EJCTS Click here to go to Edwards website
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 QUICK SEARCH:   [advanced]


     


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Craig, S.R.
Right arrow Articles by Walker, W.S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Craig, S.R.
Right arrow Articles by Walker, W.S.
Related Collections
Right arrow Lung - other

Eur J Cardiothorac Surg 2001;20:455-463
© 2001 Elsevier Science NL

Acute phase responses following minimal access and conventional thoracic surgery

S.R. Craiga, H.A. Leaverb, P.L. Yapc, G.C. Pughd, W.S. Walkera

a Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, Scotland, UK
b Department of Clinical Neurosciences, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, Scotland, UK
c Department of Clinical and Surgical Sciences, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, Scotland, UK
d Department of Anaesthetics, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, Scotland, UK

Received 9 March 2001; received in revised form 18 April 2001; accepted 31 May 2001.

Corresponding author. Tel.: +44-131-536-4183; fax: +44-131-229-0659
e-mail: wsw{at}holyrood.ed.ac.uk


    Abstract
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objectives: Major thoracic surgery is associated with trauma-related immunological changes. These may impair anti-tumour immunity. We hypothesize that the reduced operative trauma associated with a video-assisted thoracic surgery (VATS) approach may decrease acute phase responses and, consequently, lead to better preservation of immune function. This prospective randomized study compared the effects of conventional open thoracic surgery and VATS on acute phase responses in patients undergoing pulmonary lobectomy. Methods: Acute phase indicators were analyzed in patients undergoing lobectomy for suspected bronchogenic carcinoma. Surgery was prospectively randomized to pulmonary lobectomy by VATS or limited postero-lateral thoracotomy. Blood was taken pre-operatively and at 4, 24, 48, 72, 120 and 168 h post-operatively for analysis of C-reactive protein (CRP; 41 patients: open, n=22; VATS, n=19) interleukin (IL)-6, tumour necrosis factor (TNF) receptors (TNF-sR55, TNF-sR75) and P-selectin (24 patients: open, n=12; VATS, n=12). Samples taken at 48 and 168 h were also analyzed for phagocyte reactive oxygen species (ROS) production (25 patients: open, n=16; VATS, n=19). Results: Surgery increased acute phase responses. VATS was associated with lower CRP and IL-6 levels. In the open surgery group, significant increases in ROS in neutrophils (up to 36% greater than before surgery, n=12, P<0.02–0.05) were detected at 2 days after surgery, but in the VATS group, the increase after surgery (of up to 17%, n=18) did not reach significance. Similarly, monocyte ROS increases of up to 25% in the mean ROS in the open surgery group and of up to 17% in the VATS group were detected on days 2 and 7 after surgery. Conclusions: VATS pulmonary lobectomy is associated with reduced peri-operative changes in acute phase responses. This finding may have implications for peri-operative tumour immuno-surveillance in lung cancer patients.

Key Words: Acute phase • Cytokine • Minimally invasive surgery


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
The application of minimally invasive surgery for pulmonary lobectomy, utilizing video-assisted thoracic surgery (VATS), has been reported [1,2]. However, the implementation of VATS has been limited, due partly to concerns about effects on tumour recurrence and survival in patients undergoing resection for pulmonary malignancy [3,4]. However, conventional open thoracic surgery in the cancer patient is associated with immunological changes which may impair anti-tumour immunity at a critical period, and theoretically enhance the risk of tumour metastasis, recurrence, and hence, mortality [5,6]. Additionally, there is evidence that the systemic inflammatory response to cardiovascular surgery leads to hyperdynamic circulatory instability and organ dysfunction [7], which contributes towards morbidity and mortality [8].

Post-surgical changes in cytokine and acute phase mediators are associated with phagocyte and endothelial cell activation and increased reactive oxygen species (ROS) secretion [5,912]. There is evidence that minimally invasive abdominal surgery is less disruptive to metabolic and inflammatory responses than open laparotomy [10,12,13]. Currently, less is known about acute phase responses to minimally invasive thoracic surgery, whose pathophysiology differs in many respects from acute phase responses to abdominal surgery. Thus, for example, in cardio-thoracic surgery, phagocyte responses play a more prominent role and the acute phase immune response is closely connected with neutrophil activation [5,712,14]. The resultant acute phase reactants influence local vascular, immune and circulatory responses crucial to immediate and long-term survival, which also affect tumour growth, development and metastatic capability [69,11,1417]. Thus, acute phase responses play a prominent role in the immune, pulmonary and vascular responses to major thoracic surgery, but no prospective randomized analyses exist comparing these parameters in VATS and open thoracotomy lobectomy cases.


    2. Patients and methods
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
The patients have been described elsewhere [16], but are summarized in Table 1. The VATS technique [1] involved a 4–5 cm submammary incision with three stab incisions over the postero-lateral chest wall. The open approach involved a limited postero-lateral thoracotomy which avoided trapezius and the rhomboid muscles, but divided the latissimus dorsi and the posterior third of serratus anterior. The VATS operative technique used is an exact analogue of our open technique. This typically involves initial identification of the pulmonary artery and division of the fused fissures. Individual dissection and division of the hilar structures is then undertaken taking the arterial branches, lobar vein and, finally, the bronchus in turn. Equivalent nodal dissection was carried out in open and VATS cases, with both groups having undergone mediastinoscopy. Full hilar node dissection was performed and mediastinal node sampling/station excision as clinically appropriate to supplement the mediastinoscopic sampling.


