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Effects of neutrophil elastase inhibitor in patients undergoing esophagectomy: a systematic review and meta-analysis.

AIM
To evaluate the benefit and safety of sivelestat (a neutrophil elastase inhibitor) administration in patients undergoing esophagectomy.


METHODS
Online databases including PubMed, EMBASE, the Cochrane Library, Web of Knowledge, and Chinese databases (Wanfang database, VIP and CNKI) were searched systematically up to November 2013. Randomized controlled trials and high-quality comparative studies were considered eligible for inclusion. Three reviewers evaluated the methodological quality of the included studies, and Stata 12.0 software was used to analyze the extracted data. The risk ratio (RR) was used to express the effect size of dichotomous outcomes, and mean difference (MD) or standardized mean difference was used to express the effect size of continuous outcomes.


RESULTS
Thirteen studies were included in this systematic review and nine studies were included in the meta-analysis. The duration of mechanical ventilation was significantly decreased in the sivelestat group on postoperative day 5 [I (2) = 76.3%, SMD = -1.41, 95%CI: -2.63-(-0.19)]. Sivelestat greatly lowered the incidence of acute lung injury in patients after surgery (I (2) = 0%, RR = 0.27, 95%CI: 0.08-0.93). However, it did not decrease the incidence of pneumonia, intensive care unit stay or postoperative hospital stay, and did not increase the incidence of complications such as anastomotic leakage, recurrent nerve palsy, wound infection, sepsis and catheter-related fever.


CONCLUSION
A neutrophil elastase inhibitor is beneficial in patients undergoing esophagectomy. More high quality, large sample, multi-center and randomized controlled trials are needed to validate this effect.


Study selection
Randomized controlled trials and high-quality comparative studies were considered eligible for inclusion if: (1) the participants were esophageal carcinoma patients undergoing esophagectomy; (2) neutrophil elastase inhibitor was compared with placebo (saline); and (3) outcomes mainly included data on postoperative clinical course, oxygenation, blood and cytokines. Studies on patients undergoing other major surgeries were excluded. Quantitative data were not necessary for inclusion. According to the inclusion criteria, two reviewers independently reviewed the searched literature and any disagreement was resolved by discussion.

Data extraction and quality assessment
Data were extracted and a form, which was devised in advance, was completed. The following data were recorded: basic information (author, country and year of publication), characteristics (sex, age and arm), treatment protocol (case, sivelestat dosage and usage), surgical background (operative time, blood loss, surgical procedure), outcome measures [duration of mechanical ventilation, intensive care unit (ICU) stay, SIRS, postoperative hospital stay, and P/F ratio], and complications. Another two reviewers carried out the data extraction, and the results were then crosschecked. Disagreement was resolved by discussion.
Three reviewers evaluated the methodological neutrophil elastase inhibitor, actively protects patients with acute respiratory diseases. The efficacy and safety of sivelestat administered during esophagectomy has produced conflicting results and the conclusions from relevant studies are presented. This metaanalysis revealed that sivelestat is beneficial in patients undergoing esophagectomy, especially in terms of the duration of mechanical ventilation and the incidence of pulmonary complications.

INTRODUCTION
Esophageal carcinoma is the sixth leading cause of cancer-related deaths worldwide, and its incidence is increasing rapidly [1,2] . In recent years, multidisciplinary treatments have been adopted more and more frequently. Of these treatments, curative surgery remains the most important treatment option [3,4] .
Previous studies have shown that patients undergoing radical esophagectomy after neoadjuvant therapy achieved the highest long-term survival [4][5][6] . Radical esophagectomy, which consists of videoassisted thoracoscopic esophagectomy, cervical esophagogastrostomy and two-or three-field lymph node dissection, is one of the most invasive surgical techniques performed in the gastrointestinal system [7] . This excess surgical stress has led to a perioperative mortality rate of approximately 3%-10% [8,9] , and is mainly caused by systemic inflammatory response syndrome (SIRS)-associated complications, of which pulmonary disorders account for approximately 30%-60% [10] .
The lung is the main target organ for overproduced cytokines in SIRS; thus, pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) occur frequently in patients undergoing esophagectomy [11,12] . Current studies have demonstrated that neutrophil elastase (NE), which is secreted by IL-8 induced mature neutrophils, could represent the severity of postoperative pulmonary disorders [13] . In addition, Suda et al [14] stated that a drug that could relieve SIRS and control neutrophil function might improve the postoperative clinical course following transthoracic esophagectomy. Sivelestat sodium hydrate, a synthetic NE inhibitor, can competitively inhibit NE activity and does not affect other proteases [15] . A positive treatment effect was reported in many studies, and the Japanese Respiratory Society recommends sivelestat for the treatment of ALI in the Guidelines for Treatment of quality of the included studies according to the standard recommended by the Cochrane handbook [20] for systematic reviews and meta-analyses. By studying the materials and methods section, quality assessment was performed by identifying the study type, randomization, blinding, allocation concealment, eligibility criteria, baseline comparability, participants lost to follow-up, ITT analysis, selective reporting, incomplete outcome and other biases. Stata 12.0 software was used to analyze the extracted data. The risk ratio (RR) was used to express the effect size of dichotomous outcomes, and the mean difference (MD) or standardized mean difference was used to express the effect size of continuous outcomes. Cochran's Q-test and the I 2 statistic were used to estimate the heterogeneity among the pooled studies. If P > 0.05 or I 2 < 50%, the heterogeneity was thought to be insignificant, and a fixed-effect model was adopted in the meta-analysis. If the heterogeneity was significant, a random-effect model was adopted and the source of heterogeneity was investigated using clinical and statistical aspects. In addition, sensitivity was assessed to judge the reliability of the evidence, and both Begg's test and Egger's test were conducted to determine publication bias.

