Systematic Review: The Effect of Preemptive Ketamine Administration on Post-Surgical Neutrophil to Lymphocyte Ratio And Interleukin-6 (Il-6) Levels
Abstract
Surgical stress induces systemic inflammation characterized by increased neutrophil-to-lymphocyte ratio and interleukin-6 levels, which may contribute to postoperative pain, immune dysfunction, and complications. This systematic review aimed to evaluate the effects of preemptive ketamine administration on postoperative neutrophil-to-lymphocyte ratio and interleukin-6 levels. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Relevant studies were identified through PubMed, ScienceDirect, the Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalKey. Study selection was based on predefined population, intervention, comparison, outcome, and study-design criteria. Data were extracted using standardized tables, methodological quality was assessed using appropriate risk-of-bias instruments, and the findings were synthesized narratively according to ketamine dose, surgical procedure, biomarker measurement time, and clinical outcomes. Of 807 records identified, 17 studies were included in the final synthesis. Preemptive intravenous ketamine or S-ketamine generally reduced the early postoperative increase in the neutrophil-to-lymphocyte ratio and suppressed interleukin-6 secretion, particularly at subanesthetic doses of 0.3–0.75 milligrams per kilogram. These immunomodulatory effects were accompanied by lower postoperative pain scores, reduced opioid requirements, fewer episodes of postoperative nausea and vomiting, and a lower risk of chronic postsurgical pain. However, variations in dosage, surgical procedures, anesthetic techniques, and biomarker measurement times limited direct comparisons between studies. Preemptive ketamine appears to provide beneficial analgesic and immunomodulatory effects by attenuating postoperative systemic inflammation, although further standardized randomized trials are required to determine the optimal dosing regimen.
References
Alvarez, A., Singh, P. M., & Sinha, A. C. (2014). Postoperative analgesia in morbid obesity. Obesity Surgery, 24(4), 652-659. https://doi.org/10.1007/s11695-014-1185-2
Bohringer, C., Astorga, C., & Liu, H. (2020). The benefits of opioid free anesthesia and the precautions necessary when employing it. Translational perioperative and pain medicine, 7(1), 152.
Domagalska, M., Ciftsi, B., Janusz, P., Reysner, T., Kolasinski, J., & Wieczorowska-Tobis, K., et al. (2023). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels following erector spinae plane block (ESPB) in posterior lumbar decompression: A randomized, controlled trial. European Spine Journal, 32(12), 4192–4199. https://doi.org/10.1007/s00586-023-07913-z
Domagalska, M., Reysner, T., Kowalski, G., Daroszewski, P., Mularski, A., & Wieczorowska-Tobis, K. (2023). Pain management, functional recovery, and stress response expressed by NLR and PLR after the iPACK block combined with adductor canal block for total knee arthroplasty: A prospective, randomised, double-blinded clinical trial. Journal of Clinical Medicine, 12(22), 7088. https://doi.org/10.3390/jcm12227088
Elsharkawy, H., Clark, J. D., & El-Boghdadly, K. (2025). Evidence for regional anesthesia in preventing chronic postsurgical pain. Regional Anesthesia & Pain Medicine, 50(2), 153-159. https://doi.org/10.1136/rapm-2024-105611
ELSharkawy, R., Elmorshedi, M., Mohammed, M., Mohasseb, A. M., & Abo-Zeid, M. (2025). Immune-Mediatory Response of Intravenous Ketamine Versus Propofol for Elective Open Colectomy: A Prospective Randomised Study. Egyptian Journal of Anaesthesia, 41(1), 323-328.
