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Ann Thorac Surg 2000;70:243-247
© 2000 The Society of Thoracic Surgeons

Original articles: General thoracic

VATS lobectomy reduces cytokine responses compared with conventional surgery

Anthony P.C. Yim, MDa, Song Wan, MD, PhDa, Tak Wai Lee, FRCSa, Ahmed A. Arifi, FRCSa

a Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

Address reprint requests to Dr Yim, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
e-mail: yimap{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Video-assisted thoracic surgery (VATS) lobectomy for early lung cancer has been shown to be technically feasible. Comparative studies on laparoscopic versus open procedures indicate that laparoscopy may reduce inflammatory reactions as reflected by the lesser release of cytokines. We investigated the cytokine responses following VATS and conventional lobectomy for clinical stage I lung cancer.

Methods. Thirty-six patients with clinical stage I nonsmall cell lung cancer were studied. 18 patients underwent VATS lobectomy and the other 18 by conventional thoracotomy. There were no differences between the two groups with respect to age, gender, pulmonary function, smoking history, comorbidity, tumor size, and pathology. Plasma levels of tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin (IL)-1ß, IL-6, IL-8, and an antiinflammatory cytokine IL-10 were measured before surgery, at the end of the procedure, and 4, 8, 24, and 48 hours thereafter in all patients.

Results. There was no mortality or major complication in either group. Analgesic requirement was significantly less in the VATS group. Although the release of TNF-{alpha} and IL-1ß were minimal after surgery in both groups, the levels of IL-6, IL-8, and IL-10 were elevated. IL-6 and IL-8 levels were significantly lower in the VATS group at the end of surgery than in the open group. In addition, reduced release of IL-10 was also observed in the VATS group shortly after surgery.

Conclusions. VATS lobectomy is associated with reduced postoperative release of both proinflammatory and antiinflammatory cytokines compared with the open approach. The clinical significance of these findings remains to be fully elucidated.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
The introduction of laparoscopic cholecystectomy in the late 1980s marked the beginning of a revolution of minimal access surgery, which has since spread to involve almost every surgical subspecialty [1]. The benefits of minimal access procedures over conventional surgery include reduced postoperative pain and complications. Such advantages have been attributed to reduced access trauma, as well as a lowered metabolic and immune response to injury [2].

It is recognized that the cytokine network plays a pivotal role in inducing the acute-phase inflammatory and immunologic response to surgical trauma [2, 3]. Several laparoscopic procedures have been shown to be associated with decreased release of cytokines compared with their open counterparts [4–10]. There have been, however, few investigations comparing cytokine productions after video-assisted thoracic surgery (VATS) versus the conventional approach. The objective of this study was to examine the cytokine responses to VATS and conventional lobectomy in patients with stage I lung cancer.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
From January 1997 to December 1998, 38 patients with clinical stage I nonsmall cell lung cancer and tumor size less than 4 cm in maximal diameter were recruited into the study. There were 24 men and 14 women (mean age, 62 years; range, 53 to 88 years). Routine mediastinoscopy was performed on all patients, among whom 2 were diagnosed to have N2 disease. These 2 patients received neoadjuvant chemotherapy and were excluded from the final analysis. The remaining 36 patients underwent routine VATS exploration as described previously [11].

VATS resection was carried out whenever it was technically advisable—whenever there were complete or near completes fissures, with minimal or no pleural adhesions. Those patients who were considered not suitable for VATS on anatomic grounds underwent conventional posterolateral thoracotomy (Fig 1). All patients received identical anesthesia with selective one lung ventilation. The actual surgical procedure carried out was similar in both groups irrespective of the approach—major lung resection using individual ligation technique, followed by systematic mediastinal lymph node sampling at various stations as suggested by Naruke and colleagues [12]. Our technique on VATS major lung resection emphasizing the use of conventional instruments and no rib spreading has been reported previously [13–15]. Intraoperative intercostal block with 0.5% bupivacaine (Astra, North Ryde, Australia) was given to both groups of patients at the conclusion of the procedure. Patient-controlled analgesia with meperidine hydrochloride (Antigen Pharmaceuticals Ltd, Roscrea, County Tipperary, Ireland) was administered in the postoperative period and the dosage recorded. Epidural analgesic was not used.



