Eur J Cardiothorac Surg 2007;32:431-434. doi:10.1016/j.ejcts.2007.06.017
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Inflammation and outcome after general thoracic surgery
David Amara,*,
Hao Zhanga,
Bernard Parkb,
Paul M. Heerdta,
Martin Fleisherc,
Howard T. Thalerd
a Department of Anesthesiology and Critical Care Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, United States
b Department of Surgery, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, United States
c Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, United States
d Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, United States
Received 19 April 2007;
received in revised form 14 June 2007;
accepted 18 June 2007.
* Corresponding author. Address: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, M-304, New York, NY 10021, United States. Tel.: +1 212 639 6798; fax: +1 212 772 8646. (Email: amard{at}mskcc.org).
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Abstract
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Objective: To determine whether preoperative inflammation predisposes to major postoperative complications (PC) and poor outcome. Methods: Prospective data collection of 153 consecutive patients aged 73 ± 6 years scheduled for lung resection at a tertiary cancer center. High sensitivity C-reactive protein (CRP) and interleukin (IL)-6 levels were measured before surgery, on arrival to the postanesthesia care unit, and on the first morning after surgery. Results: PC occurred in 9/153 (5.9%) patients. In comparison to patients without PC, those with PC had a greater history of hypertension (P
= 0.047), higher frequency of non-steroidal anti-inflammatory drug use (P
= 0.007) and had a lower preoperative albumin level, 3.75 ± 0.65 g/dl versus 4.28 ± 0.33 g/dl, P
= 0.03. Receiver operating characteristic analysis demonstrated a strong association between PC and preoperative CRP (area under the curve of 0.86), albumin (area under the curve of 0.86) and less so for IL-6 (area under the curve of 0.79). Conclusions: Markers of inflammation, CRP and IL-6, can help distinguish patients who are at high risk for major PC. These preliminary and novel data suggest that in addition to low albumin, a previously described marker of outcome, systemic inflammation is likely to be important in the pathogenesis of important PC.
Key Words: Albumin • C-reactive protein • Interleukin-6
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1. Introduction
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Significant postoperative complications (PC) are seen in more than 20% of patients undergoing non-cardiac thoracic surgery and are associated with an extended hospital stay and related costs [1]. The usefulness of a low albumin level prior to thoracic surgery in order to predict PC has been described [2–4]. Our ability to further identify those patients at greatest risk for PC is limited. A better understanding of the mechanisms responsible for major PC could help design more targeted and novel prophylactic or therapeutic measures. Evidence linking inflammation to PC was suggested in two studies of patients undergoing thoracic surgery [5,6]. The magnitude of the systemic inflammatory state, which often can be measured with high sensitivity C-reactive protein (CRP), has been found to predict the duration of cancer and non-cancer related survival [7]. Activation of the complement system and release of pro-inflammatory cytokines occur early after surgery, suggesting the presence of an intense inflammatory process [8,9]. The thought of having a highly sensitive, albeit nonspecific, predictor of significant postoperative morbidity in elderly patients is appealing. Therefore, this prospective pilot study was designed to further explore the association of systemic inflammation and risk for significant PC in patients 
60 years undergoing general thoracic surgery and potential use of CRP as a perioperative predictor of PC.
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2. Patients and methods
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Over a 12-month period consecutive patients 60 year scheduled for major thoracic surgery that met inclusion criteria were approached to enroll in this study subject to the availability of research staff. A subset of patients from this study participated in another study of postoperative arrhythmias [10]. With Institutional Review Board approval and written informed consent, 153 patients who had pulmonary lobectomy (n
= 117), pneumonectomy (n
= 5), and sub-lobar pulmonary resection (wedge or segmentectomy) (n
= 31) were included, while eight patients who had an exploratory thoracotomy only were excluded. Patients already taking corticosteroids prior to surgery were not enrolled. Use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, which might reduce CRP, was recorded. The primary end point of the study was the new onset of any of the following major complications after surgery: pneumonitis, acute lung injury requiring mechanical ventilation, myocardial infarction, cerebrovascular accident, acute renal failure or pulmonary embolism. Postoperative atrial arrhythmias were not considered among the major PCs, as the majority resolves early and their occurrence has not been linked to inflammation in patients undergoing thoracic surgery [10]. Operations were performed using standard anesthesia regimens and thoracotomy approaches. According to surgeon preferences, postoperative pain relief was provided to patients by continuous administration of either epidural opioid (usually fentanyl with bupivacaine 0.05%) (n
= 122) or intravenous opioid (usually morphine) patient-controlled analgesia (n
= 31). A research assistant monitored patients and their medical records for cardiac or pulmonary complications throughout the hospital stay and as outpatients through electronic medical records. An investigator reviewed these medical records.