Fiore, N. T., Debs, S. R., Hayes, J. P., Duffy, S. S., & Moalem-Taylor, G. (2023). Pain-resolving immune mechanisms in neuropathic pain. Nature Reviews Neurology, 19(4), 199-220. https://doi.org/10.1038/s41582-023-00777-3
Fuller, A. M., Bharde, S., & Sikandar, S. (2023). The mechanisms and management of persistent postsurgical pain. Frontiers in Pain Research, 4, 1154597. https://doi.org/10.3389/fpain.2023.1154597
Gan, T. J., Belani, K. G., Bergese, S., Chung, F., Diemunsch, P., Habib, A. S., ... & Philip, B. K. (2020). Fourth consensus guidelines for the management of postoperative nausea and vomiting. Anesthesia & Analgesia, 131(2), 411-448. https://doi.org/10.1213/ane.0000000000004833
Gigliotti, S., Guerriero, G., Mazza, G., Garofalo, E., Pavia, G., Amaddeo, A., ... & Matera, G. (2026). Perioperative blood biomarkers of infectious and non-infectious postoperative pulmonary complications: a narrative review. Journal of Clinical Medicine, 15(2), 699. https://doi.org/10.3390/jcm15020699
Gilbert, J. E., Zhang, T., Esteller, R., & Grill, W. M. (2023). Network model of nociceptive processing in the superficial spinal dorsal horn reveals mechanisms of hyperalgesia, allodynia, and spinal cord stimulation. Journal of neurophysiology, 130(5), 1103-1117. https://doi.org/10.1152/jn.00186.2023
Guo, J., Qiu, D., Gu, H. W., Wang, X. M., Hashimoto, K., Zhang, G. F., & Yang, J. J. (2023). Efficacy and safety of perioperative application of ketamine on postoperative depression: a meta-analysis of randomized controlled studies. Molecular psychiatry, 28(6), 2266-2276. https://doi.org/10.1038/s41380-023-01945-z
Hallikeri, S. V., Sinha, R., Ray, B. R., Pandey, R. K., Darlong, V., Puji, J., et al. (2024). Effect of low-dose ketamine on inflammatory markers, perioperative analgesia, and chronic pain in patients undergoing laparoscopic inguinal hernia surgery: A prospective, randomized, double-blind, comparative study. Turkish Journal of Anaesthesiology and Reanimation, 52(6), 231–239. https://doi.org/10.4274/tjar.2024.241771
Jin, L., Zhang, Y., Li, J., Song, L., Luo, Y., Dong, T., & Zhang, X. (2026). Integrating systemic inflammation biomarker and clinical predictors for surgical site infection risk assessment in closed pilon fractures: A risk prediction model. Plos one, 21(4), e0346298. https://doi.org/10.1371/journal.pone.0346298
Kriplani, A., Pandit, S., Chawla, A., de la Rosette, J. J., Laguna, P., Jayadeva Reddy, S., & Somani, B. K. (2022). Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and lymphocyte–monocyte ratio (LMR) in predicting systemic inflammatory response syndrome (SIRS) and sepsis after percutaneous nephrolithotomy (PNL). Urolithiasis, 50(3), 341-348. https://doi.org/10.1007/s00240-022-01319-0
Krotov, V., & Kopach, O. (2026). Targeting spinal dorsal horn sensitisation in chronic pain: mechanisms and translational strategies. Neuroscience Bulletin, 1-23. https://doi.org/10.1007/s12264-026-01642-1
Luetkemeier, M. K. H., Wentling, J. G., Ahmadzadeh, S., Shekoohi, S., & Kaye, A. D. (2026). Scientific Basis of Ketamine in Immunomodulation. In Anesthesia Therapeutics in Modern Medicine (pp. 39-45). Cham: Springer Nature Switzerland. https://doi.org/10.3390/ijms26157500
Lukaszewski, R. A., Jones, H. E., Gersuk, V. H., Russell, P., Simpson, A., Brealey, D., ... & Singer, M. (2022). Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures. Intensive care medicine, 48(9), 1133-1143. https://doi.org/10.1007/s00134-022-06769-z
Lullau, A. P., Haga, E. M., Ronold, E. H., & Dwyer, G. E. (2023). Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression. Frontiers in Neuroscience, 17, 1223145. https://doi.org/10.3389/fnins.2023.1223145
Moyano, J., & Aguirre, L. (2019). Opioids in the immune system: from experimental studies to clinical practice. Revista da Associação Médica Brasileira, 65(2), 262-269. https://doi.org/10.1590/1806-9282.65.2.262
Niu, G., Zheng, X., Deng, B., Du, Y. S., & Mei, Y. (2024). The effects of prophylactic use of esketamine on postoperative depression and quality of life: A meta-analysis. Minerva Anestesiologica, 90(4), 321–329. https://doi.org/10.23736/s0375-9393.24.17703-6
Oriquat, G., Mohammed, M. H., Badraldin, S. Q., Rizaev, J., Abdusamiyeva, N., Salih, R. M., & Jaber, M. A. (2026). Inflammatory biomarkers in chronic kidney disease. Clinica Chimica Acta, 121139. https://doi.org/10.1016/j.cca.2026.121139
Perek, A., Reysner, T., Rosada-Kurasińska, J., Pietraszek, P., Marszałek-Buko, J., Perek, B., ... & Reysner, M. (2026). Inflammatory Biomarkers Following Orthopedic Surgery: Current Evidence, Clinical Applications, and Future Perspectives—A Narrative Review. Journal of Clinical Medicine, 15(14), 5399. https://doi.org/10.3390/jcm15145399
Plein, L. M., & Rittner, H. L. (2018). Opioids and the immune system–friend or foe. British journal of pharmacology, 175(14), 2717-2725. https://doi.org/10.1111/bph.13750
Rahman, A. S., Harijanto, T., Negara, A. K., Marsetio, D., & Fadhilah, N. L. (2024). Relationship of neutrophil lymphocyte ratio with appendicitis incidence: Review of appendicitis patients at Ibnu Sina Hospital, Gresik Regency in 2022–2023. NUCLEUS, 5(2), 117–124. https://doi.org/10.37010/nuc.v5i02.1776
Ren, Q., Hua, L., Zhou, X., Cheng, Y., Lu, M., Zhang, C., et al. (2022). Effects of a single sub-anesthetic dose of ketamine on postoperative emotional responses and inflammatory factors in colorectal cancer patients. Frontiers in Pharmacology, 13, 818822. https://doi.org/10.3389/fphar.2022.818822
Rizvanović, N., Nesek Adam, V., Kalajdžija, M., Čaušević, S., Dervišević, S., & Smajić, J. (2023). Effects of preoperative oral carbohydrate loading on neutrophil/lymphocyte ratio and postoperative complications following colorectal cancer surgery: A randomized controlled study. European Surgical Research, 64(2), 278–285. https://doi.org/10.1159/000530124
Semerci, T., Tugcugil, E., & Besir, A. (2024). Relation between neutrophil-to-lymphocyte ratio with epidural analgesia timing and thoracotomy pain. Cirugía y Cirujanos, 92(1), 33–38. https://doi.org/10.24875/ciru.23000161
Seo, K. H., Choi, S. C., Kwak, J., & Kim, N. J. (2025). The effect of perioperative ketamine and esketamine administration on postoperative nausea and vomiting in patients undergoing general anesthesia: a systematic review and meta-analysis. Korean Journal of Anesthesiology, 79(2), 182-200. https://doi.org/10.4097/kja.24930
Serden, A., Sislituna, T., Şahin, M. E., Soner, A., Tire, Y., & Mermer, A. (2025). The effect of preemptive analgesia on postoperative pain in patients with high neutrophil-to-lymphocyte ratios: A prospective, randomized, double-blind, placebo-controlled trial. Annals of Surgical Treatment and Research, 109(4), 272–277. https://doi.org/10.4174/astr.2025.109.4.272
Shu, B., Xu, F., Zheng, X., Zhang, Y., Liu, Q., Li, S., ... & Duan, G. (2023). Change in perioperative neutrophil-lymphocyte ratio as a potential predictive biomarker for chronic postsurgical pain and quality of life: an ambispective observational cohort study. Frontiers in Immunology, 14, 1177285. https://doi.org/10.3389/fimmu.2023.1177285
Tang, L., Qu, S., Du, Z., Zhu, Y., Wu, L., & Wang, J. (2026). Efficacy of esketamine in reducing nausea and vomiting after anesthesia: a systematic review and meta-analysis of randomized controlled trials. Annals of Medicine, 58(1), 2604409. https://doi.org/10.1080/07853890.2025.2604409
Tantri, A. R., Rahmi, R., Marsaban, A. H. M., Satoto, D., Rahyussalim, A. J., & Sukmono, R. B. (2023). Comparison of postoperative IL-6 and IL-10 levels following erector spinae plane block (ESPB) and classical thoracolumbar interfascial plane (TLIP) block in a posterior lumbar decompression and stabilization procedure: A randomized controlled trial. BMC Anesthesiology, 23(1), 13. https://doi.org/10.1186/s12871-023-01973-w
Tassou, A., Richebe, P., & Rivat, C. (2025). Mechanisms of chronic postsurgical pain. Regional Anesthesia & Pain Medicine, 50(2), 77-85. https://doi.org/10.1136/rapm-2024-105964
Viderman, D., Mukazhan, D., Kapessova, K., Tungushpayev, M., & Badenes, R. (2024). The impact of ketamine on outcomes in acute pain management: An umbrella review. Journal of Clinical Medicine, 13(24), 7699. https://doi.org/10.3390/jcm13247699
Xiong, H. Y., Hendrix, J., Schabrun, S., Wyns, A., Campenhout, J. V., Nijs, J., & Polli, A. (2024). The role of the brain-derived neurotrophic factor in chronic pain: links to central sensitization and neuroinflammation. Biomolecules, 14(1), 71. https://doi.org/10.3390/biom14010071
Xuan, C., Yan, W., Wang, D., Li, C., Ma, H., Mueller, A., et al. (2022). Efficacy of preemptive analgesia treatments for the management of postoperative pain: A network meta-analysis. British Journal of Anaesthesia, 129(6), 946–958. https://doi.org/10.1016/j.bja.2022.08.038
Yao, W., Wang, W., Tang, W., Lv, Q., & Ding, W. (2023). Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) to predict postoperative pneumonia in elderly hip fracture patients. Journal of Orthopaedic Surgery and Research, 18(1), 673. https://doi.org/10.1186/s13018-023-04157-x
Yediyıldız, M. B., Durmuş, İ., Ak, H. Y., Taşkın, K., Ceylan, M. A. D., Yüce, Y., ... & Aydoğmuş, E. (2025). Comparison of inhalation and total intravenous anesthesia on inflammatory markers in microdiscectomy: a double-blind study. BMC anesthesiology, 25(1), 238. https://doi.org/10.1186/s12871-025-03119-6
Zhang, J., Ma, Q., Li, W., Li, X., & Chen, X. (2023). S-Ketamine attenuates inflammatory effect and modulates the immune response in patients undergoing modified radical mastectomy: A prospective randomized controlled trial. Frontiers in Pharmacology, 14, 1128924. https://doi.org/10.3389/fphar.2023.1128924
Copyright (c) 2026 Journal La Medihealtico
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
