Ann Thorac Surg 2007;83:252-256
© 2007 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Cytokine Response is Lower After Lung Volume Reduction Through Bilateral Thoracoscopy Versus Sternotomy
Michael E. Friscia, MDa,
Jianliang Zhu, MDa,
Jeffrey W. Kolff, MDa,
Zhen Chen, PhDb,
Larry R. Kaiser, MDa,
Clifford S. Deutschman, MDc,
Joseph B. Shrager, MDa,d,*
a Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
b Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
c Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
d Department of Surgical and Research Services, Philadelphia VA Medical Center, Philadelphia, Pennsylvania
Accepted for publication August 3, 2006.
* Address correspondence to Dr Shrager, 4 Silverstein, HUP, 3400 Spruce St, Philadelphia, PA 19104 (Email: joseph.shrager{at}uphs.upenn.edu).
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Abstract
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BACKGROUND: Lung volume reduction surgery performed through bilateral video-assisted thoracoscopy (BVATS) was associated in the National Emphysema Treatment Trial with a statistically significant reduction in intensive care unit days, failure to wean, hospital stay, and cost, and earlier recovery compared with median sternotomy. Studies comparing other minimally invasive techniques with "open" procedures, including pulmonary lobectomy, have demonstrated reduced serum proinflammatory mediators postoperatively. We measured these levels after lung volume reduction surgery through BVATS and sternotomy.
METHODS: Serum cytokine levels were measured by radioimmunoassay in 9 consecutive, steroid-free patients undergoing sternotomy and lung volume reduction surgery and 6 undergoing BVATS and lung volume reduction surgery. The groups were not statistically different with respect to age, partial pressure of arterial carbon dioxide, percent forced expiratory volume in 1 second, percent residual volume, percent total lung capacity, diffusion capacity of the lung for carbon monoxide, 6-minute walk, or apical perfusion fraction. Proinflammatory interleukin 6 and interleukin 8 and antiinflammatory interleukin 10 were evaluated preoperatively and postoperatively on days 1, 4, and 5. Clinical data were prospectively collected.
RESULTS: There were no major postoperative complications or deaths. Interleukin 6 levels were lower in the BVATS than the sternotomy group (p = 0.016 by repeated measures analysis of variance). Interleukin 8 levels were lower in the BVATS group at most postoperative time points, but there were no significant differences in interleukin 8 or interleukin 10 levels between the sternotomy and BVATS groups at any individual time point or by analysis of variance.
CONCLUSIONS: Use of a BVATS approach to lung volume reduction surgery is associated with reduced postoperative release of proinflammatory cytokines compared with a sternotomy approach. This may account for the reduction in recovery time and some measures of postoperative morbidity seen with the BVATS approach.
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Introduction
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Lung volume reduction surgery (LVRS), when compared with best medical management, results in significant functional improvement in selected patients with emphysema and improved survival in a subset of patients with upper lobe emphysema and low exercise capacity [1]. Controversy remains, however, whether bilateral LVRS is best performed through median sternotomy (MS) or video-assisted thoracoscopy. The National Emphysema Treatment Trial (NETT) Research Group reported in a separate publication that morbidity and mortality rates between the MS and bilateral video-assisted thoracoscopic (BVATS) approaches were "comparable" [2]. However, when data from centers that randomized between these two surgical approaches were analyzed, a significantly higher rate of "failure to wean" was noted in the MS group. Further, the data from nonrandomized patients revealed a trend (p = 0.10) toward a higher rate of pneumonia and statistically significant longer intensive care unit stays in the MS group. Data from both nonrandomized and randomized patients showed that the BVATS patients had significantly lower median hospital stay, time to return to independent living, and costs.
A number of minimally invasive approaches to surgical procedures have been shown to alter inflammatory cytokine and protein levels, neutrophil activation, and T-cell regulation [3–11] in ways that appear to reflect a reduction in the postoperative systemic stress response versus the corresponding "open" procedure. These findings correlate with reduced postoperative pain when comparing video-assisted thoracoscopic surgery (VATS) with thoracotomy for lobectomy in early stage lung cancer [12–14]. Increased levels of proinflammatory cytokines also have been associated with a higher incidence of postoperative infections [15] and respiratory failure [16, 17].