Blood specimens for measurement of high sensitivity CRP and interleukin (IL)-6 levels were obtained before surgery, on arrival to the postanesthesia care unit (PACU), and on the first morning after surgery. Serum was separated by centrifugation and stored at –70 °C until analysis. IL-6 quantitation was performed on a Diagnostics Products Corporation Immulite 1000 analyzer using sequential immunometric chemiluminescent analysis. Within assay precision of less than 5% coefficient of variation was obtained at a concentration of 400 pg/ml; CRP was measured on a Beckman-Coulter Immage immunochemistry analyzer using rate nephelometry. Assay precision at all levels of quality control concentration during routine analysis was less than 5.2% coefficient of variation.
Characteristics between patients with and without PC were examined by univariate analysis using Student's t-test, logistic regression, or Fisher's exact test. Due to non-normal distribution, CRP and IL-6 data were log transformed prior to analysis. Repeated measures analysis of variance (ANOVA) was done for CRP and IL-6. Receiver operating characteristic (ROC) analysis for PC and albumin, CRP or IL-6 was done. Data are presented as mean value ± standard deviation unless otherwise indicated and P
<0.05 was considered significant. Statistical analysis was performed with the software SPSS version 10.0 (SPSS, Chicago, IL) and SAS version 9.0 (SAS Institute Cary, NC).
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3. Results
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Patient characteristics and surgical data are presented in Table 1
. Major complications occurred in 9/153 (5.9%) patients after surgery as follows: pneumonia (n
= 4), ARDS (n
= 3), myocardial infarction (n
= 1), pulmonary embolism (n
= 1), and acute renal failure (n
= 1). Patients with PC had a greater history of hypertension (P
= 0.01), were taking significantly more aspirin and other non-steroidal anti-inflammatory drugs (P
= 0.003), and had a significantly lower preoperative albumin level (P
= 0.02), when compared to those without PC, respectively, (Table 1). The incidence of new onset atrial fibrillation did not differ between patients who did or did not develop PC 3/9 versus 35/144, P
= 0.69, respectively. Using the preoperative median albumin level for the entire study population as a cut-off, PC occurred in 9/73 (12%) with an albumin <4.25 g/dl [four PC occurred in patients within the lowest quartile of albumin <4.0 g/dl and five in the second quartile 4.0–4.25 g/dl] compared to 0/80 (0) patients with an albumin >4.25 g/dl, P
= 0.0006. Patients who developed PC did not differ in the presence of a preoperative infection when compared to those without PC, 0/9 (0%) versus 4/144 (2.8%), P
= 0.99, respectively.