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  		Fig 1. Flow diagram of the 38 patients recruited for the study.

 
Venous blood was taken in all patients before surgery (base line), at the end of the operation, and at 4, 8, 24, 48 hours thereafter. Samples were immediately cooled to 4°C and centrifuged (3,000 g for 10 minutes at 4°C). Plasma was stored at -70°C until assay. Levels of tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin (IL)-1ß, IL-6, IL-8, and IL-10 were determined by the same technologist using commercially available enzyme-linked immunosorbent assays (R & D Systems, Minneapolis, MN). The technologist was blinded to the surgical procedures.

A two-way analysis of variance for repeated measures were used for comparison of each cytokine between the two groups at each time point. Data were stored and analyzed using standard computer software (StatView, Brainpower Inc, Calabasas, CA). Values of cytokines are presented as mean ± SEM. Clinical data are shown as mean ± SD. Two-tailed t test was used for comparison of clinical parameters. Probability values less than 0.05 were considered to indicate statistical significance.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Because of the design of the study, we finished recruiting the 18 patients in the VATS group before we finished with the open group (n = 18). There was no difference between the two groups with respect to preoperative pulmonary function (forced expiratory volume in 1 second and forced vital capacity), smoking history and comorbidity. No mortality or intraoperative complications were encountered in either group, and no conversion occurred in the VATS group. The demographics, nature of the operation and pathologic results of the two groups are presented in Table 1, in which no statistical intergroup differences were found.


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  		Table 1. Surgical and Pathological Results

 
There were few postoperative complications in either group. No significant differences were found between groups with respect to operating time, chest drain duration, and hospital stay. No patient in either group required blood transfusion. Persistent air leak requiring prolonged chest drainage was noted in 1 patient in each group, up to 7 and 10 days, respectively. However, patients in the VATS group experienced much less postoperative pain as reflected by the amount of parenteral narcotics required (Table 2).


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  		Table 2. Hospital Course and Parenteral Narcotic Requirement

 
The generation of TNF-{alpha} and IL-1ß were minimal in all patients during and after surgery. The mean values of TNF-{alpha} and IL-1ß at any time point were never more than 10 pg/mL and 5 pg/mL, respectively. However, IL-6, IL-8, and IL-10 levels were elevated postoperatively (Fig 2). The levels of IL-6 and IL-8 were lower in the VATS group at the end of operation (Figs 2A, 2B). The release of IL-10, an antiinflammatory cytokine, was also reduced in the VATS group shortly after surgery (Fig 2C). There was no correlation between the presence of pleural adhesions with the level of cytokines.



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  		Fig 2. Plasma levels of IL-6 (A), IL-8 (B), and IL-10 (C) in patients undergoing video-assisted thoracic surgery (n = 18) or conventional (n = 18) lobectomy. Data are mean ± SEM. (BS = before surgery; End = at the end of surgery; 4, 8, 24, and 48 hours = time points after surgery.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Our data suggests that in comparison with the conventional open approach, VATS lobectomy is associated with a lesser release of both proinflammatory and antiinflammatory cytokines, indicating a reduced as well as balanced postoperative inflammatory reaction.

Inflammatory response serves a protective function to the body that could become harmful when it reaches a pathologic and systemic level. Recent studies of laparoscopic versus open procedures demonstrate that the degree of such an inflammatory response following the two surgical approaches may be different [4–10]. The body’s response to surgical trauma is complex and involves the interaction of several systems. The primary mechanism involved in this complex cascade can be related largely to the release of the cellular messengers, such as the cytokines, which are known to further trigger or enhance endothelium–leukocyte activation [2, 3]. Indeed, a growing body of evidence indicates that proinflammatory cytokines such as IL-6 and IL-8 are induced by surgical trauma and they may play an important role in the development of postoperative complications [2, 3].

Several comparative investigations between laparoscopic versus open procedures on cholecystectomy [4–6], colectomy [7], hysterectomy [8, 9], and Nissen fundoplication [10] suggest that laparoscopy is commonly associated with a lesser release of proinflammatory cytokines and C-reactive protein. The observation of lowered cytokines release in laparoscopic surgery, however, is not universal. Brune and colleagues [16] recently reported that the release of TNF-{alpha} was actually suppressed after open but not laparoscopic cholecystectomy, whereas production of IL-10 remained unchanged in both groups. These findings suggested that the open approach may alter the balance of the proinflammatory and antiinflammatory cytokines. It seems logical that it is the balance among many interactive mediators that is crucial in determining the extent of inflammatory injury.