It was not intuitively obvious to us a priori that a single MS incision induces greater surgical stress than multiple, bilateral, intercostal VATS incisions; in fact, the inflammatory response to VATS—either unilateral or bilateral—has not to our knowledge been compared with the response to MS. The goal of this study, then, was to examine the cytokine response to bilateral LVRS through MS versus BVATS. We hypothesized that if these levels were found to be lower with the BVATS approach, that this might underlie the slightly improved outcomes documented with this approach in the NETT.
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Patients and Methods
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Fifteen consecutive patients scheduled to undergo bilateral LVRS by a single surgeon at the Hospital of the University of Pennsylvania were recruited into the study and consented to sequential blood sampling for cytokine analysis and prospective data collection. The protocol was approved by our institutional review board. The operating surgeon had performed 75 prior LVRS procedures and was highly experienced with both the BVATS and the MS techniques. The choice of surgical approach (MS or BVATS) was determined by this surgeon and the patient in nonrandomized fashion. Key factors in this determination were the surgeon’s assessment of specific patient characteristics and patient preference. Patients selected to undergo surgery had evidence of severe airflow obstruction with a forced expiratory volume in 1 second ranging from 16% to 38% predicted, diffusion capacity of the lung for carbon monoxide ranging from 29% to 75% predicted, hyperinflation with a residual volume measured by body plethysmography ranging from 191% to 323% predicted, and heterogeneous distribution of disease by computed tomography and quantitative perfusion scanning. Patients were required to spend 6 weeks in an outpatient pulmonary rehabilitation program before surgery. Individuals on corticosteroids were excluded from the study because of the known effect of steroids on cytokine production.
In the MS group, operation was performed on a supine patient through a standard, full MS incision. A bougie retractor was used to alternately elevate each hemisternum to the minimal degree that allowed sufficient exposure for adhesiolysis and resection. A single 28F chest tube was placed on each side through approximately the eighth intercostal space at the anterior axillary line. In the BVATS group, operation was performed on a patient in full lateral decubitus thoracotomy position. After completion of one side, the patient was repositioned to the opposite lateral decubitus position. The VATS technique involved three individual 2 to 3 cm intercostal incisions on each side, and a 28F chest tube was tunneled on each side through a separate skin incision to and through the most caudal of the previously created intercostal incisions.
The method of parenchymal excision in both groups was by wedge resection using a linear stapling device. In the MS group, the staple lines were reinforced with polytetrafluoroethylene strips (Gore Inc, Flagstaff, AZ); in the VATS group, no staple line reinforcements were used. In all patients, the most diseased areas as assessed by preoperative imaging or intraoperative inspection were resected with a goal of 20% to 25% lung volume reduction. All patients were extubated in the operating room, and patient-controlled epidural analgesia with fentanyl and bupivacaine was maintained until both chest tubes were removed, but at least until postoperative day (POD) 5. Ketorolac was used as needed during the first 48 hours postoperatively if not contraindicated by ulcer disease or renal insufficiency. Ibuprofen was used on an as-needed basis after 48 hours to supplement the epidural or oral narcotics. In patients with prolonged air leaks and thus prolonged chest drainage, epidurals were removed on POD 7 and oral narcotics were started. Patients with unilateral air leaks that persisted beyond 10 days without an associated large pneumothorax were managed with a Heimlich valve and discharged to home if otherwise clinically well.
Blood samples were taken from each patient preoperatively (before incision), immediately postoperatively after extubation, and on the mornings of PODs 1, 4, and 5. Samples were kept on wet ice for no longer than 1 hour before separating serum from cellular elements by centrifugation. Serum was then frozen at –80°C until the time of assay. Levels of interleukin (IL) 6, IL-8, and IL-10 were determined using commercially available enzyme-linked immunosorbent assays (Biosource International, Camarillo, CA).
For the comparison of preoperative characteristics or postoperative measures between MS and BVATS groups, we used two-tailed Student’s t test assuming unequal variances for continuous variables and Fisher’s exact tests for categorical variables (eg, presence of infection, prolonged air leak). For postoperative cytokine comparisons at each time point, we used two-tailed Student’s t test with unequal variances. We also implemented the repeated measurements analysis of variance method to test whether the cytokine levels differed after the two types of procedures. Clinical data and values of cytokines are reported as mean ± standard error of the mean. Statistical significance was set for probability values less than 0.05. Initial data were analyzed after 15 patients had been enrolled because a power analysis that we had performed suggested that this number of subjects was likely to provide significant differences on one or more of the cytokine levels measured.