Mean levels of CRP and IL-6 are shown in Table 2
. CRP levels in both groups increased significantly on the first postoperative day in comparison to preoperative and PACU values, P
< 0.0001, ANOVA. IL-6 levels in both groups were greater in the PACU as well as on the first postoperative day when compared to preoperative values, P
< 0.0001, ANOVA. Patients with PC had a near threefold elevation in baseline CRP and twofold elevation in baseline IL-6 compared to patients without PC [Table 2]. ROC analysis demonstrated a stronger association between PC and baseline CRP (area under the curve = 0.86) than for baseline IL-6 (area under the curve = 0.79) or albumin (area under the curve = 0.86). The proportion of patients with a preoperative CRP 0.8 mg/dl (upper limit of normal in our laboratory) was significantly greater for patients with PC 7/9 (78%) versus 31/144 (22%), P
= 0.001, than for those without PC, respectively. The proportion of patients with a preoperative IL-6 8 pg/ml (upper limit of normal in our laboratory) was significantly greater for patients with PC 7/9 (78%) versus 28/144 (19%), P
= 0.0001, than for those without PC, respectively. The relatively small total number of patients with PC, precluded formulation of a precise prediction model using logistic regression. However, to explore the combined effect of the risk factors, we dichotomized the significant continuous (CRP, IL-6, albumin, use of NSAIDs) and ordered categorical (extensive operation) variables and simply counted the number present for each patient. Table 3
shows that the likelihood of a PC increased markedly with the number of risk factors. (No P-value shown since the ‘model’ was post hoc). Length of hospital stay was significantly greater for patients with PC compared to those without, 12 ± 5 versus 6 ± 3 days, P
= 0.005, respectively. The incidence of postoperative PC did not differ between patients who did or did not have epidural analgesia, 8/122 (7%) versus 2/31 (6%), P
= 0.99, respectively. Within the subgroups of patients with or without PC, neither CRP nor IL-6 levels differed based on whether or not patients received statins (data not shown).
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4. Comment
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The main findings of this study are that in addition to traditional markers of poor nutritional status such as serum albumin, markers of inflammation, CRP or IL-6 can help distinguish patients who are at high risk for major cardiopulmonary complications after general thoracic surgery. CRP performed better than IL-6 for this purpose based on ROC analysis. These preliminary and novel data suggest that preoperative sub-clinical systemic inflammation that is detected by CRP is likely to be important in the pathogenesis of important PC. Because of the small number of patients with major complications in our study we could not further determine the ability of CRP or IL-6 to predict PC in comparison to low albumin. Other risk factors for PC were history of hypertension, extensive surgery such as pneumonectomy, and intriguingly patients who were taking NSAIDs prior to surgery as these patients were also more likely to develop PC. While it is not surprising that patients undergoing extensive operations are likely to develop complications, we cannot speculate as to the relationship of a history of hypertension or NSAID use to major pulmonary events after surgery and perhaps attribute some of these findings to the relatively small number of patients with PC.
To the best of our knowledge, only one other study showed a correlation between an elevation in postoperative CRP and mostly empyema or pneumonia after pneumonectomy in 151 consecutive patients [11]. In contrast to our data, preoperative CRP in that study did not discriminate patients who were likely to develop PC. Furthermore, these investigators only focused on pneumonectomy patients and did not examine the relationship of CRP to non-pulmonary complications that have been linked to inflammatory mechanisms [11]. Recently Shaw et al. [6] studied 160 patients undergoing general thoracic surgery and showed an association between single nucleotide polymorphism changes of the IL-6 and TNF genes and the development of postoperative cardiopulmonary complications. These investigators did not measure plasma cytokine levels of the concerned genes [6]. Nevertheless these two reports support an association for inflammation contributing to significant perioperative morbidity in general thoracic surgery patients. McMillan et al. [7] evaluated 772 cancer patients of whom 404 had lung cancer and found that poor prognosis correlated with increasing CRP reflecting the presence and magnitude of a systemic inflammatory response [7]. Although some workers have shown that preoperative chemotherapy induces an elevation in cytokines prior to surgery [8], it is unclear whether this heightened inflammatory state in itself is a direct cause of long-term morbidity and poor outcome independent of cancer stage severity [11,12].
Statins are known to have anti-inflammatory as well as antioxidant actions; their use has been associated with a significant reduction in PC [13–15]. Although the above-mentioned studies in surgical patients were retrospective, due to the large number of patients studied the consistent favorable effects of this class of drugs are encouraging. We speculate that future efforts directed at early interventions with such therapies such as antibiotic, anti-inflammatory or antioxidant prophylaxis, days before surgery, may also prove beneficial in mitigating the systemic inflammatory response to surgery [13,16].
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5. Conclusions
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CRP distinguished patients who developed major PC somewhat better than IL-6. These preliminary and novel data suggest that in addition to nutritional status as indicated by preoperative albumin level, systemic inflammation is likely to be important in the pathogenesis of important PC.
