|Year : 2014 | Volume
| Issue : 8 | Page : 314-318
Clinical analysis of acute lung injury after esophagectomy
Wei-chun Wu1, Yongqing Wang2, Xiaolin Wang2, Aizemaiti Rusidanmu2
1 Department of Cardiothoracic Surgery, Yuhang Hospital, Hangzhou Normal University College of Medicine, Hangzhou 310003, China
2 Department of Thoracic Surgery, First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China
|Date of Web Publication||17-Feb-2015|
Department of Thoracic Surgery, First Affiliated Hospital, Zhejiang University, Qingchun Road 79, Hangzhou 310003
Source of Support: None, Conflict of Interest: None
Objective: Acute lung injury (ALI) is one of the most severe postoperative complications after esophagectomy for esophageal cancer patients. In order to clarify the mechanism of ALI, we, therefore, studied the operative course of a group of patients who underwent elective esophagectomy.
Materials and Methods: We retrospectively analyzed 75 patients underwent an esophagectomy and reconstruction for thoracic esophageal cancer.
Results: No statistically significant differences were observed between the two groups regarding their clinical backgrounds, such as their age, smoking index, preoperative pulmonary function, the location of the main tumor, and the tumor nodes metastasis stage. Operative time is thus considered to be a significant factor. The odds ratio (OR) of ALI in cases whose preoperative pulmonary function was 6.70 in comparison to the abnormal preoperative pulmonary functions. The OR for more intraoperative bleeding (>1000 g) was 0.83, compared with a lesser intraoperative bleeding although the difference was not statistically significant (P = 0.076). Anastomotic leakage occurred in four patients (44%) in Group I while it only occurred in two patient (6%) among the 33 Group II patients (P = 0.011).
Conclusion: Greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extrathoracic site, such as necrosis and local infection around anastomosis may, therefore, be the second attack. Furthermore, ALI may cause not only systemic inflammatory response syndrome but also other complications such as anastomotic leakage.
Keywords: Acute lung injury, complications, esophagectomy
|How to cite this article:|
Wu Wc, Wang Y, Wang X, Rusidanmu A. Clinical analysis of acute lung injury after esophagectomy. J Can Res Ther 2014;10, Suppl S4:314-8
| > Introduction|| |
Esophageal cancer is a devastating disease. Although some patients can be cured, the treatment for esophageal cancer is protracted, diminishes the quality-of-life, and is lethal in a significant number of cases. , Prognosis of esophageal cancer is generally poor because of its biological aggressiveness and anatomic characteristics.  Esophagectomy, the surgical removal of all or part of the esophagus, is a surgical procedure that is associated with high morbidity and mortality. Pulmonary complications are an especially important postoperative problem.  Therefore, many perioperative strategies to prevent pulmonary complications after esophagectomy have been investigated and introduced in daily clinical practice.  In order to improve the prognosis, an extended radical esophagectomy with radical lymphadenectomy is often performed, however, this treatment modality may also increase the amount of surgical stress. Among the postoperative complications, pulmonary complications as well as anastomotic leakage tend to be the most critical. , Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are well-established conditions which sometimes occur as a response to various kinds of surgical stress. ALI is frequently observed and reflects various kinds of pulmonary complications after esophagectomy. ARDS, in particular, is considered to be the most severe type of ALI and is sometimes fatal: The mortality rate after a transthoracic esophagectomy has been reported to be 78%. ALI and ARDS are still life-threatening diseases in esophagectomy patients.  They are the manifestations of an inflammatory response of the lung to both direct and indirect insults and are characterized by severe hypoxemia, hypercapnia, diffuse infiltration in the chest X-ray, and a substantial reduction in pulmonary compliance.
A detailed description of the pathogenesis of ALI on different levels (Cellular, molecular, and so on) was published previously. , The pathogenesis of ALI after an esophagectomy is still unclear. Major surgery induces a systemic inflammatory response syndrome (SIRS). High levels of pro-inflammatory cytokines interleukin-1 (IL-1) β,-6,-8,-12, tumor necrosis factor alpha and interferon gamma play an important role in the occurrence of the inflammatory response as well as lung injury. Among these cytokines, multiple groups reported that IL-8 in the pulmonary airspaces contributes to the occurrence of pulmonary complications after an esophagectomy or ARDS in high-risk patients. On the other hand, the increased secretion of IL-1 β and tumor necrosis factor-α (TNF-α) in lung alveolar macrophages activates neutrophils, thus leading to tissue damage and an increase of these cytokines in the lung is considered to play an important role in the occurrence of pulmonary complications. Pleural drainage fluid is easily collected from postoperative patients, and the cytokine levels of the fluid are considered to accurately reflect a pulmonary cytokine condition. However, the relationship between cytokines in the pleural effusion and the occurrence of ALI has never been evaluated.
In order to clarify the mechanism of ALI after an extended radical esophagectomy, we therefore, studied retrospectively the operative course of a group of patients who underwent elective esophagectomy at a single center and evaluated both the clinical factors and inflammatory cytokine levels in the pleural effusion as well as in the peripheral blood of such patients.
| > Materials and methods|| |
Seventy-five patients underwent an esophagectomy and reconstruction for thoracic esophageal cancer at the Department of Thoracic Surgery at our Institution. Among them, 42 patients provided their informed consent and agreed to participate in this study, including the collection of their blood samples, were enrolled to this study. The patients consisted of 33 Chinese men and 9 Chinese women in this series with a mean age of 64.3 years (range 44-76 years). All lesions were histologically proven to be squamous cell carcinomas of the thoracic esophagus. A subtotal esophagectomy, as well as a lymphadenectomy, was performed with both a right open thoracotomy and an open laparotomy. An esophageal reconstruction was performed with a gastric tube for all patients. The clinicopathological factors were evaluated according to the guidelines for clinical and pathologic studies on carcinomas of the esophagus.
Extubation of the tracheal tube was performed when the following criteria were fulfilled: (i) The patients' were conscious and sufficiently alert and cooperative with minimal work of breathing and Minimal secretions; (ii) forced vital capacity ≥10 cc/kg, the arterial oxygen pressure/fraction of inspired oxygen (PaO 2 /FiO 2 ) level was more than 300; (iii) the PaCO 2 and PaO 2 levels were stable. Extubation was performed from 1 to 7 days (mean 4.5 days) after surgery.
We evaluated the presence of ALI during the whole period of mechanical ventilation. ALI is defined as an acute lung disease with bilateral pulmonary infiltrate in a chest radiograph consistent with the presence of edema and no clinical evidence of left atrial hypertension; or (if measured) a pulmonary wedge pressure of 18 mmHg or less. In addition, the ratio of arterial oxygen to the fraction of inspired oxygen (PaO 2 /FiO 2 ) must be 300 mmHg or less, regardless of the level of positive end-expiratory pressure. ARDS, the most severe form of ALI, is defined by a ratio of arterial oxygen to fraction of inspired oxygen of 200 mmHg or less. Among the 42 patients investigated, nine patients fulfilled the criteria of ALI during the mechanical ventilation period (Group I) while the other 33 patients showed a normal lung status (Group II). In all patients of Group I, mechanical ventilation was required at least for 3 days after surgery. On the other hand, we reconfirmed that all the patients in Group II had no pulmonary dysfunction based on symptoms, chest X-ray findings and PaO 2 after extubation of the tracheal tube. In addition, no patients were found to be suffering from ARDS.
We also examined the duration of SIRS after surgery, according to the definition of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. SIRS is manifested by two or more of the following conditions: (i) Body temperature < 36°C (96.8°F) or > 38°C (100.4°F); (ii) heart rate > 90 beats/min; (iii) Tachypnea, with > 20 breaths/min; or, PaCO 2 <<sub> 4.3 kPa (32 mmHg); and (iv) leukocytes < 4000 cells/mm 3 ( 4 × 109 cells/L) or > 12,000 cells/mm 3 (12 × 10 9 cells/L); or the presence of > 10% immature neutrophils (band forms) band forms > 3% is called bandemia or a "left-shift".
Measurement of cytokine levels of serum and pleural drainage fluid
A 28 French thoracic drain was inserted into the right thoracic cavity before closing the thoracotomy, and a drain was maintained for at least 5 days after surgery in all patients. The drain was removed when the drainage fluid was serous and < 150 mL/day and no air leakage was recognized. Blood samples and thoracic drainage fluid samples were obtained immediately after surgery (day 0) and on days 1, 2 and 3 thereafter. Both the blood samples and pleural fluid samples were centrifuged at 1300 g for 10 min to remove cells as well as cell debris. Next, both the serum and the supernatant of the pleural fluid were collected and frozen at -70°C until the cytokine levels were measured.
We measured the levels of IL-6, IL-8, IL-1 β, and TNF-α of serum and pleural drainage fluid. The cytokine levels were measured using a commercially available enzyme-linked immunosorbent assay kit according to the manufacturer's instructions (IL-6 and IL8, R and D Systems Inc., Minneapolis, MN; IL-1 β and TNF-α, Japanese Immunoresearch Laboratories Co, Ltd, Takasaki, Japan).
The differences in the clinical factors between both groups were analyzed by either Fisher's exact test or the unpaired t-test. A logistic regression analysis was used to evaluate independent factors associated with the occurrence of ALI. The differences in the cytokine levels were evaluated by Mann-Whitney's U-test. The data were analyzed using the SPSS for Windows 8.1 (SPSS Inc., Chicago, IL, USA).
| > Results|| |
[Table 1] shows the clinical background of each group according to the presence of ALI after an esophagectomy. No statistically significant differences were observed between the two groups regarding their clinical backgrounds, such as their age, smoking index, preoperative pulmonary function, the location of the main tumor, and the tumor nodes metastasis stage.
A logistic regression analysis was adopted in order to clarify the independent factors associated with the occurrence of ALI [Table 2]. Among the clinical factors, operative time is thus considered to be a significant factor. The odds ratio (OR) of ALI in cases whose preoperative pulmonary function was 6.70 in comparison to the abnormal preoperative pulmonary functions. The OR for more intraoperative bleeding (>1000 g) was 0.83, compared with a lesser intraoperative bleeding although the difference was not statistically significant (P = 0.076).
|Table 2: Analysis of the factors associated with the occurrence of ALI based on a logistic regression analysis|
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[Table 3] shows the postoperative events. Anastomotic leakage occurred in four patients (44%) in Group I while it only occurred in two patient (6%) among the 33 Group II patients (P = 0.011). Persistent SIRS of 4 days or more was recognized in seven patients (78%) in Group I while it was observed in 5 patients (15%) in Group II (P = 0.023). Anastomotic leakage occurred from 7 to 14 days after surgery in four patients from Group I, while it occurred 4 days after surgery in two patients from Group II. The duration of mechanical ventilation was significantly longer in Group I than in Group II (P = 0.041). Furthermore, persistent SIRS lasting 4 days or more was recognized in four of seven patients in the ALI group while it was observed in 5 (15%) of the 33 patients in the non-ALI group.
Cytokine levels of serum and pleural drainage fluid
In most cases, the IL-6 and IL-8 level of the serum as well as pleural drainage fluid after an esophagectomy could not be detected before surgery. Immediately after surgery, both the IL-6 and IL-8 levels were at maximal level in both the serum and the pleural fluid and then gradually decreased until the day 3. Both cytokine levels of pleural fluid were approximately 100 times higher than that of the peripheral blood.
Interleukin-6, interleukin-8 and acute lung injury after an esophagectomy
The IL-6 levels of the serum in the cases with ALI (Group I) were significantly higher than those without ALI (Group II) immediately after surgery, on days 1 and 2 after surgery (P < 0.05). In both groups, the IL-6 levels of serum gradually decreased and the difference between them was only minimal on day 3. Regarding the IL-6 levels of pleural effusion, no differences were recognized between Groups I and II. On the other hand, the serum IL-8 levels of Group I were constantly higher than those of Group II. The differences in the IL-8 levels between Groups I and II were statistically significant at day 2 (441 and 61, P < 0.05). The IL-8 levels of the pleural effusion in the ALI patients were higher than in the non-ALI group and the difference was significant on day 3 (P < 0.05).
Neither IL-1 β nor TNF-α could be detected in the peripheral blood, even after surgery. Both these levels in the patients with ALI (Group I) were higher than those without ALI (Group II). IL-1 β gradually decreased at 2 and 3 days after surgery in Group II, while it continued to show a high level for up to 3 days after surgery in Group I. The IL-1 β level at day 3 after surgery in Group I was significantly higher than that in Group. II (P < 0.05). The mean TNF-α levels increased up to postoperative day 3 in both groups. However, the increase was greater in Group I than in Group II, although the differences were not significant.
| > Discussion|| |
Several studies have demonstrated that major surgery induces a series of inflammatory responses mediated by IL-6 and IL-8.  Kooguchi et al.  examined the expression of both IL-6 and IL-8 in alveolar macrophages as well as the concentration in the bronchoalveolar lavage fluid (BALF) after an esophagectomy. As a result, a high expression in alveolar macrophages was observed while, in addition, the concentration of cytokines in the BALF was elevated after an esophagectomy. In the current study, both of the IL-6 and IL-8 levels were approximately 100 times higher in the pleural effusion than in the peripheral blood. These results support the notion that cytokines are considered to be induced and mainly secreted in the operative field and almost simultaneously appear in the bloodstream at a 1/100 level of dilution early in the postoperative course. ALI, as well as ARDS, is major contributors to respiratory mortality and morbidity after an esophagectomy.  The incidence of ALI was 42% in our series, however, no patients met the criteria for ARDS. In the current study, the IL-8 levels of the pleural effusion as well as the peripheral blood of ALI patients were higher than in the non-ALI group. These results indicate that pro-inflammatory cytokines such as IL-8 reflect the damage of organs and cause SIRS.
Regarding TNF-α and IL-1 β, Katsuta et al.  examined the TNF-α and IL-1 β-producing capacity of monocytes of the peripheral blood after an esophagectomy and found this capacity to be elevated when lung injury occurred after the operation. An animal experiment clearly demonstrated that locally produced TNF-α mediated IL-2 induced lung inflammation and tissue injury. Furthermore, the pleural TNF-α level is elevated in cases that are complicated with parapneumonic effusion. In the current study, the IL-1 β level of pleural drainage fluid was higher in the ALI group than the non-ALI group after an esophagectomy. These support the view that topical cytokines such as IL-1 β play an important role in the occurrence of ALI.
When considering the development of organ failure, including ALI, following surgical insult, the existence of a second attack is thought to be important: First, surgical insults such as major surgery cause tissue destruction and necrosis. The ensuring hypercytokinemia induces neutrophil accumulation in the vital organs (priming). If subsequent complications occur, then macrophages can be reactivated and cytokines are released a second time. These cytokines stimulate the neutrophils accumulated in the vital organs, thus causing organ damage (triggering). A patient undergoing a long operation is, therefore, a candidate for suffering an increased effect of the first attack, leading to ALI.
In this study, we made a comparison of the operation times between the ALI and non-ALI groups only in patients undergoing gastric tube reconstruction as well as manova regarding the factors associated with this analysis. As a result, the operation time tended to be longer in the ALI group and the manova also revealed an increased elevated OR as an independent factor, although the difference was not statistically significant. These data suggest that the greater surgical stress caused by a long operation may play an important role in the first attack that leads to ALI. When we paid special attention to the serum IL-6 levels, significant differences were recognized within 2 days after surgery between the presence and absence of ALI and this indicates that the cytokine levels can be considered to reflect the degree of the first attack.
Anastomotic leakage seems to be one of the important complications closely related to the development of ALI. In the current study, ALI was significantly associated with the occurrence of anastomotic leakage as well as persistent SIRS. This result is consistent with those of another report.
When considering the close relationship between the development of ALI and that of anastomotic leakage, two hypotheses can be considered. One is that some cases of anastomotic leakage may be the result of ALI. The ALI developing in the early phase after an esophagectomy may have an adverse influence on wound healing and can also cause anastomotic leakage. The fact that the symptoms of leakage were recognized later than 7 days after surgery in all cases associated with ALI also supports this possibility. Another hypothesis is that the factors related to anastomotic leakage, such as necrosis or infection around the anastomotic site, may cause the ALI. According to this hypothesis, the events had already developed around the anastomosis without any symptoms in the early days after surgery. However, obvious symptoms of the anastomotic leakage subsequently became apparent after day 7. Furthermore, these events which develop at the extrathoracic site may play an important role in the second attack which leads to ALI. Our results based on a manova, which show colon interposition to be a factor associated with ALI independent from surgical stress, like the operative time, may support this hypothesis. On the other hand, the serum IL-8 levels of ALI group were higher than in the ALI negative group, not only immediately after the operation but also at days 2 and 3 postoperatively. However, this rebound phenomenon was never observed in the pleural effusion. These results also support the view that some instances of a second attack might occur outside of the lung.
| > Conclusion|| |
Large amounts of surgical stress such as a longer operative time cause hypercytokinemia and thus play an important role as the first attack of ALI after an esophagectomy. The adverse events developing at the extrathoracic site, such as a blood flow disturbance or local infection around anastomosis, may thus represent a second attack. Furthermore, ALI may not only cause persistent SIRS but also play an important role in the development of other complications, like anastomotic leakage.
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[Table 1], [Table 2], [Table 3]