View this table:
[in this window]
[in a new window]
 
Table 1. Clinical characteristics of patients undergoing conventionala and minimally invasiveb pulmonary lobectomyc,d

 
The anaesthetic and analgesic regimens were identical between the two surgical groups. Patients were admitted to a high dependency unit for 2 days following surgery in order to facilitate monitoring and sampling in this study. Post-operative pain control during this time was managed with patient-controlled morphine administration supplemented by intercostal nerve blocks as required. Oral analgesia was subsequently used. Non-steroidal drugs were omitted in both groups. Blood transfusion, which is associated with immunosuppression [14,17], was not required for any patient in this study.

The persons involved in analyses related to the study were unaware of the operative technique used. Thus, patient details were given to those carrying out the laboratory analyses, but not the surgical technique used. This code was not supplied until the end of the study. Analyses were performed on 41 patients enrolled to the study during the allocated 18 months. Only one individual carried out each test, and therefore, the number of patient samples analyzed for acute phase reactants depended on assay availability and varied between the full cohort of 41 for C-reactive protein (CRP) and the partial cohort of 24–25 for the other analyses. However, samples taken from the same day were always analyzed in full and the randomization process ensured that at least one patient from each group was analyzed on each day. Also, the mean and median tumour grades of the smaller group were not significantly different from those of the full cohort shown in Table 1 (mean grade: open group (n=12), 1.17; (n=21), 1.32; VATS group (n=12), 1.08; (n=19), 1.21; the median grade was 1 in all groups). The distribution of acute phase reactants in the larger group and the smaller group is shown for CRP in Fig. 1B and for interleukin (IL)-6 in Fig. 2B .



View larger version (21K):
[in this window]
[in a new window]
 
Fig. 1. (A) Effect of minimally invasive (VATS) and conventional (open) pulmonary lobectomy on CRP mean, CRP+SE (n=8–22), in patients undergoing either conventional pulmonary lobectomy (diamonds, continuous line) or VATS (squares, discontinuous line). The asterisk indicates results which are significantly different, comparing VATS and open surgery groups: P=0.02 (48 h); P=0.03 (120 h); **P<0.0041 (24 h) using the unpaired Student's t-test; therefore, using the Bonferroni correction for multiple comparisons at the 5% significance level, the 24 h difference was significant (P<0.007). (B) The distribution of individual patient CRP values in the open and VATS groups, described in terms of the tumour stage of individual patients. Pathological stage is denoted by the following symbols: triangle, 0 (reactive/inflammatory tissue); diamond, I (T1N0–T2N0); (square), II (T2N1–T2N1); circle, III (>T2N1 and metastases).

 


View larger version (19K):
[in this window]
[in a new window]
 
Fig. 2. (A) Effect of minimally invasive (VATS) and conventional (open) pulmonary lobectomy on IL-6. Mean IL-6+SE (n=3–12) in patients undergoing either conventional pulmonary lobectomy (diamonds, continuous line) or VATS (squares, discontinuous line). The asterisk indicates results which are significantly different, comparing VATS and open surgery groups: P=0.035 (24 h); P=0.031 (48 h); P=0.032 (120 h), using the unpaired Student's t-test. However, using the Bonferroni correction for seven multiple comparisons at the 5% significance level, these three results did not reach significance (P<0.07). (B) The distribution of individual patient IL-6 values within each group are described in terms of the tumour stage of individual patients. Pathological stages of each individual are denoted by the following symbols: triangle, 0 (reactive/inflammatory tissue); diamond, I (T1N0–T2N0); square, II (T2N1–T2N1); circle, III (>T2N1 and metastases).

 
Clinical outcomes such as septic complications, pain profiles, air leak, post-operative stay and mortality were recorded as part of an ongoing audit of patients undergoing open and VATS major pulmonary resection in the thoracic surgical unit. Patients were allocated randomly to alternative study groups on the day of surgery. Between two and five patients were in the unit and within the study on each operating day. Thus, at least one patient from each group was always present in the assay samples.

2.1. Sampling details
Blood samples were collected in EDTA (2 mg/ml) before operation and at 4, 24, 48, 72, 120 and 168 h post-operatively. Blood for analysis of CRP, IL-6, TNF-sR and P-selectin was stored on ice and centrifuged at 4°C within 20 min of withdrawal and stored at -70°C for 3–12 months before analysis. Samples taken pre-operatively and at 48 and 168 h were analyzed for T and B lymphocytes, CD4, CD8, natural killer (NK) cell populations (see [16]) and for monocyte, neutrophil and lymphocyte ROS production. These samples were analyzed within 4 h of withdrawal. Blood from healthy donors, withdrawn at the same time was used as a contemporary control.

2.2. CRP, IL-6, tumour necrosis factor, tumour necrosis factor receptor and P-selectin
These were analyzed using previously described methods [18]. Serum CRP concentration was measured by laser nephelometry (Behring, Marburg, Germany; sensitivity, 2.5 mg/l). Plasma IL-6, soluble human TNF-R type I/II (p55/p75) and P-selectin were measured using monoclonal antibodies (Monosan, Brussels, Belgium and British Biotechnology, London, respectively) and an enzyme-linked immunoassay.