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References
|
|---|
- Duque JL, Ramos G, Castrodeza J, Cerezal J, Castanedo M, Yuste MG, Heras F. Early complications in surgical treatment of lung cancer. A prospective, multicenter study. Ann Thorac Surg 1997;63:944-950.[Abstract/Free Full Text]
- Busch E, Verazin G, Antkowiak JG, Driscoll D, Takita H. Pulmonary complications in patients undergoing thoracotomy for lung carcinoma. Chest 1994;105:760-766.[CrossRef][Medline]
- Brunelli A, Fianchini A, Gesuita R, Carle F. POSSUM scoring system as an instrument of audit in lung resection surgery. Ann Thorac Surg 1999;67:329-371.[Abstract/Free Full Text]
- Rovera F, Imperatori A, Militello P, Morri A, Antonini C, Dionigi G, Dominion L. Infections in 346 consecutive video-assisted thoracoscopic procedures. Surg Infect 2003;4:45-51.[CrossRef]
- Icard P, Fleury JP, Regnard JF, Libert JM, Magdeleinat P, Gharbi N, Brachet A, Levi JF, Levasseur P. Utility of C-reactive protein measurements for empyema diagnosis after pneumonectomy. Ann Thorac Surg 1994;57:933-936.[Abstract]
- Shaw AD, Vaporciyan AA, Wu X, King TM, Spitz MR, Putnam JB, Dickey BF. Inflammatory gene polymorphisms influence risk of postoperative morbidity after lung resection. Ann Thorac Surg 2005;79:1704-1710.[Abstract/Free Full Text]
- McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone JJ, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 2001;41:64-69.[CrossRef][Medline]
- Endo S, Sato Y, Hasegawa T, Tetsuka K, Otani S, Satio N, Tezuka Y, Sohara Y. Preoperative chemotherapy increases cytokine production after lung cancer surgery. Eur J Cardiothorac Surg 2004;26:787-791.[Abstract/Free Full Text]
- Spies CD, Kern H, Schroder T, Sander M, Sepold H, Lang P, Stangl K, Beherens S, Sinha P, Schaffartzik W, Wernecke KD, Kox WJ, Jain U. Myocardial ischemia and cytokine response are associated with subsequent onset of infections after noncardiac surgery. Anesth Analg 2002;95:9-18.[Abstract/Free Full Text]
- Amar D, Zhang H, Heerdt PM, Park B, Fleisher M, Thaler HT. Statin use is associated with a reduction in atrial fibrillation after noncardiac thoracic surgery independent of C-reactive protein. Chest 2005;128:3421-3427.[CrossRef][Medline]
- Fujita S, Katakami N, Takahashi Y, Hirokawa K, Ikeda A, Tabata C, Mio T, Mishima M. Postoperative complications after induction chemoradiotherapy in patients with non-small-cell lung cancer. Eur J Cardiothorac Surg 2006;29:896-901.[Abstract/Free Full Text]
- Martin J, Ginsberg RJ, Abolhoda A, Bains MS, Downey RJ, Korst RJ, Weigel TL, Kris MG, Venkatraman ES, Rusch VW. Morbidity and mortality after neoadjuvant therapy for lung cancer: the risks of right pneumonectomy. Ann Thorac Surg 2001;72:1149-1154.[Abstract/Free Full Text]
- Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE. Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 2001;88:431-433.[CrossRef][Medline]
- Poldermans D, Bax JJ, Kertai, MD, Krenning B, Westerhout CM, Schinkel AF, Thomson IR, Lansberg PJ, Fleisher LA, Klein J, van Urk H, Roselandt JR, Boersma E. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003;107:1848-1851.[Abstract/Free Full Text]
- Lindenauer PK, Pekow P, Wang K, Gutierrez B, Benjamin EM. Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. J Am Med Assoc 2004;291:2092-2099.[Abstract/Free Full Text]
- Talwar D, Ha TK, Scott HR, Cooney J, Fell GS, O’Reilly DS, Lean ME, McMillan DC. Effect of inflammation on measures of antioxidant status in patients with non-small cell lung cancer. Am J Clin Nutr 1997;66:1283-1285.[Abstract/Free Full Text]
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Abstract
1. Introduction
