 10 min after arrival in the ICU (Time C) and 2 h after arrival in the ICU (Time D). These values were determined using standard equations. Mechanical ventilation parameters were standardized (respiratory rate 12 breath/min, tidal volume 10 ml/kg, fraction of inspired oxygen (FIO2) 1.0, positive end-expiratory pressure +3 cm H2O, inspiratory to expiratory ratio 1:3) for at least 10 min before each of the four data points. After the completion of surgery, the patients were transferred to the ICU. Postoperative care was standardized and tracheal extubation was accomplished at the earliest clinically appropriate time. The criteria for extubation in the ICU included an appropriate sensorium, normothermia, hemodynamic stability, adequate pulmonary function (PaO2 >80 mmHg with FIO2 0.5) and a minimal chest tube output. The discharge criteria from the ICU included weaning to a minimal dose of vasoactive and inotropic infusions, extubation without pulmonary support and no evidence of major organ failure. The discharge criteria from the hospital included stable cardiac rhythm, no supplemental oxygen, tolerance of oral intake and a sufficient level of physical recovery which enabled the patients to live at home with his or her family support. If discontinuation of the study protocol occurred, it was recorded. Postoperative complications and treatments were recorded daily until hospital discharge. The data are expressed as the mean±S.D. unless otherwise indicated. Statistical analysis was performed using SPSS 12.0 (SPSS, Inc, Chicago, IL) for Windows XP (Microsoft Inc, Seattle, WA). Fisher's exact test or the 2-test was applied to categorical data. Student's t-test or the Welcht test was used to compare the means between the two groups. A repeated measures two-way analysis of variance (ANOVA), followed by Bonferroni multiple comparisons, was used to analyze the group and time effects in the pulmonary data. Repeat ANOVA and paired t-tests with Bonferroni's correction were used to compare the mean change within groups at each time point. The relative changes in pulmonary data from pre-CPB values were also computed and analyzed. A P<0.05 was considered to be statistically significant.
Twenty-two patients scheduled for elective, isolated on-pump coronary artery bypass were assessed for eligibility, and 20 patients provided informed consent and participated in this study. Ten patients were randomized into each group. The demographic and clinical characteristics and intra-operative data are presented in Tables 1 and 2, respectively. Despite randomization, patients in the Sivelestat group tended to have a longer cross-clamp time than did the patients in the placebo group (P=0.05).
3.1. Completeness of the study protocol All patients completed the study protocol. The postoperative clinical results are presented in Table 3 . No patient died in either group. There were no strokes. One patient had a peri-operative myocardial infarction in the Sivelestat group. All of the patients were extubated within 24 h, postoperatively. Two patients had atrial fibrillation in the Sivelestat group and five patients had it in the placebo group (P=0.34). The number of total adverse outcomes was nine in seven patients in the placebo group and four in four patients in the Sivelestat group (P=0.37). Nine adverse outcomes in the placebo group included five atrial fibrillations, two superficial chest wound infections, one deep sternal infection and one delayed cardiac tamponade. Five adverse outcomes in the Sivelestat group consisted of one perioperative myocardial infarction, two atrial fibrillations and one superficial chest wound infection.
3.3. Other clinical outcomes The mean duration of postoperative hospital stay in the Sivelestat group was shorter than in the placebo group (19.0±3.4 vs. 25.6±9.1, P=0.04). The mean intubation time in the Sivelestat group was not statistically different from that of the placebo group (P=0.47). The mean length of ICU stay was not statistically different (P=0.26). The pulmonary data are presented in Table 4. The relative changes from pre-CPB values are presented in Fig. 1.
As shown in Fig. 1, there were trends of stabilization of A-aDO2 and Qs/Qt during the entire treatment period in the Sivelestat group. A-aDO2 increased after CPB in comparison to pre-CPB level only in the placebo group (P=0.04). Qs/Qt tended to increase after CPB in comparison to the pre-CPB level in both groups (Fig. 1). The increase in Qs/Qt was more eminent in the placebo group. Inter-group difference was not statistically significant by a two-way repeated ANOVA in either A-aDO2 (P=0.08) and Qs/Qt (P=0.10). Regarding dynamic lung compliance, the Sivelestat group showed a temporal increase of compliance immediately after CPB (P=0.02), whereas the placebo group showed a gradual decline towards 2 h after arriving in the ICU (Fig. 1). Dynamic lung compliance was higher in the Sivelestat group than in the placebo group at Time B (P<0.05 P=0.025). The inter-group difference was not statistically significant according to two-way repeated ANOVA (P= 0.41).
Sivelestat sodium hydrate is a small molecular weight inhibitor of neutrophil elastase [4]. Its efficacy for acute lung injury was shown in multiple animal models and a phase 3 study of Sivelestat conducted in Japan in acute lung injury patients in ICUs showed that the drug improved pulmonary function and reduced the length of stay in the ICU [7]. Sivelestat has been commercially available and commonly used as a treatment for acute lung injury associated with systemic inflammatory response in Japan since 2002. Several investigators, including the authors, administer Sivelestat to attenuate lung injury associated with CPB in different animal models [5, 8, 9]. All showed that Sivelestat reduced inflammation related to CPB and three showed protective effects on pulmonary functions [5, 8]. This current study was designed as a pilot study with a primary objective to determine the feasibility and safety of treatment with Sivelestat in humans. There has been concern regarding its safety since the results of STRIVE [Sivelestat Trial in ALI patients requiring mechanical Ventilation] was published [10]. Since no data were available to estimate the proper sample size to test the hypothesis that Siverestat attenuates lung injury in humans, this study was also intended to obtain preliminary efficacy data in lung functions and clinical outcomes. 0.3 mg/kg/h is the recommended dose for clinical use to treat acute lung injury in Japan. All patients completed the study protocol. Thus, peri-operative intravenous administration of Sivelestat seemed to be feasible. No adverse effects could be attributed to Sivelestat treatment with respect to mortality and morbidity. There were nine adverse events in the placebo group and four in the Sivelestat group. These results are therefore expected to encourage the planning of further clinical trials. The results showed that patients in the Sivelestat group had a shorter hospital stay in comparison to the patients in the placebo group. Several observational studies in surgical patients who had undergone an esophagectomy reported shorter ventilation time and ICU stays when Sivelestat was administered intra-operatively [11, 12]. The length of hospital stay in this study was comparative with that of previously reported studies done in Japan [13, 14]. The relatively longer hospital stay in Japan in comparison to other countries may be explained by the lack of established rehabilitation facilities and home care nursing system in this country. All of the medical personnel caring for the patients were strictly blinded in group allocation in this study, as already described. A-aDO2, Qs/Qt and dynamic compliance were measured as pulmonary parameters in this study. These parameters were chosen because the deterioration of these parameters after CPB have been documented in many clinical studies [15] and were relatively easy to obtain in the setting of standard peri-operative care. It is important to emphasize that this study was conducted to facilitate the planning of larger trials and was not powered to detect statistically significant results, when interpreting the data of these exploratory efficacy outcomes. The most important limitation of this study was the insufficient power to assess the efficacy of Sivelestat therapy. Another limitation of this study is that, despite randomization, patients in the Sivelestat group had a longer cross-clamp time. Since the patients in the Sivelestat group also tended to have more grafts than the placebo group did, it is likely that the patients in the Sivelestat group had more target vessels than the patients in the placebo group. The findings from the current trial, although exploratory, support the feasibility and safety of Sivelestat administration during and after CPB in patients undergoing cardiac surgery.
We thank Dr Nobuyuki Hamajima, MD, MPH, PhD for statistical review.
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Abstract
1. Introduction