2.3. Leucocyte ROS
Leukocyte preparations, purified within 2 h of venepunture using hypotonic lysing solution (Ortho-lyse), were incubated for 10 min at 37°C with 5 M 2',7'-dichlorofluorescein diacetate (Kodak, Harrow, UK). The cell viability was >85% using cell permeability to ethidium homodimer [19] and was not significantly different between patient and control leukocytes. Flow cytometry of patient and control samples was carried out using an Ortho flow cytometer with Immunocount software and Ortho-count calibration (Ortho, High Wycombe, UK). ROS production was analyzed in mononuclear and polymorphonuclear phagocytes from the same individual. The rate of ROS generation was analyzed using flow cytometry in duplicate patient and control samples at 30 s intervals [9,16,19]. Oxidative activity was determined for 7 min before, then for 13 min after the addition of n-6 essential fatty acid, using arachidonic acid (AA; Sodium salt, Sigma, Poole, UK) or gamma-linolenic acid (GLA; Lithium salt, Scotia Pharmaceuticals, Stirling, UK) or saline control. Preliminary analysis indicated a normal distribution of fluorescence, and therefore, the mean fluorescence of phagocyte populations was used to estimate ROS generation. Monocytes were identified using Coulter anti-CD57 and Scottish Antibody Production Unit UCHMI antibodies, and neutrophils were routinely identified using Ortho anti-CD16 to detect the Fc{gamma} III receptor for aggregated and immune complex IgG and anti-CD65 (Coulter, High Wycombe, UK) against the granulocyte fucoganglioside antigen.

2.4. Statistical analysis
The data were analyzed using the Statistical Analysis Software (SAS Institute, Inc., North Carolina, 1991) program. The data were compared using the Student's t-test, after checking for normality of distribution, or the Wilcoxon signed rank test for non-normally distributed data. Changes within groups were analyzed using the paired t-test, pairing results from the same individual before and after surgery. Differences between groups were analyzed using the unpaired t-test. The Bonferroni correction was utilized for multiple comparisons.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
3.1. CRP, IL-6, soluble tumour necrosis factor receptors and P-selectin
Increases in plasma CRP, IL-6, soluble TNF-R p-55 and p-75 concentrations were observed in both patient groups after surgery. The increase in CRP in open surgery and VATS groups followed similar kinetics, increasing at 24 h by 8–14-fold, reaching a maximum at approximately 48 h and declining over the subsequent 72–168 h period (Fig. 1A). However, the mean circulating CRP in the conventional open surgery group was detected earlier than that in the VATS group. Thus, at 4 h after surgery, the CRP in patients in the open surgery group was significantly elevated compared with pre-surgical CRP levels (P=0.033, using Wilcoxon signed rank test). The increase in CRP at 4 h after surgery in VATS patients was not significantly different from the pre-surgical CRP value using the same test. Significant differences between CRP concentrations in VATS and open surgery groups were detected at 24 h.

The distribution of individual patient CRP values in the open surgery and the VATS groups are described in terms of the tumour stage of individual patients (Fig. 1B). In contrast to IL-6 release into the circulation after open surgery, elicited CRP concentrations appeared to be independent of stage, although there was possible evidence of an elevated pre-surgical release of these reactants in both surgical groups in the patients with higher grade tumours (grey symbols).

The response of the cytokine IL-6 to surgery also showed a lower peak concentration in the VATS group, compared with the conventional open surgery group (Fig. 2A). The mean plasma IL-6 increased rapidly in both open surgery and VATS groups 4 h after surgery (P=0.025 in the open group and P=0.002 in the VATS group, using the Wilcoxon signed rank test to compare pre-surgical and 4 h post-surgical IL-6 in the same individuals). The peak IL-6 in the VATS group appeared to occur earlier, compared with peak IL-6 in the open surgery group. The distribution of individual patient IL-6 values within each group are described in terms of the tumour stage of individual patients (Fig. 2B). This indicates that the range of IL-6 released into the circulation after open surgery is wider than that elicited in the VATS group. Comparison of post-surgical IL-6 levels released from high grade tumours (grey symbols) in the two groups raises the intriguing possibility that the exaggerated CRP response detected in high grade patients may be attenuated in patients undergoing VATS.

The responses in the tumour necrosis factor (TNF) receptors and in P-selectin were smaller than those of the acute phase metabolites, CRP and IL-6. TNF-sR55 and TNF-sR75 release during cardiopulmonary procedures have been demonstrated and there is evidence that TNF-sR55 may mediate cellular responses such as neutrophil activation [8,20]. TNF-sR75 shows a distinct pattern of release and activity, but may be associated with immunoregulation rather than inflammatory activity. An increase in plasma concentrations of 1–2 mg/l of both TNF-R55 and TNF-R75 was observed in both patient groups 48–168 h post-surgery. When plasma TNF-sR55 levels in VATS and conventional open surgery groups were directly compared, the difference between surgical groups was not significant. However, a greater post-operative increase in TNF-sR55 (compared with the pre-surgical TNF-sR55 in the same patient) was observed in the conventional open surgery group (data not shown). When the plasma TNF-R75 levels in VATS and conventional open surgery groups were compared, no significant difference between surgical groups was observed (data not shown). P-selectin in the circulation is an indicator of endothelial cell–leucocyte interaction and is elevated in severe trauma. When circulating P-selectin concentrations in the two surgical groups were directly compared, no difference between VATS and open surgery groups was detected. However, when the post-surgical change within each group was monitored, a decrease in the release of P-selectin was detected in the VATS group 24 h after surgery, while the conventional open surgery group showed a more gradual, but more sustained increase in P-selectin.