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Results
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Lung volume reduction was performed through MS in 9 patients and BVATS in 6 patients. The seventh recruited BVATS patient was excluded from the study because of conversion to thoracotomy secondary to prohibitive pleural adhesions. Preoperative characteristics of the groups are shown in Table 1. Although the possibility of type II error exists with such small n, p values well above 0.05 on all of these factors suggest that there are at least not large differences between the relevant preoperative characteristics of the two groups.
Data for postoperative course are shown in Table 2. There were no postoperative deaths. One MS and 2 BVATS patients had persistent air leak after 10 days. All 3 were discharged with a Heimlich valve with chest tube removal as an outpatient. There were no other major complications. No patients required bronchoscopy postoperatively. Three patients experienced postoperative pneumonia defined by presence of fever, cough, and infiltrate on chest roentgenogram. One patient had tracheobronchitis defined by presence of productive cough and fever without infiltrate. Each of these patients was treated with a course of antibiotics, and the infection resolved. There were no other minor postoperative complications.
There was no significant difference between baseline (preoperative) levels of any of the measured cytokines in the MS versus BVATS groups. Mean serum levels of IL-6 were significantly elevated above baseline for all times measured for both MS and BVATS groups. Mean serum IL-10 values were also significantly elevated above baseline immediately postoperatively and on POD 1 but in the MS group only. Mean serum IL-8 levels were not significantly elevated over baseline at any time in either group.
When comparing cytokine responses between the two approaches, mean serum IL-6 levels were higher in the MS group than the BVATS group at all times, and this difference reached statistical significance immediately postoperatively (p = 0.03), and on POD 4 (p = 0.02) and POD 5 (p = 0.049; Fig 1). By repeated measures analysis of variance, the curves for IL-6 levels were found to be statistically different between MS and BVATS (p = 0.016) and to change significantly with time (p < 0.001). There was no significant interaction between time and procedure group for IL-6 levels.
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Fig 1. Serum interleukin 6 levels. Data are mean ± standard error of the mean. Asterisk (*) denotes p < 0.05 at that time. Repeated measures analysis of variance p = 0.016 for group effect; p < 0.001 for time effect. (BVATS = bilateral video-assisted thoracoscopy [filled diamonds and solid line]; MS = median sternotomy [open boxes and dashed line]; Postop = immediately postoperatively; Preop = immediately before incision.)
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Mean serum IL-8 and IL-10 levels did not differ significantly between the MS group and the BVATS group at any time (Figs 2, 3),
although IL-8 was substantially higher in the MS group (p = 0.10) immediately postoperatively. Interleukin 8 and IL-10 levels were also not significantly different between groups by analysis of variance, although IL-10 levels did change significantly with time.
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Fig 2. Serum interleukin 8 levels. Probability values were not significant for any time. Repeated measures analysis of variance p = 0.54 for group effect; p = 0.08 for time effect. (BVATS = bilateral video-assisted thoracoscopy [filled diamonds and solid line]; MS = median sternotomy [open boxes and dashed line]; Postop = immediately postoperatively; Preop = immediately before incision.)
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Fig 3. Serum interleukin 10 levels. Probability values were not significant for any time. Repeated measures analysis of variance p = 0.36 for group effect; p = 0.001 for time effect. (BVATS = bilateral video-assisted thoracoscopy [filled diamonds and solid line]; MS = median sternotomy [open boxes and dashed line]; Postop = immediately postoperatively; Preop = immediately before incision.)
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Comment
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The NETT established that LVRS produces significant functional improvement for patients with upper lobe emphysema and those with non–upper lobe emphysema and low exercise capacity, as well as improved survival for the subset of patients with upper lobe emphysema and a low exercise capacity [1]. The NETT also included under its aegis both a randomized (within a few institutions) and a larger nonrandomized comparison of LVRS performed through BVATS or MS. This comparison revealed that the two approaches produce similar improvements in exercise capacity, forced expiratory volume in 1 second, and general and disease-specific quality of life, with "comparable" morbidity and mortality. A careful reading of the publication reporting this analysis, however, reveals that the MS approach did, in fact, lead to a significantly higher rate of failure to wean, longer hospital stay, and longer time to recovery, and greater costs [2]. In addition, before the NETT, three of the four published retrospective case series comparing BVATS with MS for LVRS showed reduced morbidity with the BVATS approach [18–21].
