The immune response is the body’s biggest defense against external pathogens in the environment. However, the many mechanisms it employs may, when activated incorrectly, lead to deleterious autoimmune responses, such as tumor growth, rejection of organ transplantation, asthma, and allergies [1]. To protect the body from an overactive immune system, there must be a constant balance of pro-inflammatory and anti-inflammatory cytokines, secreted proteins which serve in endocrine communication [2]. Excessive release of pro-inflammatory cytokines can lead to dysregulation of the immune system and overwhelming systemic inflammation, while anti-inflammatory cytokines work to dampen this immune activation. Several studies have indicated general anesthetics have a significant impact on these immune system cytokines [1,3].
Intravenous anesthetics are administered through an intravenous port (IV); common examples include propofol, ketamine, and sodium thiopental. A preclinical investigation found both thiopental and ketamine to significantly decrease natural-killer cell activity and increase tumor growth [4]. Metastasis was greatest after ketamine administration; in addition, ketamine is shown to inhibit NF-kappa beta and AP-21, two transcription factors vital in producing pro-inflammatory cytokines [4,5]. Thiopental has a strong immunosuppressive effect, significantly downregulating the number of receptors for the main leukocyte growth factor IL-2 [6]. Like ketamine, thiopental inhibits lipopolysaccharide-induced production of pro-inflammatory cytokines like interleukin-1beta (IL-1beta), interleukin-6 (IL-6), as well as the anti-inflammatory tumor necrosis factor-alpha (TNF-alpha) [7].
Among IV anesthetics, propofol is widely favored because its short half-life mitigates the extent of adverse effects [8]. By binding to the beta-2 subunit of the GABA A receptor, propofol closes chloride ion channels, inhibiting phagocytosis and cellular clean-up by macrophages and microglia [9]. In vitro studies of propofol indicate its anti-inflammatory properties, reducing both pro-inflammatory cytokines such as IL-1 and IL-6 as well as anti-inflammatory cytokines such as TNF-alpha, IL-8, IL-10 [10]. Although propofol’s attenuation of pro-inflammatory cytokines can be beneficial for septic patiences, studies have also found propofol to block the expression of certain cellular adhesion molecules (CAMs), which are critical in neurodevelopment as well as during migration of leukocytes across the endothelium [10].
Inhalational anesthetics is another large class of anesthetics commonly used in clinical care. In the human body, they have been shown to reduce natural-killer cells and inhibit cytokine production [1]. For example, a murine study showed isoflurane increases pro-inflammatory cytokines in brain tissue; compared to microglia, primary neurons were more strongly affect [11]. The authors conclude this neuroinflammation is a risk factor for the development of Alzheimer’s Disease. On the other hand, sevoflurane does not change pro-inflammatory cytokine levels. However, a clinical study showed increased levels of the anti-inflammatory IL-8 in lung tissue after sevoflurane inhalation [12]/ Another preclinical study used enzyme-linked immunosorbent assay (ELISA) and found that sevoflurane inhibited production of anti-inflammatory cytokines like TNF-alpha and IL-10 [13].
Opioids are often used as adjuvants in general anesthesia. The findings around the effect of opioids on immune system cytokines are contradictory, as both suppressive and stimulative effects are reported. Bussiere et. al associated morphine with the depressed production of pro-inflammatory cytokines [14], but findings from researchers in Italy indicate morphine amplifies production of IL-1 and IL-6 [15].
Anesthesiologists should be aware of the varying effects of general anesthetics on immune system cytokines and administer the preferred anesthesia method for patients with immune imbalances. Clinical findings in the extant literature are limited by confounding variables such as gender, duration of anesthesia and surgical procedure; therefore, greater research must be conducted to maximize positive patient outcomes.