These data from the laparoscopic literature should not be extrapolated to include VATS, as there are important differences between laparoscopic surgery and VATS that could influence cytokine release. VATS is performed under ipsilateral lung collapse (creating an obligatory right-to-left transpulmonary shunt), whereas laparoscopy is carried out using CO2 insufflation. The contribution of these factors toward cytokine response remains to be further explored. On the other hand, the presence of malignancy per se may also influence cytokine release. In patients undergoing thoracotomy for resection of early lung cancer, it has been recently shown that the base line levels of TNF-{alpha} and IL-10 were raised preoperatively without significant postoperative changes compared with a control group of patients without malignancy [17]. These observations, however, need to be substantiated.

In the current study, we found that VATS lobectomy is associated with reduced postoperative release of both proinflammatory (IL-6, IL-8) and antiinflammatory (IL-10) cytokines compared with the open approach. Moreover, although many clinical end points were not significantly different between the two groups, patients in the VATS group experienced much less postoperative pain indicating reduced access trauma. The base line level of IL-8 in the open group was higher than that in the VATS group in our study. However, we do not think the difference in these low levels (less than 10 pg/mL) is of significance. None of the other cytokines we studied show a difference in base line levels. Also, we do not believe that adhesiolysis or doing more dissection on the fissure per se during lobectomy would significantly affect the cytokine response (compared with the lobectomy procedure or the trauma of access), even though the evidence for this is currently not available.

Our current finding is consistent with some other recent circumstantial observations suggesting that the decreased release of both proinflammatory and antiinflammatory cytokines may be beneficial. For instance, compared with conventional coronary artery bypass grafting (CABG) using cardiopulmonary bypass, a reduced release of both IL-8 and IL-10 is associated with off-pump multivessel CABG [18]. Such a reduction in proinflammatory and antiinflammatory cytokine responses is associated with a lesser degree of myocardial injury [18]. In another prospective randomized study, lowering the production of IL-6, IL-8, and IL-10 by the use of heparin-coated extracorporeal circuit was found to be associated with reduced myocardial injury in patients undergoing heart or heart–lung transplantation [19]. On the other hand, high IL-6 and IL-8 serum levels following thoracic procedures have been shown to be associated with an increased incidence of postoperative infection [20].

We acknowledge that this study has two limitations. First, we initially planned to randomize our patients into two groups using different surgical approaches. However, practical difficulties made us change the design of the study because few patients agreed to be randomized when presented the choice of VATS resection. Despite the inherent flaw in the study, the two groups of patients were comparable in their demographics as well as in their pathology. Second, we have now learned that the plasma levels of cytokines might not adequately reflect their tissue concentrations, and the latter may be even more important in determining the severity as well as prognosis of injury [3]. Therefore, in addition to measuring these cytokines systemically, we should also aim at quantifying the local cytokine responses in the pleural cavity and lung tissue, and these focal studies may be particularly relevant to patients with malignancy [21]. This is an area we plan to explore.

Although the clinical significance of the findings in this study remains to be fully elucidated, we have shown that VATS elicits a reduced inflammatory response compared with the conventional open approach. Further investigations are certainly warranted to study the other humoral and cellular components of the body inflammatory and immunologic responses—such as immunoglobulin and complement levels as well as neutrophil and lymphocyte functions. These parameters are currently under investigation independently by Walker’s group [22] and our team. The intermediate survival data following VATS lobectomy for early lung cancer have been shown to be at least as good, if not better, than the published results using the conventional thoracotomy approach [23–25]. The VATS technique, however, is almost universally associated with lesser postoperative pain and faster recovery. Elucidation of the mechanism behind these clinical benefits may have profound implications on the future development of therapeutic strategies in the management of intrathoracic malignancies.


   Acknowledgments
 
This work was supported by a grant from the Research Grant Council of the Hong Kong Special Administrative Region (CUHK 280/96 mol/L).


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication December 31, 1999.





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