Statistical analysis
This review was performed in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The present protocol has not been published or registered elsewhere.
There was significant heterogeneity among the trials. To investigate the source of heterogeneity, according to postoperative day (POD) of sivelestat administration, subgroup analysis including POD 3 (sivelestat was administrated until POD3 and POD 5 (sivelestat was administrated until POD 5) was performed. When compared with the control group, the duration of mechanical ventilation was significantly decreased in the sivelestat group on POD 5 [I 2 = 76.3%, SMD = -1.41, 95%CI: -2.63-(-0. 19)].
Although the duration of mechanical ventilation was also decreased in the sivelestat group on POD 3, it failed to reach statistical significance (I 2 = 0%, SMD= -0.68, 95%CI:-1.38-0.02). Begg's test and Egger' s test showed that publication bias might exist (P = 0.027, 95%CI: -8.82-1.06). These data are shown in Figures 2 and 3. The data in the other three studies are summarized in Table 4.

ICU stay
Six studies provided data on ICU stay [14,22,24,[26][27][28] , and three of these studies were pooled quantitatively in the fixed effect analysis [26][27][28] . The results showed that sivelestat decreased ICU stay, but this failed to achieve statistical significance [I 2 = 0%, SMD = -0.22, 95%CI: -0.54-(-0.11)], as shown in Figure  6. In the other three studies, one study reported no statistically significant difference, and two studies found a statistically significant difference between the sivelestat group and the control group, as summarized in Table 4.

Other complications
With the exception of pulmonary complications, other complications such as anastomotic leakage, recurrent nerve palsy, wound infection and sepsis were also reported in the included studies. Fixed effects analysis demonstrated that no significant difference existed between the sivelestat group and the control group in terms of anastomotic leakage (I 2 = 0%, RR = 1. 26