3.2. Neutrophil and monocyte ROS
Both monocyte and neutrophil ROS production were stimulated by up to 40% on post-operative day 2 compared with leukocytes from healthy controls analyzed at the same time (Figs. 3 and 4) . The pre-surgical neutrophil ROS was approximately 10% above the control ROS, which may indicate local pulmonary inflammatory processes (Fig. 4). AA and GLA consistently stimulated neutrophil and monocyte ROS by up to 40% and this stimulated ROS, when compared with control stimulation, was also upregulated after surgery. Significant increases in neutrophil ROS were detected in the conventional open surgery group, but not in the VATS group (Fig. 4). Similarly, monocyte ROS increased after surgery in the conventional open surgery group compared with ROS in normal control monocytes (Fig. 3).



View larger version (26K):
[in this window]
[in a new window]
 
Fig. 3. Effect of minimally invasive (VATS) and conventional (open) pulmonary lobectomy monocyte ROS production. ROS in open surgery and VATS patients: (0), before surgery; and (2 and 7), in the same patients 2 and 7 days after surgery. Mean basal rates of ROS formation in patient samples were expressed as the percentage of normal control ROS. Black bars indicate basal ROS and grey bars indicate n-6 fatty acid stimulated ROS. Error bars indicate the SE of 9–19 samples. Patient ROS were compared with control ROS using the Mann–Whitney U-test, and patient/control ROS ratios significantly different from pre-surgical ratios are indicated using the following superscripts: a, unstimulated d2, P=0.011; b, stimulated d2, P=0.046; c, unstimulated d7, P=0.02; d, stimulated d7, P=0.025.

 


View larger version (36K):
[in this window]
[in a new window]
 
Fig. 4. Effect of minimally invasive (VATS) and conventional (Open) pulmonary lobectomy on neutrophil ROS production. ROS in open surgery and VATS patients, before surgery (day 0) and in the same patients 2 and 7 days after surgery (2 and 7). Mean basal rates of ROS production in patient samples were expressed as the percentage of normal control ROS production. Black bars indicate basal ROS and grey bars indicate n-6 fatty acid stimulated ROS and SE in 9–19 paired samples. Patient ROS was compared with control ROS using the Mann–Whitney U-test, and patient/control ROS ratios significantly different from pre-surgical ratios are indicated using the following superscripts: a, stimulated d2, P=0.02; b, stimulated d7, P=0.043.

 
3.3. Patient outcomes
Three patients initially randomized to open surgery refused to proceed with this option prior to surgery and were withdrawn from the study. They were subsequently operated on using a VATS approach outwith the study and have been excluded from the analyses.

All patients survived and were discharged well. The duration of surgery, length of stay and pathological characteristics are listed in Table 1. These do not differ significantly, although it should be noted that, except for a few patients who lived locally in regard to the hospital, the minimum length of stay was defined by the 7 day sampling requirement. Important complications occurred in two VATS cases and four open cases. One VATS case with severe intrapleural adhesions bled from pleural adhesions and developed secondary lung collapse which required several days to reinflate; the other had very poor pre-operative respiratory function with persistent smoking and required ventilatory support for 32 h. Three of the open cases developed post-operative pulmonary infections which required minitracheostomy in two cases and suction bronchoscopy in one; the other complicated open case experienced troublesome cardiac dysrythmias.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Changes in the immune system following surgery for cancer may provide information relevant to the short-term and long-term patient survival. Surgery, anaesthetics and transfusion influence the production of humoral mediators, including lipid mediators, cytokines, acute phase proteins, adrenocorticoids, catecholamines and local mediators, including ROS [79,11,12,1417]. These mediators have profound effects on the metabolic responses to trauma, including effects on cellular immunity and on vascular function, affecting vascular permeability, vascular and organ function and tissue catabolism after thoracic surgery. Minimally invasive thoracic surgery utilizing VATS techniques has shown benefits in terms of reduction in pain and related morbidity [1,2]. VATS lobectomy is technically demanding and, for this reason, training of thoracic surgeons in VATS procedures is crucial [1]. We have argued, however, that VATS pulmonary lobectomy is technically feasible, provides considerable benefit in the peri-operative period and is safe in skilled hands. Furthermore, we and others have suggested that the reduction in surgical trauma and immune suppression associated with VATS may have a considerable impact on the surgical management of stage I lung cancer surgery patients.

In this study, we have compared pulmonary lobectomy using a VATS approach to a limited conventional open thoracotomy. It could be argued that stage I lesions are resected using either a muscle sparing or limited axillary thoracotomy in some centres, both of which might be less traumatic than our open thoracotomy model. However, the open thoracotomy approach we used is in widespread general use, provides a consistent reference point and offers good access to the chest. It would have complicated our study to have utilized an alternative type of thoracotomy which may have required conversion in some cases to a more extended procedure and might be less applicable to general thoracic surgical practice.

Our results suggest that the VATS approach was associated with less tissue and vascular trauma, and consequently, reduced the activity of acute phase associated cytokines and their receptors (IL-6, TNF-sR55) and mediators (CRP, ROS) and effector cells of cellular immunity. In the same patients, we observed less adverse immunological responses with a minimally invasive VATS approach to pulmonary resection when circulating lymphocyte numbers were analyzed [16]. The effects of surgery on acute phase responses occurred before the decrease in lymphocyte numbers and oxidative activity observed in the same patients.

