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Respiratory failure from acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pneumonia are the major cause of morbidity and mortality following an oesophagectomy for oesophageal cancer. This study was performed to investigate whether an intraoperative corticosteroid can attenuate postoperative respiratory failure.
Between November 2005 and December 2008, 234 consecutive patients who underwent an oesophagectomy for oesophageal cancer were reviewed. A 125-mg dose of methylprednisolone was administered after performing the anastomosis. ALI, ARDS and pneumonia occurring before postoperative day (POD) 7 were regarded as acute respiratory failure.
The mean age was 64.2 ± 8.7 years. One hundred and fifty-one patients were in the control group and 83 patients in the steroid group. Patients' characteristics were comparable. The incidence of acute respiratory failure was lower in the steroid group (P = 0.037). The incidences of anastomotic leakage and wound dehiscence were not different (P = 0.57 and P = 1.0). The C-reactive protein level on POD 2 was lower in the steroid group (P < 0.005). Multivariate analysis indicates that the intraoperative steroid was a protective factor against acute respiratory failure (P = 0.046, OR = 0.206).
Intraoperative corticosteroid administration was associated with a decreased risk of acute respiratory failure following an oesophagectomy. The laboratory data suggest that corticosteroids may attenuate the stress-induced inflammatory responses after surgery.
Oesophageal surgery is one of the most stressful procedures that thoracic surgeons perform. In spite of the recent improvements in surgical skills and perioperative care, the postoperative mortality rate from oesophageal surgery has been reported to be around 2–14% . Respiratory failures, particularly acute lung injury (ALI) and acute respiratory distress syndromes (ARDS), are the major causes of morbidity and mortality following an oesophagectomy . These complications require extended intensive care and result in functional impairments, even when the patients recover from respiratory failure .
Recent studies have reported that surgical trauma results in the release of inflammatory cytokines that usually peak during the immediate postoperative period or on postoperative day (POD) 1 [4, 5]. These inflammatory cytokines are thought to be the cause of many postoperative complications, such as lung injury, liver failure, acute renal failure and multi-organ failure [6, 7]. Corticosteroids have been reported to suppress the inflammatory response secondary to sepsis and other stress-related diseases [8, 9]. Therefore, several clinical studies have been performed to prove the efficacy of steroids in reducing the inflammatory cytokine release after surgery. In the field of thoracic surgery, the efficacy of steroids have been widely studied, especially in oesophagectomies. Shimada et al.  reported that perioperative steroid therapy was effective in inhibiting the release of inflammatory mediators and improving the postoperative clinical course of patients with oesophageal cancer. Recently, Engelman and Maeyens  reported the meta-analysis of these steroid studies, but they failed to confirm the efficacy of steroids because of the low quality of the included studies. They analyzed eight clinical studies, but each study enrolled only a small number of patients and the timing of steroid administration was heterogeneous. Therefore, we retrospectively reviewed our clinical data based on a large number of patients. This study was performed to investigate whether intraoperative corticosteroid administration plays a role in attenuating postoperative morbidities, and especially focussing on acute respiratory failure.
This protocol was reviewed by the institutional review board and approved as a retrospective study (NCCNCS-10-407). Between November 2005 and December 2008, the data of 234 consecutive patients who underwent an oesophagectomy for oesophageal squamous cell carcinoma at the National Cancer Center in Korea were reviewed. All data were collected prospectively. Comorbid conditions were defined as diabetes mellitus, hypertension, coronary artery disease and pulmonary diseases.
Surgical indication, preoperative evaluation, surgical methods and postoperative care were all consistent and standardized during the study period. Oesophageal surgeries included total oesophagectomy and total lymphadenectomy with reconstruction using portions of the stomach or colon. All patients underwent an oesophagectomy via a right thoracotomy, median laparotomy and bilateral cervical U-shaped incision. The replacement conduit was pulled up in all patients through a posterior mediastinal route. Anastomotic sites were decided based on the tumour level. A three-field lymph node dissection (3-FLND) and a cervical anastomosis were performed in the cases of upper oesophageal cancer, and a 2-FLND and an intrathoracic anastomosis were performed for mid- and lower-oesophageal cancer. The transhiatal approach was excluded.
Since 2007, we have routinely administered a 125-mg dose of methylprednisolone sodium succinate intravenously after the anastomosis. Before 2007, the intraoperative steroid was not a routine procedure. Patients were admitted to the intensive care unit after extubation in the operation room and were transferred to the general ward on POD 1. The postoperative course was monitored daily, and any postoperative complications were described. The serum concentration of C-reactive protein (CRP) was checked daily until POD 7.
We defined ‘acute respiratory failure’ as ALI, ARDS or pneumonia that occurred on or before POD 7. Clinically, differentiating between pneumonia and lung injury was difficult, and some patients had more than one of these diseases at the same time; therefore, we grouped these diseases together. ALI was defined according to the following criteria: (i) acute onset; (ii) bilateral infiltrates consistent with pulmonary oedema; (iii) a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) between 201 and 300 mmHg, regardless of the level of positive end-expiratory pressure; and (iv) no clinical evidence for an elevated left atrial pressure. The definition of ARDS was the same as for ALI except that there is more severe hypoxemia (PaO2/FiO2≤ 200 mmHg). Pneumonia was diagnosed when fever and purulent sputum were present and the presence of organisms was confirmed in the sputum cultures. In-hospital mortality was defined as any mortality related to the operation that occurred during the hospitalization, and 30-day mortality was defined as any mortality within 30 days of the operation.
The t-test, χ2 test, Fisher's exact test and Mann–Whitney test were used to determine the significant differences in variables between the two groups. A multiple logistic regression was performed to find the risk factors for acute respiratory failure. The postoperative CRP levels were analyzed using a linear mixed model for the repeated measures. The square root of the CRP levels was used as a response variable due to the skewed distribution of the CRP levels, and the unstructured covariance structure was used to model the variations within each subject. Two-sided P-values of <0.05 were considered to be statistically significant. The statistical analyses were performed with STATA 11.0.
The mean age of patients was 64.21 ± 8.73 years, and there were 221 male patients. There were 151 patients in the control group and 83 patients in the steroid group. Patient characteristics were not significantly different between the two groups (Table 1). The total number of respiratory events for all patients during their hospitalization was 35 (14.9%).
Acute respiratory failure occurred in 16 patients (10.5%) from the control group and in two patients (2.4%) from the steroid group. In the control group, there were four patients with ARDS, 10 with ALI and four with pneumonia. Two patients had ALI and pneumonia concomitantly. In the steroid group, there was one patient with ARDS and one patient with pneumonia. The pathogens isolated in the cases of pneumonia were as follows: methicillin-resistant Staphylococcus aureus (two), Pseudomonas (two) and Enterococcus (one). The incidence of acute respiratory failure was lower in the steroid group than in the control group (Table 2).
Among the 18 patients who suffered from acute respiratory failure, two patients died from the effects of respiratory failure and one patient died of an acute myocardial infarction (AMI). The disease course is described in Fig. 1. Hospital stays were longer for patients in the control group than in the steroid group by 2.5 days (23.70 ± 31.82 vs. 21.23 ± 29.85 days, P = 0.02). Intraoperative steroid administration did not increase the rate of anastomotic leakage or wound dehiscence (P = 0.57 and P = 1.0, respectively). Vocal cord palsy developed in 34 patients in the control group and in 12 patients in the steroid group (P = 0.17).
In-hospital mortality occurred in 10 patients (4.3%), whereas 30-day mortality occurred in seven patients. The rates of in-hospital and 30-day mortality did not differ significantly between the two groups (P = 0.50 and P = 1.00, respectively). Among the cases of in-hospital mortality, two patients from the steroid group died of ARDS after POD 7, likely due to aspiration pneumonitis. Of the eight patients from the control group who suffered in-hospital mortality, six died of ARDS, with two of the deaths occurring on or before POD 7 and four occurring after POD 7 due to aspiration pneumonitis. One patient died of an AMI that developed postoperatively, and one patient died of sepsis secondary to conduit necrosis.
