23 Feb 2022

Surgical Stress: Immune, Hematological, and Neural Responses

In the late 1920s, David Cuthbertson observed an abnormal rise in intracellular metabolites in post-surgical patients, a finding supplemented by subsequent studies establishing an association between fever and posttraumatic catabolic state [1]. Surgical stress involves a spectrum of bodily changes, including but not limited to hematological, metabolic, immunological and neuroendocrine responses [2]. Often, multiple systems are involved in negative effects associated with surgery; for example, higher levels of adrenocorticotropic hormone (ACTH) can lead to excessive cortisol release and ultimately insulin resistance. Resulting hyperglycemia has been shown to cause postoperative surgical site infection (SSI) [3].

Mice acutely stressed before surgical sponge implantation showed a 2 to 3-fold increase in neutrophil, macrophage, natural killer (NK) cell, and T-cell infiltration compared to unstressed mice [4]. Chemo-attractants such as TNF-α (a pro-inflammatory cytokine) and LTN (a lymphocyte-specific chemokine) determine which leukocytes subpopulations will show greater trafficking, i.e. mice implanted with sponges that had been treated with TNF-α showed more neutrophil and macrophage trafficking, while mice implanted with LTN-treated sponges showed greater NK and T-cell trafficking [4]. These unnecessary leukocyte increases may aggravate immunopathology in autoimmune or inflammatory diseases. Interestingly, the choice of anesthetic may also modulate the immune response. Ketamine, thiopental, and halothane all significantly suppressed NK-cell activity and increased tumor metastasis in mice surgically injected with MADB106, a cell line causing pulmonary metastasis of mammary adenocarcinoma [5]. However, the intravenous anesthetic propofol showed no such effect. A clinical study with breast cancer patients showed propofol significantly decreases IL-1β, a cytokine which promotes tumor migration and induces tumor-mediated immunosuppression, compared to the volatile anesthetic sevoflurane [6]. Further indicating the negative effects of volatile anesthetics on immune function, an in vitro study using both human platelets and cell-free assays found sevoflurane and isoflurane to diminish platelet activation and clot stability compared to propofol [7].

The neuroendocrine response is the brain’s most significant contribution to surgical stress. A clinical study on patients receiving aortic surgery suggested epidural anesthesia, when combined with general anesthesia, induces powerful endocrine shifts; specifically, attenuating cortisol levels and catecholamine release, indicating a reduction in the physiological surgical stress response [8]. Postoperative cognitive dysfunction (POCD), a post-surgical state of mind associated with increased mortality, lower quality of life, dependence on social transfer payments, and early retirement, can occur through increased levels of cortisol or proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) [2,9,10]. A randomized study found no significant difference between the effects of general (GA) versus regional (RA) anesthesia on POCD development at 3 months post-surgery, though incidence at 1 week was significantly greater in the GA group. However, this study was limited by a relatively high drop-out rate [11].  

Surgical stress is also presumed to initiate other negative consequences; for instance, some studies have found associations between and risk of developing Alzheimer’s Disease (AD) or dementia in elderly patients, while others have suggested a link between anesthesia and cognitive decline [12]. AD is linked to a build-up of amyloid plaques in the brain and is associated with increased inflammatory cytokine activity in neural tissue [2]. Tang et al. presented strong internal validity in their study by using two control groups: one that was exposed to desflurane without surgery and one exposed to only air. Using the murine model, these researchers found surgery (with desflurane) increased amyloid plaque density compared to desflurane alone [13]. As previously discussed, cytokine levels are greatly increased after surgery; as such, since the inflammatory response is entwined with surgical stress, it is possible downregulation of such stress may improve prognosis and outcomes of elderly patients with AD.

Much of current research is still based on murine models, especially studies focusing on molecular constituents of POCD and AD; however, animal research provides a solid foundation from which future clinical studies may benefit.