Quantitatively, the greatest difference between VATS and the conventional open surgery groups were observed in CRP and IL-6 (Figs. 1 and 2). CRP and IL-6 are acute phase response markers associated with post-operative complications such as respiratory distress syndrome and multiple organ failure [21,22]. Differences between surgical groups were also observed in the kinetics of IL-6 and soluble TNF-R (p55 and p75) responses. A transient but significant increase in IL-6 was detected in the VATS group 4 h post-operatively (Fig. 2). The earlier peak in IL-6 in the VATS cases may be partly due to the earlier onset (by approximately 15 min) of pulmonary retraction and hilar dissection in this group and to the slightly longer mean operative duration (141 min VATS vs. 121 min open). This evidence of very early IL-6 responses requires further investigation using more frequent intra-operative and early post-operative sampling.

Smaller differences were observed when post-surgical changes in soluble TNF-R (p55 and p75) were monitored. TNF-sR55 and TNF-sR75 are released in a wide range of immune responses and TNF-sR55 was associated with mortality in patients undergoing cardiopulmonary bypass [8]. An increase in the plasma concentrations of TNF-sR55 and TNF-sR75 was observed in both patient groups 48–168 h post-surgery. The difference between surgical groups was not, overall, significant, but in the open surgery group, the increase in TNF-sR55 was approximately 20% greater than in the conventional open surgery group.

There is evidence in patients undergoing cardio-thoracic surgery that, although certain cytokine responses result in homeostasis, the catabolic state elicited by acute phase mediators may be serious or fatal [21,22]. Therefore, the duration, as well as the extent of cytokine and ROS release during the post-surgical period may be critical to organ function and anti-tumour responses. This study is consistent with reports that minimally invasive abdominal surgery is associated with an attenuation of acute phase and phagocyte responses [12,13]. Currently, less is known about acute phase responses to minimally invasive thoracic surgery, whose pathophysiology differs in many respects from responses to abdominal surgery. Thus, for example, in cardio-thoracic surgery, the acute phase immune response is closely connected with neutrophil activation. The resultant acute phase reactants influence local immune and circulatory responses crucial to the immediate and long-term survival, which also affect tumour growth, development and metastatic capability.

A neutrophil leukocytosis is common in the post-operative period. The production of ROS by phagocytes is upregulated by intrinsic and extrinsic stimuli [5,20,23]. These stimuli may be generated during invasive procedures, as humoral factors released during dialysis have been reported to stimulate monocyte and neutrophil ROS using the same assay used to detect ROS in the current study [23]. We detected upregulation of phagocyte ROS after pulmonary resection, but, in common with other acute phase responses, the mean increase in ROS was lower in the VATS group (Figs. 3 and 4). This has functional implications, as it has been reported that the neutrophil population circulating after surgery may function inadequately in antibacterial defence [5,12]. Defects in neutrophil chemotaxis, phagocytosis, lysosomal enzyme content and antibacterial defence processes have also been identified in patients following surgery [5,9]. There is evidence that minimally invasive surgery may affect phagocyte responsiveness less than conventional open surgery [10,12,14]. This is consistent with the results of this study, which detected upregulation in phagocyte activity after pulmonary resection, and an associated decline in the ability of phagocytes to undergo an oxidative burst stimulated by the intracellular signalling molecule, arachidonic acid. A previous analysis of mononuclear and polymorphonuclear phagocyte activation by arachidonic acid in vitro also indicated a lower response to arachidonic acid after surgery [9].

The interaction between phagocytes and tumour cells and their products are complex. However, phagocyte infiltration and activation may limit tumour growth [24]. ROS are involved in cytotoxic reactions involving phagocytes, and we have also demonstrated tumour-associated ROS activity stimulated by arachidonic acid which may be involved in tumour apoptosis [25]. In summary, therefore, major surgery is associated with abnormalities of phagocyte function and our results are consistent with reports of a decreased effect of minimally invasive surgery on phagocyte activation.

The release of P-selectin, which is expressed in the effector phase of leukocyte recruitment, was used to monitor endothelial cell activation and tissue damage, as elevated selectin levels have been reported in organ dysfunction, including pulmonary trauma [11]. No significant differences in P-selectin between surgical groups were detected after surgery, but, when post-surgical changes within individuals were compared, an gradual increase in P-selectin was detected in the open surgery group. Thus, greater release of the cytokine, IL-6, and the acute phase reactants, CRP and phagocyte ROS, in the open surgery group was followed by evidence of greater endothelial cell–leukocyte interaction detected using P-selectin.

The results obtained in this study suggest that VATS pulmonary lobectomy, when compared with a limited conventional open thoracotomy, was associated with less traumatic insult to the patient, and consequently, reduced the activity of the acute phase cytokine IL-6 and mediators (CRP, ROS) and effector cells of cellular immunity. We have also demonstrated in this patient group that VATS was associated with less effect on circulating T (CD4) cells at 2 days after surgery and on NK lymphocytes at 7 days after surgery [16]. Thus, in this patient group, there is evidence that elements of both specific anti-tumour immunity (T and NK cells) and non-specific secondary immunity (phagocyte responses) were less affected in the VATS group. These data suggest that, during surgery, the degree of procedural invasiveness may influence the extent of immunosuppression in patients undergoing lobectomy for pulmonary neoplasm. The specific molecular and cellular interactions which underlie these phenomena remain to be determined, but, from a clinical perspective, it is apparent that the choice of an open or VATS operative strategy may have implications for tumour recurrence and long-term survival in lung cancer patients.