The postoperative CRP levels were elevated after the operation and peaked on POD 2 in both groups. After POD 2, the CRP levels decreased gradually. According to the linear mixed model, there was no significant effect of intraoperative steroid use on the postoperative CRP levels (P = 0.305). However, we did find a significant interaction between steroid use and PODs (P = 0.033), which implies that changes in the CRP levels during the postoperative period were different for the steroid group vs. the control group. In other words, the CRP levels of the steroid group dropped slightly more quickly than the control group. By analyzing each POD individually, it was noted that the CRP level on POD 2 was significantly lower in the steroid group than in the control group (15.92 ± 4.95 vs. 17.86 ± 5.12, P < 0.005; Fig. 2).
The postoperative CRP levels were significantly higher in patients who developed acute respiratory failure compared with those patients who did not (P = 0.045). The interaction effect between the development of acute respiratory failure and the number of PODs on the CRP levels was marginal (P = 0.064; Fig. 3).
A univariate analysis revealed that intraoperative steroid administration was related to acute respiratory failure (P = 0.040). A multivariate analysis also revealed that intraoperative steroid administration still had a protective effect against respiratory failure (OR = 0.206, P = 0.046) even after adjusting the other risk factors (Table 3).
Respiratory failure following an oesophagectomy is a catastrophic complication. The published incidence of lung injury after an oesophagectomy ranges from 14.5 to 33%, and the mortality rate of respiratory failure has been reported at ~50% . Less is known about the causes and patterns of lung injury after elective oesophageal surgery, but proposed mechanisms include increased pulmonary vascular permeability due to the production of plasma and pulmonary cytokines and inflammatory mediators secondary to surgical trauma, reperfusion injury and barotrauma during single-lung ventilation . Among these, the release of inflammatory cytokines is most often considered to be a contributing factor .
Steroids are believed to suppress inflammatory reactions by reducing inflammatory cytokines. Steroids inhibit the transcription of mRNA that codes for inflammatory cytokines and, consequently, reduce the cytokine and acute-phase reactant production . Steroids also directly inhibit the generation of acute-phase reactants. Sato et al.  reported that perioperative steroid therapy significantly reduced the postoperative cardiovascular and respiratory failure rates. Takeda et al.  showed that the preoperative administration of methylprednisolone may attenuate the postoperative reduction in arterial oxygen saturation by suppressing the release of cytokines. These studies support the protective effects of steroids against respiratory failure such as ALI and ARDS.
We assumed that the cases of acute respiratory failure that occurred on or before POD 7 were related to inflammatory cytokines and that respiratory failure that occurred after POD 7 was related to the other causes such as aspiration. Therefore, we hypothesized that steroids could prevent acute respiratory failure by suppressing the release of inflammatory cytokines. In this study, as expected, intraoperative steroid administration was correlated with a reduced risk of acute respiratory failure. The incidence of acute respiratory failure was significantly lower in the steroid group, and a multivariate analysis revealed that intraoperative steroids may have protective effects against acute respiratory failure. We cannot decisively argue that only steroids are protective against respiratory failure because there are many factors associated with the development of this complication, including intraoperative fluid balance, anaesthesia and barotrauma during ventilation . However, we think that the intraoperative administration of a corticosteroid could play an important role in the prevention of acute respiratory failure by reducing the production of inflammatory cytokines.
This study has limitations. First, this study is not prospective or randomized in its design. However, the general characteristics of patients were statistically comparable. Also, we performed a multivariate analysis with all possible risk factors for acute respiratory failure. Even though the administration of steroids is divided by the time period, we have performed an oesophagectomy for oesophageal cancer with consistent surgical policies and methods since 2001. Actually, to overcome this limitation, a prospective and randomized study will be needed. Second, inflammatory cytokines, which are direct markers of inflammation in vivo, were not measured. However, given that previous studies have enrolled fewer than 100 patients in heterogeneous groups and used various administration of steroids , our series enrolled more than 200 patients over 3 years with a uniform manner of steroid administration. In conclusion, the prophylactic administration of intraoperative, single-bolus, low-dose corticosteroids might be associated with a decrease in postoperative acute respiratory failure in patients undergoing an oesophagectomy. Randomized studies are needed to prove the efficacy of steroids in the future.
Conflict of interest: none declared.