We sought to determine whether there was a biochemical correlate to this increase in several measures of morbidity after LVRS through MS versus BVATS. The major finding of our study is that the BVATS approach to LVRS led to significantly lower serum levels of IL-6 at all but one postoperative time studied, and on repeated measures analysis of variance, when compared with LVRS performed through MS.
This finding is consistent with most publications focused on postoperative serum cytokine levels when comparing minimally invasive abdominal surgical procedures with the corresponding "open" approach [5, 8–11]. Several studies have compared postoperative serum IL-6 levels when performing pulmonary lobectomy using VATS versus thoracotomy for early stage lung cancer [12–14, 22, 23]. Although nearly all found more elevation of postoperative serum IL-6 levels in the thoracotomy group, Sugi and colleagues [23] found no significant changes in postoperative serum IL-6 or IL-8. However, Yim and associates [14] also found significant elevations of serum IL-8 and IL-10 in the thoracotomy group. We are not aware of any other literature comparing cytokine responses after minimally invasive versus open thoracic surgery.
Interleukin 6 and IL-8 are proinflammatory cytokines that mediate both inflammatory and immune responses [24]. Peak serum IL-6 level and its duration correlates with the magnitude of surgical trauma [25]. Reduction in the response of IL-6 after several minimally invasive procedures versus the open counterpart has correlated well with reduced postoperative pain [7, 23, 25, 26]. Administration of IL-6 can increase the response to mechanical pain in animals, and IL-6 can interact with neural tissue to alter the perception of pain [27]. Postoperative pain plays a critical role in the adequacy of pulmonary toilet after thoracic surgery. We are unaware of any published studies that directly measured pain levels after unilateral or bilateral VATS versus MS, but our findings suggest that LVRS through MS produces more pain than through BVATS. This may account for the apparently slightly increased morbidity and length of stay in the sternotomy patients found in the NETT.
Elevated markers of systemic inflammation including IL-6 have also been associated with reduced ratio of arterial partial pressure of oxygen to inspired fraction of oxygen and elevated alveolar to arterial oxygen gradients after elective abdominal aortic aneurysm repair [28]. Interleukin 6 can modulate epithelial permeability in airways [29] and may have an effect on the pulmonary vasculature [30]. It remains unclear whether elevated proinflammatory cytokine levels play a significant role in end-organ damage or are merely a marker of this damage, but any associated pulmonary dysfunction would certainly be detrimental to the recovery of severe chronic obstructive pulmonary disease patients after LVRS.
Certainly, randomization would have been the ideal study design to prove that the BVATS and MS groups were equivalent and thus that the elevated cytokine levels in the MS group did not result from some bias in selecting patients for the two approaches. We cannot with certainty rule out a role for any of the biases that can occur in a retrospective study. However, we believe that given the evidence that our MS and BVATS groups were well-matched on baseline variables (Table 1), it is reasonable to conclude that the reduced IL-6 levels after LVRS through BVATS versus MS are a result of BVATS eliciting a less severe surgical insult.
Although mortality from each surgical approach to LVRS has been demonstrated in the NETT to be equivalent, we have come to believe, consistent with the data presented here and in the NETT, that the most fragile of our LVRS candidates may benefit when a VATS approach is used. We do believe that the MS approach provides slightly better exposure for lysis of adhesions and minimizes the pitfall of removing too little lung at the time of LVRS—a pitfall that is encouraged by the magnification provided by VATS—and we therefore prefer MS for the sturdier of our LVRS candidates. However, in those older than 70 years of age or with arterial partial pressure of carbon dioxide greater than 45 mm Hg, forced expiratory volume in 1 second or diffusion capacity of the lung for carbon monoxide less than 20% predicted, a 6-minute walk distance test of less than 600 feet, homogeneous disease, or evidence of nutritional depletion, we believe that the BVATS approach is optimal. It likely reduces the early postoperative insult that these most compromised patients can least tolerate.
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Acknowledgments
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The authors would like to acknowledge Joel Cooper, MD, for his critical review of this manuscript.
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Abstract
Introduction