  1. Wilmore, D. W. (2002). From Cuthbertson to fast-track surgery: 70 years of progress in reducing stress in surgical patients. Annals of Surgery236(5), 643–648. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422623/
  2. Iwasaki, M., Edmondson, M., Sakamoto, A., & Ma, D. (2015). Anesthesia, surgical stress, and “long-term” outcomes. Acta Anaesthesiologica Taiwanica53(3), 99–104. https://doi.org/10.1016/j.aat.2015.07.002
  3. Ata, A., Lee, J., Bestle, S. L., Desemone, J., & Stain, S. C. (2010). Postoperative hyperglycemia and surgical site infection in general surgery patients. Archives of Surgery145(9), 858–864. https://doi.org/10.1001/archsurg.2010.179
  4. Viswanathan, K., & Dhabhar, F. S. (2005). Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proceedings of the National Academy of Sciences102(16), 5808–5813. https://doi.org/10.1073/pnas.0501650102
  5. Melamed, R., Bar-Yosef, S., Shakhar, G., Shakhar, K., & Ben-Eliyahu, S. (2003). Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: Mediating mechanisms and prophylactic measures: Anesthesia & Analgesia, 1331–1339. https://doi.org/10.1213/01.ANE.0000082995.44040.07
  6. Deegan, C. A., Murray, D., Doran, P., Moriarty, D. C., Sessler, D. I., Mascha, E., Kavanagh, B. P., & Buggy, D. J. (2010). Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery. Regional Anesthesia & Pain Medicine35(6), 490–495. https://doi.org/10.1097/AAP.0b013e3181ef4d05
  7. Yuki, K., Bu, W., Shimaoka, M., & Eckenhoff, R. (2013). Volatile anesthetics, not intravenous anesthetic propofol bind to and attenuate the activation of platelet receptor integrin αiibβ3. PLOS ONE8(4), e60415. https://doi.org/10.1371/journal.pone.0060415
  8. Smeets, H. J., Kievit, J., Dulfer, F. T., & van Kleef, J. W. (1993). Endocrine-metabolic response to abdominal aortic surgery: A randomized trial of general anesthesia versus general plus epidural anesthesia. World Journal of Surgery17(5), 601–606. https://doi.org/10.1007/BF01659119
  9. Fidalgo, A. R., Cibelli, M., White, J. P. M., Nagy, I., Maze, M., & Ma, D. (2011). Systemic inflammation enhances surgery-induced cognitive dysfunction in mice. Neuroscience Letters498(1), 63–66. https://doi.org/10.1016/j.neulet.2011.04.063
  10. Steinmetz, J., Christensen, K. B., Lund, T., Lohse, N., Rasmussen, L. S., & the ISPOCD Group. (2009). Long-term consequences of postoperative cognitive dysfunction. Anesthesiology110(3), 548–555. https://doi.org/10.1097/ALN.0b013e318195b569
  11. Rasmussen, L. S., Johnson, T., Kuipers, H. M., Kristensen, D., Siersma, V. D., Vila, P., Jolles, J., Papaioannou, A., Abildstrom, H., Silverstein, J. H., Bonal, J. A., Raeder, J., Nielsen, I. K., Korttila, K., Munoz, L., Dodds, C., Hanning, C. D., & Moller, J. T. (2003). Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiologica Scandinavica47(3), 260–266. https://doi.org/10.1034/j.1399-6576.2003.00057.x
  12. Kapila, A. K., Watts, H. R., Wang, T., & Ma, D. (2014). The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer’s disease development: Biomarkers and preventive strategies. Journal of Alzheimer’s Disease41(1), 1–13. https://doi.org/10.3233/JAD-132258
  13. Tang, J. X., Mardini, F., Janik, L. S., Garrity, S. T., Li, R. Q., Bachlani, G., Eckenhoff, R. G., & Eckenhoff, M. F. (2013). Modulation of murine Alzheimer pathogenesis and behavior by surgery. Annals of Surgery257(3), 439–448. https://doi.org/10.1097/SLA.0b013e318269d623
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