    Acknowledgments
 
The authors are very grateful to: Helen Mason and Jim Whitelaw of HIV and Clinical Immunology for flow cytometry facilities; Dr S. Burns and her staff at the Regional Virology Laboratory, City Hospital, Edinburgh for separating and storing blood samples; Dr J.A. Ross, Department of Surgery, Royal Infirmary of Edinburgh, for cytokine assays; Dr J. Gillon, Regional Blood Transfusion Unit, for control samples; Heather Peterson, Edinburgh Neuro-Oncology Centre, Western General Hospital, Edinburgh for help with computer facilities; and Dr R. Prescott, Department of Medical Statistics, Edinburgh University for help with statistical analyses.


    References
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

  1. Walker W.S. Major pulmonary resection. In: Walker W.S., ed. Video-assisted thoracic surgery. Oxford: Isis Medical Media, 1999:135-159.
  2. Iwasaki A., Shirakusa T., Kawahara K., Yoshinaga Y., Okabayashi K., Shiraishi T. Is video-assisted thorascopic surgery suitable for resection of primary lung cancer?. Thorac Cardiovasc Surg 1997;45:13-15.[Medline]
  3. Lewis R.J., Caccavale R.J., Sisler G.E., Bocage J.P. Does VATS favor seeding of carcinoma of the lung more than a conventional operation?. Int Surg 1997;82:127-130.[Medline]
  4. Buhr J., Hurtgen M., Kelm C., Schwemmle K. Tumor dissemination after thoracoscopic resection for lung cancer. J Thorac Cardiovasc Surg 1995;110:855-856.[Free Full Text]
  5. Christou N.V., Meakins J.L. Phagocytic and bactericidal functions of polymorphonuclear neutrophils from anergic surgical patients. Can J Surg 1982;25:444-448.[Medline]
  6. Pollock R.E., Lotzova E., Stanford S.D. Surgical stress impairs natural killer cell programming of tumour for lysis in patients with sarcomas and other solid tumours. Cancer 1992;70:2192-2202.[Medline]
  7. Cremer J., Martin M., Redl H., Bahrami S., Abraham C., Graeter T., Haverich A., Schlag G., Borst H.G. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714-1720.[Abstract/Free Full Text]
  8. Saatvedt K., Lindberg H., Michelsen S., Pedersen T., Seem E., Geiran O. Release of soluble tumour necrosis factor alpha receptors during and after paediatric cardiopulmonary bypass. Correlation with haemodynamic and clinical variables. Cytokine 1996;8:944-948.[Medline]
  9. Leaver H.A., Craig S.R., Yap P.L., Williams J.R., Walker W.S. Arachidonic acid activation of monocyte and neutrophil reactive oxygen in lung cancer patients undergoing pulmonary resection. Biologicals 1996;24:319-324.[Medline]
  10. Klava A., Windsor A., Boylston A.W., Reynolds J.V., Ramsden C.W., Guillou P.J. Monocyte activation after open and laparoscopic surgery. Br J Surg 1997;84:1152-1156.[Medline]
  11. Ortmann C., Brinkmann B. The expression of P-selectin in inflammatory and non-inflammatory lung tissue. Int J Legal Med 1997;110:155-158.[Medline]
  12. Carey P.D., Wakefield C.H., Thayeb A., Monson J.R., Darzi A., Guillou P.J. Effects of minimally invasive surgery on hypochlorous acid production by neutrophils. Br J Surg 1994;81:557-560.[Medline]
  13. Schietroma M., Risetti A., Carlei F., Maggi G., Cianca G., DeSantis C. Response of IL-6 in patients undergoing laparoscopic or laparotomic cholecystectomy. Minerva Chir 1998;53:359-362.[Medline]
  14. Walker W.S., Leaver H.A., Yap P.L. The immune response to surgery: conventional and video assisted thorascopic pulmonary lobectomy. In: Yim A.P.C., ed. Minimal access cardiothoracic surgery. Philadelphia, PA: Saunders, 1999:127-134.
  15. Yamaguchi H., Kobayashi E., Yoshida T., Kiyozaki H., Kohyama R., Suminaga Y., Sakurabayashi A., Fujimura A., Miyata M. Changes in immune–endocrine response after surgery. Cytokine 1998;10:549-554.[Medline]
  16. Leaver H.A., Craig S.R., Yap P.L., Walker W.S. Lymphocyte responses following open and minimally invasive thoracic surgery. Eur J Clin Invest 2000;30:230-238.[Medline]
  17. Ross W.G., Leaver H.A., Yap P.L., Raab G.M., Su B.H., Carter D.C., Mao J.H., Quian W., Prescott R.J. Macrophage prostaglandin E2 and oxidative responses to endotoxin during immunosuppression associated with anaesthesia and transfusion. Prostaglandins Leukot Essent Fatty Acids 1992;42:945-954.
  18. de Beaux A.C., Goldie A.S., Ross J.A., Carter D.C., Fearon K.C. Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis. Br J Surg 1996;83:349-353.[Medline]
  19. Leaver H.A., Yap P.L., Rogers P., Wright I., Smith G., Williams P.E., France A.J., Craig S., Walker W.S., Prescott R.J. Peroxides in human leucocytes in acute septic shock: a preliminary study of acute phase changes and mortality. Eur J Clin Invest 1995;25:777-783.[Medline]
  20. Menegazzi R., Cramer R., Patriarca P. Evidence that TNF{alpha} induced activation of neutrophil respiratory burst on biological surfaces is mediated by the p55 TNF receptor. Blood 1994;84:287-293.[Abstract/Free Full Text]
  21. Oka Y., Murata A., Nishijima J., Yasuda T., Hiraoka N. Circulating IL-6 as a useful marker for predicting post-operative complications. Cytokine 1992;4:298-304.[Medline]
  22. Roumen R.M., Hendricks T., Ven-Jongekrijg J., Nieuwenhuijzen G.A., Sauerwein R.W. Cytokine patterns in patients after major vascular surgery: relation with adult respiratory distress syndrome and multiple organ failure. Ann Surg 1993;218:769-776.[Medline]
  23. Himmelfarb J., Lazarus J.M., Hakim R. Reactive oxygen species production by monocytes and polymorphonuclear leukocytes during dialysis. Am J Kidney Dis 1991;17:271-276.[Medline]
  24. Jerrells T.R., Dean J.H., Richardson G., Cannaon G.B., Herbman R.B. Increased monocyte mediated cytostasis of lymphoid cell lines in breast and lung cancer patients. Int J Cancer 1979;23:768-776.[Medline]
  25. Williams J.R., Leaver H.A., Ironside J.W., Miller E.P., Whittle I.R., Gregor A. Apoptosis in human primary brain tumours: actions of arachidonic acid. Prostaglandins Leukot Essent Fatty Acids 1998;58:193-200.[Medline]