DISCUSSION
Some studies have found that patients undergoing esophagectomy benefit from methylprednisolone administration with no adverse effects. However, even when pre-operative methylprednisolone is administered, pulmonary complications frequently occur. This may be caused by the systemic inflammatory response following esophagectomy, leading to accumulation of neutrophils in the lungs. Subsequent local release of neutrophil elastase (NE) injures the lung [18,31] . As glucocorticoids do not affect the release or function of NE, additional selective inhibition of NE might be beneficial. Indeed, the results of the meta-analysis showed that compared with the control group, the duration of mechanical ventilation support was reduced in the sivelestat group. Subgroup analysis demonstrated that this reduction in the duration of mechanical ventilation support failed to reach statistical significance in the sivelestat group on POD 3, but it was significantly decreased in the sivelestat group on POD 5. Our study revealed that sivelestat administered at different times may lead to different clinical outcomes, and the administration of sivelestat should be continued up to at least POD 5 to decrease the time required for mechanical ventilation support.
Pneumonia and ALI are common pulmonary complications after esophagectomy [10] , and our results indicated that although sivelestat may not decrease the incidence of pneumonia compared with the control, it greatly reduced the incidence of ALI in patients after surgery. Although ARDS and SIRS have been clearly defined during the American-European consensus conferences, the criteria for pneumonia differ widely [32] . Consequently, the study results for pneumonia should be considered with caution. Furthermore, pneumonia after esophagectomy can be caused by various factors such as increased infection, invasive surgical procedures, administration of methylprednisolone, decreased pulmonary function and immunity, and the use of mechanical ventilation support [33] . ALI mainly occurs because of increased levels of cytokines in the serum, especially NE secreted by neutrophils. Thus, as a specific inhibitor of NE, sivelestat, had a very limited effect on postoperative pneumonia, but a very strong effect on postoperative ALI. In addition, sivelestat had a positive effect on pulmonary function. Kawaha et al [22] reported a significant increase in PaO2/FiO2 on POD 1 and 7; Suda et al [14] reported a significant increase in PaO2/FiO2 on POD 1; and Nishiyama et al [27] reported a significant increase in PaO2 on POD 5. Most studies reported a reduction in the duration of postoperative SIRS; however, two studies found no statistically significant difference [21,26] . Of these two studies, Iwahashi et al [21] performed esophagectomy    using the cervicothoracoabdominal approach, and Nagai et al [26] performed subtotal esophagectomy via a right posterolateral thoracotomy and upper midline laparotomy. Compared with current video-assisted thoracoscopic esophagectomy [34,35] , their surgical procedures appeared to be more invasive and led to more blood loss, which induced a more acute SIRS state. Therefore, additional sivelestat administration after the more invasive surgical procedure may have little clinical benefit, and the effects of different procedures in addition to higher dose of sivelestat should be investigated in the future.
The meta-analysis results showed that sivelestat may have decreased ICU stay; however, this decrease failed to achieve statistical significance. In the other three studies mentioned previously, two studies [14,24] reported significant differences, while one study [22] reported no significant difference, thus there is no consensus on ICU stay. Postoperative hospital stay was reported in four studies [22,24,26,27] , and only two of these studies [26,27] were pooled quantitatively in the fixed effect analysis. The results showed that sivelestat might have decreased postoperative hospital stay; however, this decrease failed to achieve statistical significance. The other two studies [22,24] showed no significant difference. With sivelestat administrated after surgery, the mechanical ventilation support, pulmonary complications and SIRS were improved; however, the ICU stay and postoperative hospital stay were not significantly shortened. Possible explanations for these findings are as follows: (1) limited number of studies included in the analysis; (2) insufficient data in the studies; (3) different protocols for discharging from the ICU and hospital adopted in the studies; (4) heterogeneity between the studies; and (5) different protocols of sivelestat administration.
One study performed a cost-analysis [27] , which showed that only surgery costs were significantly lower in the sivelestat group compared with the control group, and there were no significant differences in the hospitalization, medication or total costs. Therefore, additional sivelestat did not increase medical costs. With regard to safety, our study demonstrated that sivelestat did not increase the risk of complications, including anastomotic leakage, recurrent nerve palsy, wound infection and sepsis.
There are also some weaknesses with the present evidence. Some of the included trials were non-RCTs, which may have increased the risk of random errors. Dissimilar procedures, such as minimally invasive or traditional surgery with different operative time and blood loss, could affect patient outcomes. In addition, different concentrations of sivelestat administered with inconsistent doses of methylprednisolone may decrease the risk of pulmonary complications. All of these factors suggest that there may be unavoidable bias in the pooled results, which in turn limited the strength of this meta-analysis. Minimally invasive surgery has evolved rapidly in recent years. As minimally invasive approaches reduce the factors associated with pulmonary complications (e.g., blood loss, pain and inflammation), minimally invasive esophagectomy would be particularly beneficial with respect to pulmonary complications. In the included studies, three studies performed thoracoscopyassisted surgery [22][23][24] , and two studies performed subtotal esophagectomy [23,26] ; therefore, the different procedures adopted in these studies would also have some effect on the results.
The results for perioperatively administered neutrophil elastase inhibitor are encouraging. All the trials included were conducted in Eastern populations, and genomic factors may have influenced the results [36,37] . Further trials are required in other areas to determine whether these results can be extrapolated to all populations.
In summary, neutrophil elastase inhibitor administration is beneficial in patients undergoing esophagectomy, especially in terms of the duration of mechanical ventilation, pulmonary function, pulmonary complications and SIRS state. Although many studies have reported that it also plays an active role in ICU stay and hospital stay, there is currently insufficient evidence for these effects, and more high-quality, large sample, multi-center and randomized controlled trials are needed.

Background
Esophageal carcinoma is the sixth leading cause of cancer-related deaths worldwide. Patients undergoing radical esophagectomy suffer excess surgical stress, which mainly causes pulmonary complications. Sivelestat sodium hydrate is recommended for the treatment of acute lung injury, and is considered effective in patients with esophageal carcinoma undergoing esophagectomy. However, this needs to be systematically evaluated.

Research frontiers
This meta-analysis was performed to evaluate the benefit and safety of sivelestat administration in patients undergoing esophagectomy. The outcome measures included mechanical ventilation, pulmonary complications, SIRS, ICU

Innovations and breakthroughs
This meta-analysis revealed that sivelestat is beneficial in patients undergoing esophagectomy, especially in terms of the duration of mechanical ventilation and the incidence of pulmonary complications. It may also play an active role on ICU stay, hospital stay, oxygenation and blood cytokine levels. However, there is currently insufficient evidence for these effects.

Applications
The current analysis shows that sivelestat sodium hydrate may achieve better treatment outcomes in patients with esophageal carcinoma undergoing esophagectomy. Sivelestat reduced the duration of mechanical ventilation support and the incidence of pulmonary complications. In addition, side effects did not appear to be a concern. Terminology Radical esophagectomy, which mainly consists of video-assisted thoracoscopic esophagectomy, cervical esophagogastrostomy and two-or three-field lymph node dissection, is one of the most invasive surgical techniques performed in the gastrointestinal system.

Peer-review
This is a nicely written manuscript with a thoroughly performed review and meta-analysis on the use of sivelestat perioperatively for esophagectomy, and the outcomes and analyses were really conducive.