World Journal of Surgery

, Volume 43, Issue 10, pp 2631–2639 | Cite as

Cytokine Response in the Pleural Fluid and Blood in Minimally Invasive and Open Esophagectomy

  • T. Delko
  • D. I. Watson
  • B. Beck-Schimmer
  • A. Immanuel
  • D. J. Hussey
  • U. ZinggEmail author
Original Scientific Report



Transthoracic esophagectomy for cancer triggers a massive inflammatory reaction. The data whether a minimally invasive esophagectomy (MIE) leads to less pronounced inflammatory response compared to open right-sided transthoracic esophagectomy (OE) are scarce. The aim of this study was to evaluate the extent of the inflammatory reaction, represented by levels of the pro-inflammatory interleukins IL-6 and IL-8, the anti-inflammatory IL-1 RA and the chemokines CINC-1 and MCP-1 in the right pleural fluid and the blood from patients undergoing standard OE or MIE.


Pleural drainage fluid and blood was collected at five different time points during the first 72 h following surgery, and the concentrations of IL-6, IL-8, IL-1 RA, CINC-1 and MCP-1 were analyzed using enzyme-linked immune-sorbent assays in 24 patients undergoing MIE or OE.


The groups were matched for cancer stage and comorbidities. Pro- and anti-inflammatory mediator levels in the pleural fluid were markedly increased at the end of surgery and on postoperative days 1–3. The pleural inflammatory response of all cyto- and chemokines was lower in the MIE group, reaching significance at some time points. Cyto- and chemokine response levels measured in the blood were overall lower compared to those in the pleural fluid. The chemokines CINC-1 and MCP-1 reacted less pronounced or not at all. Preoperative pulmonary comorbidity, postoperative pulmonary morbidity and length of surgery were associated with an increased reaction in selected mediators.


The minimally invasive technique attenuates the inflammatory response, especially locally in the thoracic compartment. Length of procedure, preoperative pulmonary comorbidity and postoperative pulmonary complications are mirrored in an increase in individual inflammatory markers in the pleural fluid. The value of the chemokines CINC-1 and MCP-1 as markers of inflammation in the setting of esophagectomy is unclear.



The authors thank all involved surgeons for their contribution and Mrs Ramona Bolognini for the analysis of the cyto- and chemokines. We thank Dr. Tracy Glass (PhD, Biostatistics and Epidemiology) for her statistical analysis review.

Author’s contribution

TD contributed to data collection, statistical analysis and drafted the manuscript. UZ contributed to the study design, sample and data collection and revision of the manuscript. DW and BBS were involved in the study design, manuscript content and its revision. AI and DJH were involved in samples and data collection, cytokine analysis, contribution to the manuscript and its revision. All authors read and gave approval to the final manuscript version.


The study was supported by a grant (09-2008) from the Freie Akademische Gesellschaft Basel, Switzerland.

Compliance with ethical standards

Conflict of interest

Drs. Delko, Watson, Beck-Schimmer, Immanuel, Hussey and Zingg have no conflicts of interest or financial ties to disclose in relation to this study.

Ethical approval

The study has been performed in accordance with the Declaration of Helsinki. Informed consent was obtained, and the trial was approved by the Flinders Clinical Research Ethics Committee.