This article has been cited by other articles:


Home page
Asian Cardiovasc. Thorac. Ann.Home page
C. S. Ng, I. Y. Wan, and A. P. Yim
Impact of Video-Assisted Thoracoscopic Major Lung Resection on Immune Function
Asian Cardiovasc Thorac Ann, August 1, 2009; 17(4): 426 - 432.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
R. M. Flores, B. J. Park, J. Dycoco, A. Aronova, Y. Hirth, N. P. Rizk, M. Bains, R. J. Downey, and V. W. Rusch
Lobectomy by video-assisted thoracic surgery (VATS) versus thoracotomy for lung cancer
J. Thorac. Cardiovasc. Surg., July 1, 2009; 138(1): 11 - 18.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
C. W. Seder, K. Hanna, V. Lucia, J. Boura, S. W. Kim, R. J. Welsh, and G. W. Chmielewski
The safe transition from open to thoracoscopic lobectomy: a 5-year experience.
Ann. Thorac. Surg., July 1, 2009; 88(1): 216 - 226.
[Abstract] [Full Text] [PDF]


Home page
Asian Cardiovasc. Thorac. Ann.Home page
J. Loscertales, R. Jimenez-Merchan, M. Congregado, F. J. Ayarra, G. Gallardo, and A. Trivino
Video-Assisted Surgery for Lung Cancer. State of the Art and Personal Experience
Asian Cardiovasc Thorac Ann, June 1, 2009; 17(3): 313 - 326.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
T. D. Yan, D. Black, P. G. Bannon, and B. C. McCaughan
Systematic Review and Meta-Analysis of Randomized and Nonrandomized Trials on Safety and Efficacy of Video-Assisted Thoracic Surgery Lobectomy for Early-Stage Non-Small-Cell Lung Cancer
J. Clin. Oncol., May 20, 2009; 27(15): 2553 - 2562.
[Abstract] [Full Text] [PDF]


Home page
ICVTSHome page
A. Tajima, M. Kohno, M. Watanabe, Y. Izumi, S. Tasaka, I. Maruyama, T. Miyasho, and K. Kobayashi
Occult injury in the residual lung after pneumonectomy in mice
Interactive CardioVascular and Thoracic Surgery, December 1, 2008; 7(6): 1114 - 1120.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. O. Jones, G. Casali, and W. S. Walker
Does Failed Video-Assisted Lobectomy for Lung Cancer Prejudice Immediate and Long-Term Outcomes?
Ann. Thorac. Surg., July 1, 2008; 86(1): 235 - 239.
[Abstract] [Full Text] [PDF]


Home page
J. Thorac. Cardiovasc. Surg.Home page
D. G. Nicastri, J. P. Wisnivesky, V. R. Litle, J. Yun, C. Chin, F. R. Dembitzer, and S. J. Swanson
Thoracoscopic lobectomy: Report on safety, discharge independence, pain, and chemotherapy tolerance
J. Thorac. Cardiovasc. Surg., March 1, 2008; 135(3): 642 - 647.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
R. M. Flores and N. Alam
Video-Assisted Thoracic Surgery Lobectomy (VATS), Open Thoracotomy, and the Robot for Lung Cancer
Ann. Thorac. Surg., February 1, 2008; 85(2): S710 - S715.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
T. L. Demmy and C. Nwogu
Is Video-Assisted Thoracic Surgery Lobectomy Better? Quality of Life Considerations
Ann. Thorac. Surg., February 1, 2008; 85(2): S719 - S728.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
T. J. Szczesny, R. Slotwinski, B. Szczygiel, A. Stankiewicz, M. Zaleska, M. Kopacz, and A. Olesinska-Grodz
Systematic mediastinal lymphadenectomy does not increase postoperative immune response after major lung resections
Eur. J. Cardiothorac. Surg., December 1, 2007; 32(6): 868 - 872.
[Abstract] [Full Text] [PDF]