References
1. Jafarzadeh, A., Hadavi, M., Hassanshahi, G., Rezaeian, M., & Vazirinejad, R. (2020). General anesthetics on immune system cytokines: a narrative review article. Anesthesiology and Pain Medicine, 10(4), e103033. https://doi.org/10.5812/aapm.103033
2. Lenz, A., Franklin, G. A., & Cheadle, W. G. (2007). Systemic inflammation after trauma. Injury, 38(12), 1336–1345. https://doi.org/10.1016/j.injury.2007.10.003
3. Alsina, E., Matute, E., Ruiz-Huerta, A. D., & Gilsanz, F. (2014). The effects of sevoflurane or remifentanil on the stress response to surgical stimulus. Current Pharmaceutical Design, 20(34), 5449–5468. https://doi.org/10.2174/1381612820666140325105723
4. 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, 97(5), 1331–1339. https://doi.org/10.1213/01.ANE.0000082995.44040.07
5. Welters, I. D., Hafer, G., Menzebach, A., Mühling, J., Neuhäuser, C., Browning, P., & Goumon, Y. (2010). Ketamine inhibits transcription factors Activator Protein 1 and nuclear factor-κB, interleukin-8 production, as well as CD11b and CD16 expression: Studies in human leukocytes and leukocytic cell lines. Anesthesia & Analgesia, 110(3), 934–941. https://doi.org/10.1213/ANE.0b013e3181c95cfa
6. Schneemilch, C. E., Hachenberg, T., Ansorge, S., Ittenson, A., & Bank, U. (2005). Effects of different anesthetic agents on immune cell function in vitro. European Journal of Anesthesiology, 22(8), 616–623. https://doi.org/10.1017/S0265021505001031
7. Kim, R. (2018). Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence. Journal of Translational Medicine, 16(1), 8. https://doi.org/10.1186/s12967-018-1389-
8. Marik, P. E. (2005). Propofol: An immunomodulating agent. Pharmacotherapy, 25(5 Part 2), 28S-33S. https://doi.org/10.1592/phco.2005.25.5_Part_2.28S
9. Shiratsuchi, H., Kouatli, Y., Yu, G. X., Marsh, H. M., & Basson, M. D. (2009). Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABAA receptor and dysregulation of P130CAS phosphorylation. American Journal of Physiology-Cell Physiology, 296(6), C1400–C1410. https://doi.org/10.1152/ajpcell.00345.2008
10. Lisowska, B., Szymańska, M., Nowacka, E., & Olszewska, M. (2013). Anesthesiology and the cytokine network. Advances in Hygiene and Experimental Medicine, 67, 761–769. https://doi.org/10.5604/17322693.1061412
11. Wu, X., Lu, Y., Dong, Y., Zhang, G., Zhang, Y., Xu, Z., Culley, D. J., Crosby, G., Marcantonio, E. R., Tanzi, R. E., & Xie, Z. (2012). The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiology of Aging, 33(7), 1364–1378. https://doi.org/10.1016/j.neurobiolaging.2010.11.002
12. Cho, E. J., Yoon, J. H., Hong, S. J., Lee, S. H., & Sim, S. B. (2009). The effects of sevoflurane on systemic and pulmonary inflammatory responses after cardiopulmonary bypass. Journal of Cardiothoracic and Vascular Anesthesia, 23(5), 639–645. https://doi.org/10.1053/j.jvca.2009.01.025
13. Shen, Q. Y., Fang, L., Wu, H. M., Wu, L., He, F., & Liu, R. Y. (2016). Effect of Toll-like receptor 2 on the inhibition role of sevoflurane on airway inflammation in asthmatic mice. National Medical Journal of China, 96(2), 138–141. https://doi.org/10.3760/cma.j.issn.0376-2491.2016.02.014
14. Bussiere, J. L., Adler, M. W., Rogers, T. J., & Eisenstein, T. K. (1993). Cytokine reversal of morphine-induced suppression of the antibody response. Journal of Pharmacology and Experimental Therapeutics, 264(2), 591–597. https://jpet.aspetjournals.org/content/264/2/591
15. Eisenstein, T. K. (2019). The role of opioid receptors in immune system function. Frontiers in Immunology, 10. https://www.frontiersin.org/article/10.3389/fimmu.2019.02904
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