  1. 1.
    Atkins BZ, Shah AS, Hutcheson KA, et al. Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg. 2004;78(4):1170-6; discussion 1170-6.
  2. 2.
    Avendano CE, Flume PA, Silvestri GA, King LB, Reed CE (2002) Pulmonary complications after esophagectomy. Ann Thorac Surg 73(3):922–926CrossRefGoogle Scholar
  3. 3.
    Hulscher JBF, van Sandick JW, de Boer AGEM et al (2002) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347(21):1662–1669. CrossRefPubMedGoogle Scholar
  4. 4.
    Watanabe M, Baba Y, Nagai Y, Baba H (2013) Minimally invasive esophagectomy for esophageal cancer: an updated review. Surg Today 43(3):237–244. CrossRefPubMedGoogle Scholar
  5. 5.
    Abe T, Oka M, Tangoku A et al (2001) Interleukin-6 production in lung tissue after transthoracic esophagectomy. J Am Coll Surg 192(3):322–329CrossRefGoogle Scholar
  6. 6.
    Sato N, Koeda K, Kimura Y et al (2001) Cytokine profile of serum and bronchoalveolar lavage fluids following thoracic esophageal cancer surgery. Eur Surg Res 33(4):279–284CrossRefGoogle Scholar
  7. 7.
    Aosasa S, Ono S, Mochizuki H et al (2000) Activation of monocytes and endothelial cells depends on the severity of surgical stress. World J Surg 24(1):10–16CrossRefGoogle Scholar
  8. 8.
    Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117(4):1162–1172. CrossRefPubMedGoogle Scholar
  9. 9.
    Song JQ, He YZ, Fang Y, Wu W, Zhong M (2017) The predictive value of plasma cytokines on gastroesophageal anastomotic leakage at an early stage in patients undergoing esophagectomy. J Thorac Dis 9(8):2544–2550. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Breunig A, Gambazzi F, Beck-schimmer B, Tamm M, Lardinois D, Oertli D (2011) Cytokine & chemokine response in the lungs, pleural fluid and serum in thoracic surgery using one-lung ventilation. J Inflamm 8(1):32. CrossRefGoogle Scholar
  11. 11.
    Alzoghaibi MA, Zubaidi AM (2014) Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats’ intestinal anastomotic wound healing—does it matter? Asian J Surg 37(2):86–92. CrossRefPubMedGoogle Scholar
  12. 12.
    Donnelly SC, Strieter RM, Kunkel SL et al (1993) Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet (London, England). 341(8846):643–647CrossRefGoogle Scholar
  13. 13.
    Yamada T, Hisanaga M, Nakajima Y et al (1998) Serum interleukin-6, interleukin-8, hepatocyte growth factor, and nitric oxide changes during thoracic surgery. World J Surg 22(8):783–790CrossRefGoogle Scholar
  14. 14.
    Takenaka K, Ogawa E, Wada H, Hirata T. Systemic inflammatory response syndrome and surgical stress in thoracic surgery. J Crit Care. 2006;21(1):48-53; discussion 53-5.
  15. 15.
    Baum M, Demicheli R, Hrushesky W, Retsky M (2005) Does surgery unfavourably perturb the “natural history” of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer 41(4):508–515. CrossRefPubMedGoogle Scholar
  16. 16.
    Neville A, Lee L, Antonescu I et al (2014) Systematic review of outcomes used to evaluate enhanced recovery after surgery. Br J Surg 101(3):159–170. CrossRefGoogle Scholar
  17. 17.
    Hogan BV, Peter MB, Shenoy HG, Horgan K, Hughes TA (2011) Surgery induced immunosuppression. Surgeon 9(1):38–43. CrossRefPubMedGoogle Scholar
  18. 18.
    Ogawa K, Hirai M, Katsube T et al (2000) Suppression of cellular immunity by surgical stress. Surgery 127(3):329–336. CrossRefPubMedGoogle Scholar
  19. 19.
    Zingg U, Forberger J, Frey DM et al (2010) Inflammatory response in ventilated left and collapsed right lungs, serum and pleural fluid, in transthoracic esophagectomy for cancer. Eur Cytokine Netw 21(1):50–57. CrossRefPubMedGoogle Scholar
  20. 20.
    Zingg U, Mcquinn A, Divalentino D et al (2009) Minimally invasive versus open esophagectomy for patients with esophageal cancer. ATS 87(3):911–919. CrossRefGoogle Scholar
  21. 21.
    Breunig A, Gambazzi F, Beck-Schimmer B et al (2011) Cytokine & chemokine response in the lungs, pleural fluid and serum in thoracic surgery using one-lung ventilation. J Inflamm 8:1–10. CrossRefGoogle Scholar
  22. 22.
    Okamura A, Takeuchi H, Matsuda S et al (2015) Factors affecting cytokine change after esophagectomy for esophageal cancer. Ann Surg Oncol 22(9):3130–3135. CrossRefGoogle Scholar
  23. 23.
    Morita M, Yoshida R, Ikeda K et al (2008) Acute lung injury following an esophagectomy for esophageal cancer, with special reference to the clinical factors and cytokine levels of peripheral blood and pleural drainage fluid. Dis Esophagus 21(1):30–36. CrossRefPubMedGoogle Scholar
  24. 24.
    Haga Y, Beppu T, Doi K et al (1997) Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery. Crit Care Med. 25(12):1994–2000CrossRefGoogle Scholar
  25. 25.
    Agustí A, Faner R (2012) Systemic inflammation and comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 9(2):43–46. CrossRefPubMedGoogle Scholar
  26. 26.
    Ottinger ME, Monaghan SF, Gravenstein S, Cioffi WG, Ayala A, Heffernan DS (2014) The geriatric cytokine response to trauma: time to consider a new threshold. Surg Infect (Larchmt) 15(6):800–805. CrossRefGoogle Scholar
  27. 27.
    Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16(10):626–638. CrossRefPubMedGoogle Scholar
  28. 28.
    Kawamura H, Okada K, Isizu H et al (2008) Laparoscopic gastrectomy for early gastric cancer targeting as a less invasive procedure. Surg Endosc 22(1):81–85. CrossRefPubMedGoogle Scholar
  29. 29.
    Watt DG, Horgan PG, McMillan DC (2015) Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systematic review. Surgery 157(2):362–380. CrossRefGoogle Scholar
  30. 30.
    Hisano S, Sakamoto K, Ishiko T, Kamohara H, Ogawa M (1997) IL-6 and soluble IL-6 receptor levels change differently after surgery both in the blood and in the operative field. Cytokine 9(6):447–452. CrossRefPubMedGoogle Scholar
  31. 31.
    Sakamoto K, Arakawa H, Mita S et al (1994) Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 6(2):181–186CrossRefGoogle Scholar
  32. 32.
    Mahmoodi M, Mir M-R, Daryaei P et al (2008) Cytokine response following transthoracic and transhiatal esophagectomy in patients with esophageal cancer. Eur Cytokine Netw 19(2):92–98. CrossRefPubMedGoogle Scholar
  33. 33.
    Adachi Y, Shiraishi N, Shiromizu A, Bandoh T, Aramaki M, Kitano S (2000) Laparoscopy-assisted Billroth I gastrectomy compared with conventional open gastrectomy. Arch Surg 135(7):806–810CrossRefGoogle Scholar
  34. 34.
    Kim M-C, Kim K-H, Kim H-H, Jung G-J (2005) Comparison of laparoscopy-assisted by conventional open distal gastrectomy and extraperigastric lymph node dissection in early gastric cancer. J Surg Oncol 91(1):90–94. CrossRefPubMedGoogle Scholar

Copyright information

© Société Internationale de Chirurgie 2019

Authors and Affiliations

  • T. Delko
    • 1
  • D. I. Watson
    • 1
  • B. Beck-Schimmer
    • 2
  • A. Immanuel
    • 1
  • D. J. Hussey
    • 1
  • U. Zingg
    • 1
    • 3
    Email author
  1. 1.Department of SurgeryFlinders UniversityBedford ParkAustralia
  2. 2.Institute of AnesthesiologyUniversity of ZurichZurichSwitzerland
  3. 3.Department of SurgeryLimmattal HospitalSchlierenSwitzerland

Personalised recommendations