Home page
JCOHome page
S. J. Swanson, J. E. Herndon II, T. A. D'Amico, T. L. Demmy, R. J. McKenna Jr, M. R. Green, and D. J. Sugarbaker
Video-Assisted Thoracic Surgery Lobectomy: Report of CALGB 39802 A Prospective, Multi-Institution Feasibility Study
J. Clin. Oncol., November 1, 2007; 25(31): 4993 - 4997.
[Abstract] [Full Text] [PDF]


Home page
The OncologistHome page
P. Solli and L. Spaggiari
Indications and Developments of Video-Assisted Thoracic Surgery in the Treatment of Lung Cancer
Oncologist, October 1, 2007; 12(10): 1205 - 1214.
[Abstract] [Full Text] [PDF]


Home page
Br J AnaesthHome page
T. Schilling, A. Kozian, M. Kretzschmar, C. Huth, T. Welte, F. Buhling, G. Hedenstierna, and T. Hachenberg
Effects of propofol and desflurane anaesthesia on the alveolar inflammatory response to one-lung ventilation
Br. J. Anaesth., September 1, 2007; 99(3): 368 - 375.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
T. J. Szczesny, R. Slotwinski, A. Stankiewicz, B. Szczygiel, M. Zaleska, and M. Kopacz
Interleukin 6 and interleukin 1 receptor antagonist as early markers of complications after lung cancer surgery
Eur. J. Cardiothorac. Surg., April 1, 2007; 31(4): 719 - 724.
[Abstract] [Full Text] [PDF]


Home page
ICVTSHome page
D. West, S. Rashid, and J. Dunning
Does video-assisted thoracoscopic lobectomy produce equal cancer clearance compared to open lobectomy for non-small cell carcinoma of the lung?
Interactive CardioVascular and Thoracic Surgery, February 1, 2007; 6(1): 110 - 116.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
M. E. Friscia, J. Zhu, J. W. Kolff, Z. Chen, L. R. Kaiser, C. S. Deutschman, and J. B. Shrager
Cytokine Response is Lower After Lung Volume Reduction Through Bilateral Thoracoscopy Versus Sternotomy
Ann. Thorac. Surg., January 1, 2007; 83(1): 252 - 256.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
D. Amar, A. Goenka, H. Zhang, B. Park, and H. T. Thaler
Leukocytosis and increased risk of atrial fibrillation after general thoracic surgery.
Ann. Thorac. Surg., September 1, 2006; 82(3): 1057 - 1061.
[Abstract] [Full Text] [PDF]


Home page
ChestHome page
M. E. Froudarakis, M. Klimathianaki, and M. Pougounias
Systemic inflammatory reaction after thoracoscopic talc poudrage.
Chest, February 1, 2006; 129(2): 356 - 361.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
M. Jinbo, K. Ueda, Y. Kaneda, M. Sudo, T.-S. Li, and K. Hamano
Video-assisted transcatheter lung perfusion regional chemotherapy
Eur. J. Cardiothorac. Surg., June 1, 2005; 27(6): 1079 - 1082.
[Abstract] [Full Text] [PDF]


Home page
SEMIN CARDIOTHORAC VASC ANESTHHome page
K. P. Grichnik and T. A. D'Amico
Acute Lung Injury and Acute Respiratory Distress Syndrome After Pulmonary Resection
Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2004; 8(4): 317 - 334.
[Abstract] [PDF]


Home page
BMJHome page
A. Sedrakyan, J. van der Meulen, J. Lewsey, and T. Treasure
Video assisted thoracic surgery for treatment of pneumothorax and lung resections: systematic review of randomised clinical trials
BMJ, October 30, 2004; 329(7473): 1008.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
S. Endo, Y. Sato, T. Hasegawa, K. Tetsuka, S. Otani, N. Saito, Y. Tezuka, and Y. Sohara
Preoperative chemotherapy increases cytokine production after lung cancer surgery
Eur. J. Cardiothorac. Surg., October 1, 2004; 26(4): 787 - 791.
[Abstract] [Full Text] [PDF]


Home page
Ann. Thorac. Surg.Home page
F. Gharagozloo, B. Tempesta, M. Margolis, and E. P. Alexander
Video-assisted thoracic surgery lobectomy for Stage I lung cancer
Ann. Thorac. Surg., October 1, 2003; 76(4): 1009 - 1015.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
W. S. Walker, M. Codispoti, S. Y. Soon, S. Stamenkovic, F. Carnochan, and G. Pugh
Long-term outcomes following VATS lobectomy for non-small cell bronchogenic carcinoma
Eur. J. Cardiothorac. Surg., March 1, 2003; 23(3): 397 - 402.
[Abstract] [Full Text] [PDF]


Home page
Eur. J. Cardiothorac. Surg.Home page
P. Thomas, C. Doddoli, S. Yena, X. Thirion, F. Sebag, P. Fuentes, and R. Giudicelli
VATS is an adequate oncological operation for stage I non-small cell lung cancer
Eur. J. Cardiothorac. Surg., June 1, 2002; 21(6): 1094 - 1099.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Craig, S.R.
Right arrow Articles by Walker, W.S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Craig, S.R.
Right arrow Articles by Walker, W.S.
Related Collections
Right arrow Lung - other


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS