Dose-dependent Immunomodulatory Effects of Esketamine in Pediatric Adenotonsillectomy
,
Abstract
Background:
Surgical stress in pediatric adenotonsillectomy can trigger marked immune and inflammatory disturbances. Esketamine, beyond its anesthetic role, has been reported to exhibit immunomodulatory and anti-inflammatory properties. However, its dose-dependent impact on perioperative immune homeostasis in children remains unclear.
Surgical stress in pediatric adenotonsillectomy can trigger marked immune and inflammatory disturbances. Esketamine, beyond its anesthetic role, has been reported to exhibit immunomodulatory and anti-inflammatory properties. However, its dose-dependent impact on perioperative immune homeostasis in children remains unclear. This study aimed to investigate the impact of varying doses of esketamine on perioperative inflammatory cytokines, immune cell balance, and humoral immune markers in pediatric patients undergoing adenotonsillectomy.
Ninety pediatric patients (3–10 years) were retrospectively assigned into three groups based on the esketamine dose they received: low-dose (0.25 mg/kg), medium-dose (0.5 mg/kg), or high-dose (1 mg/kg) esketamine. Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were measured to assess systemic inflammation, while CD4+/CD8+ ratios, immunoglobulin (Ig) A, and IgG were evaluated as immune function indices at baseline, 1 hour, and 24 hours postoperatively. Hemodynamic parameters and clinical recovery indices were also recorded.
Compared with the low-dose and high-dose groups, the 0.5 mg/kg esketamine group showed significantly attenuated elevations in IL-6 and CRP, a faster normalization of the CD4+/CD8+ ratio, and preservation of IgA levels within near-normal range. These immunological benefits coincided with improved postoperative recovery and fewer adverse events. No significant differences were observed in IgG levels among groups.
This study identifies 0.5 mg/kg as a potential immunoprotective threshold for esketamine, effectively mitigating perioperative immune suppression and excessive inflammation in children undergoing adenotonsillectomy, an insight beyond its known anesthetic properties.
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3. Wang J, Feng Y, Qi Z, Li J, Chen Z, Zhang J, et al. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway. Open Life Sci. 2024;19(1):20220816.
4. Cao Y, Song Y, Wang Z, Tang J, Yi J, Liu Y, et al. Effects of different dosages esketamine on cardiac conduction and heterogeneity of Cx43: the epicardial mapping in guinea pigs. Ann Transl Med. 2022;10(14):772.
5. Weiyun S, Yan Y, Wenjuan Z, Junmei X, Zhijian L, Lin Y. Esketamine mitigates systemic inflammation via modulating phenotypic transformation of monocytes in patients undergoing thoracic surgery. Life Sci. 2025;371:123594.
6. Fageeh YA. Clinical Impact of Preoperative Tonsil and Adenoid Size on Symptomatic Outcomes Following Adenotonsillectomy in Pediatric Patients. Cureus. 2023;15(10):e47093.
7. Proshad NE, Pedro P, Jenny P, Kiley FP, Ron BM, Peter S. Pediatric obstructive sleep apnea: a prospective observational study of respiratory events in the immediate recovery period after adenotonsillectomy. Anaesth Crit Care Pain Med. 2024;43(4):101385.
8. Ayuko I. Extubation and removal of supraglottic airway devices in pediatric anesthesia. Anesthesia and Pain Medicine. 2024;19.
9. Ramy M, Mohammed Sayed S, Amr AK. Opioid Free Ptyregopalatine Ganglion Block Based Multimodal Anesthesia Versus Conventional Opioid Based Multimodal Anesthesia for Tonsillectomy Operations: A Randomized Controlled Trial. Anesthesiology and Pain Medicine. 2024;14(3).
10. Passaint FH, Amany HS. Comparison of dexmedetomidine, ketamine, and magnesium sulfate for the prevention of emergence agitation following sevoflurane-based anesthesia in pediatric cardiac catheterization. Minerva Anestesiologica. 2025;91(3).
11. Liao Y, Xie S, Zhuo Y, Chen S, Luo Y, Wei Y, et al. Intranasal Dexmedetomidine-Esketamine Combination Premedication versus Monotherapy for Reducing Emergence Delirium and Postoperative Behavioral Changes in Pediatric Tonsillectomy and/or Adenoidectomy: A Randomized Controlled Trial. Drug design, development and therapy. 2024;18:4693-703.
12. Wang Y, Ma B, Wang C, Wang Y, Liu A, Hang L. The influence of low-dose s-ketamine on postoperative delirium and cognitive function in older adults undergoing thoracic surgery. J Cardiothorac Surg. 2024;19(1):324.
13. Wakabayashi N, Watanabe S, Abe T, Takenaka J, Hirata K, Kimura R, et al. Safety and efficacy of multiple-dose versus single-dose MIBG therapy in patients with refractory pheochromocytoma and paraganglioma: a single-center retrospective analysis. Ann Nucl Med. 2024;38(7):553-62.
14. Jung KW, Kim WJ, Jeong HW, Kwon HM, Moon YJ, Jun IG, et al. Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis. Anesth Analg. 2018;126(3):796-804.
15. Ye T, Zhang N, He Y, Chen C, Zha Q, Zhang A, et al. Electroacupuncture pretreatment inhibits the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and modulates microglial polarization to alleviate cerebral ischemia-reperfusion injury in rats. Neuroscience. 2024;562:33-42.
16. Singh I, Kim J, Touhidul Islam SM, Fei Q, Singh AK, Won J. The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE). Neuroscience. 2025;564:1-12.
17. Ringblom J, Wåhlin I, Proczkowska M, Korhonen L, Årestedt K. Measurement Properties of the Pediatric Anesthesia Emergence Delirium Scale: A Confirmatory Factor Analysis-Based Study. Paediatr Anaesth. 2025;35(2):155-62.
18. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs. 2003;29(2):140-6.
19. Zhu Y, Wang X, Wang L, Zhang Y. Effects of esketamine on postoperative pain and inflammatory factors in children undergoing tonsillectomy and adenoidectomy. Minerva Anestesiol. 2025;91(1-2):18-25.
20. Ruíz-López P, Domínguez JM, Morgaz J, Quirós-Carmona S, Navarrete-Calvo R, Gómez-Villamandos RJ, et al. Evaluation of the averaged parasympathetic tone activity and its dynamic variation to assess intraoperative nociception in relation to hemodynamic changes in dogs. Vet Q. 2023;43(1):1-9.
21. Shamim M, Sepideh G, Razieh Mohammad J, Shafaroodi H, Dehpour A, Sanatkar M. The N‐methyl‐D‐aspartate receptor antagonist ketamin exerts analgesic effects via modulation of the nitric oxide pathway. Fundamental Clin Pharmacol. 2022((6)):956-65.
22. Yang H, Zhao Q, Chen HY, Liu W, Ding T, Yang B, et al. The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial. Br J Clin Pharmacol. 2022;88(3):1279-87.
23. Ikeda S, Shinohara K, Kashihara S, Matsumoto S, Yoshida D, Nakashima R, et al. Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats. Hypertens Res. 2024;47(8):2133-43.
24. Zihui Y, Ziying X, Tongtong F, Shiyu L, Jinghua C, Bing Z, et al. Parallel comparison of T cell and B cell subpopulations of adenoid hypertrophy and tonsil hypertrophy of children. Nature Communications. 2025;16(1).
25. Xu Q, Milanez-Almeida P, Martins AJ, Radtke AJ, Hoehn KB, Oguz C, et al. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nat Immunol. 2023;24(1):186-99.
26. Madi A, Weisshaar N, Buettner M, Poschet G, Ma S, Wu J, et al. CD8 agonism functionally activates memory T cells and enhances antitumor immunity. Int J Cancer. 2022;151(5):797-808.
27. Pracha SH, Shrestha S, Ryan N, Upadhaya P, Lamenza FF, Jagadeesha S, et al. Targeting macrophage migration inhibitory factor to inhibit T cell immunosuppression in the tumor microenvironment and improve cancer outcomes in head and neck squamous cell carcinoma. Oral Oncol. 2025;160:107126.
28. Hanahan D, Michielin O, Pittet MJ. Convergent inducers and effectors of T cell paralysis in the tumour microenvironment. Nat Rev Cancer. 2025;25(1):41-58.
29. Wu W, Li Y, Wu X, Liang J, You W, He X, et al. Carnosic acid nanocluster-based framework combined with PD-1 inhibitors impeded tumorigenesis and enhanced immunotherapy in hepatocellular carcinoma. Funct Integr Genomics. 2024;24(1):5.
30. Qing X, Fengting Y, Liting Y, Xiaojie L, Xuelei L, Hongxin Z, et al. The CD4/CD8 ratio is associated with T lymphocyte functions in long-term virally suppressed patients with HIV. BMC Infectious Diseases. 2025;25(1).
31. Han J, Zhao L, Wu J, Diao Y, Guo Q, Yang J, et al. Role of CD4(+)T, CD8(+)T Cells, and CD4(+)T/CD8(+)T Cell Ratio in Gastric Cancer and Its Clinical Significance. Appl Bionics Biomech. 2022;2022:1094607.
32. Husien HM, Peng W, Essa MOA, Adam SY, Ur Rehman S, Ali R, et al. The Anti-Inflammatory Properties of Polysaccharides Extracted from Moringa oleifera Leaves on IEC6 Cells Stimulated with Lipopolysaccharide In Vitro. Animals (Basel). 2024;14(23).
33. Zhou X, Li Q, Luo Q, Wang L, Chen J, Xiong Y, et al. A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons. Drug Discov Ther. 2023;17(4):279-88.
34. Chen H, Zhi J, Wang L, Jin Z, Xu J, Xing F, et al. Subanesthetic Dose of Esketamine Improves the Sedative and Analgesic Effects of Dexmedetomidine and Remifentanil in Liposuction Anesthesia: A Prospective, Double-Blinded, Randomized Controlled Trial. Drug design, development and therapy. 2024;18:3645-58.
35. Ren YL, Yuan JJ, Xing F, Zhu LN, Zhang W. Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial. Pain Therapy. 2023;12(3):739-50.
36. He J, Lian X, Luo T. Evaluating dexmedetomidine in mitigating emergence agitation and perioperative complications in pediatric tonsillectomy and/or adenoidectomy: a systematic review and meta-analysis. Front Pharmacol. 2025;16:1681936.
37. Shen F, Zhang L, Wang X, Li B, Liu W, Xue Y, et al. Effect of Intravenous, Inhalational, or Combined Anesthesia Maintenance on Postoperative Respiratory Adverse Events in Children Undergoing Adenotonsillectomy (AmPRAEC): A Multicenter Randomized Clinical Trial. Anesthesiology. 2025;143(6):1484-96.
2. Mion G, Himmelseher S. Esketamine: Less Drowsiness, More Analgesia. Anesth Analg. 2024;139(1):78-91.
3. Wang J, Feng Y, Qi Z, Li J, Chen Z, Zhang J, et al. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway. Open Life Sci. 2024;19(1):20220816.
4. Cao Y, Song Y, Wang Z, Tang J, Yi J, Liu Y, et al. Effects of different dosages esketamine on cardiac conduction and heterogeneity of Cx43: the epicardial mapping in guinea pigs. Ann Transl Med. 2022;10(14):772.
5. Weiyun S, Yan Y, Wenjuan Z, Junmei X, Zhijian L, Lin Y. Esketamine mitigates systemic inflammation via modulating phenotypic transformation of monocytes in patients undergoing thoracic surgery. Life Sci. 2025;371:123594.
6. Fageeh YA. Clinical Impact of Preoperative Tonsil and Adenoid Size on Symptomatic Outcomes Following Adenotonsillectomy in Pediatric Patients. Cureus. 2023;15(10):e47093.
7. Proshad NE, Pedro P, Jenny P, Kiley FP, Ron BM, Peter S. Pediatric obstructive sleep apnea: a prospective observational study of respiratory events in the immediate recovery period after adenotonsillectomy. Anaesth Crit Care Pain Med. 2024;43(4):101385.
8. Ayuko I. Extubation and removal of supraglottic airway devices in pediatric anesthesia. Anesthesia and Pain Medicine. 2024;19.
9. Ramy M, Mohammed Sayed S, Amr AK. Opioid Free Ptyregopalatine Ganglion Block Based Multimodal Anesthesia Versus Conventional Opioid Based Multimodal Anesthesia for Tonsillectomy Operations: A Randomized Controlled Trial. Anesthesiology and Pain Medicine. 2024;14(3).
10. Passaint FH, Amany HS. Comparison of dexmedetomidine, ketamine, and magnesium sulfate for the prevention of emergence agitation following sevoflurane-based anesthesia in pediatric cardiac catheterization. Minerva Anestesiologica. 2025;91(3).
11. Liao Y, Xie S, Zhuo Y, Chen S, Luo Y, Wei Y, et al. Intranasal Dexmedetomidine-Esketamine Combination Premedication versus Monotherapy for Reducing Emergence Delirium and Postoperative Behavioral Changes in Pediatric Tonsillectomy and/or Adenoidectomy: A Randomized Controlled Trial. Drug design, development and therapy. 2024;18:4693-703.
12. Wang Y, Ma B, Wang C, Wang Y, Liu A, Hang L. The influence of low-dose s-ketamine on postoperative delirium and cognitive function in older adults undergoing thoracic surgery. J Cardiothorac Surg. 2024;19(1):324.
13. Wakabayashi N, Watanabe S, Abe T, Takenaka J, Hirata K, Kimura R, et al. Safety and efficacy of multiple-dose versus single-dose MIBG therapy in patients with refractory pheochromocytoma and paraganglioma: a single-center retrospective analysis. Ann Nucl Med. 2024;38(7):553-62.
14. Jung KW, Kim WJ, Jeong HW, Kwon HM, Moon YJ, Jun IG, et al. Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis. Anesth Analg. 2018;126(3):796-804.
15. Ye T, Zhang N, He Y, Chen C, Zha Q, Zhang A, et al. Electroacupuncture pretreatment inhibits the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and modulates microglial polarization to alleviate cerebral ischemia-reperfusion injury in rats. Neuroscience. 2024;562:33-42.
16. Singh I, Kim J, Touhidul Islam SM, Fei Q, Singh AK, Won J. The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE). Neuroscience. 2025;564:1-12.
17. Ringblom J, Wåhlin I, Proczkowska M, Korhonen L, Årestedt K. Measurement Properties of the Pediatric Anesthesia Emergence Delirium Scale: A Confirmatory Factor Analysis-Based Study. Paediatr Anaesth. 2025;35(2):155-62.
18. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. Pediatr Nurs. 2003;29(2):140-6.
19. Zhu Y, Wang X, Wang L, Zhang Y. Effects of esketamine on postoperative pain and inflammatory factors in children undergoing tonsillectomy and adenoidectomy. Minerva Anestesiol. 2025;91(1-2):18-25.
20. Ruíz-López P, Domínguez JM, Morgaz J, Quirós-Carmona S, Navarrete-Calvo R, Gómez-Villamandos RJ, et al. Evaluation of the averaged parasympathetic tone activity and its dynamic variation to assess intraoperative nociception in relation to hemodynamic changes in dogs. Vet Q. 2023;43(1):1-9.
21. Shamim M, Sepideh G, Razieh Mohammad J, Shafaroodi H, Dehpour A, Sanatkar M. The N‐methyl‐D‐aspartate receptor antagonist ketamin exerts analgesic effects via modulation of the nitric oxide pathway. Fundamental Clin Pharmacol. 2022((6)):956-65.
22. Yang H, Zhao Q, Chen HY, Liu W, Ding T, Yang B, et al. The median effective concentration of propofol with different doses of esketamine during gastrointestinal endoscopy in elderly patients: A randomized controlled trial. Br J Clin Pharmacol. 2022;88(3):1279-87.
23. Ikeda S, Shinohara K, Kashihara S, Matsumoto S, Yoshida D, Nakashima R, et al. Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats. Hypertens Res. 2024;47(8):2133-43.
24. Zihui Y, Ziying X, Tongtong F, Shiyu L, Jinghua C, Bing Z, et al. Parallel comparison of T cell and B cell subpopulations of adenoid hypertrophy and tonsil hypertrophy of children. Nature Communications. 2025;16(1).
25. Xu Q, Milanez-Almeida P, Martins AJ, Radtke AJ, Hoehn KB, Oguz C, et al. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nat Immunol. 2023;24(1):186-99.
26. Madi A, Weisshaar N, Buettner M, Poschet G, Ma S, Wu J, et al. CD8 agonism functionally activates memory T cells and enhances antitumor immunity. Int J Cancer. 2022;151(5):797-808.
27. Pracha SH, Shrestha S, Ryan N, Upadhaya P, Lamenza FF, Jagadeesha S, et al. Targeting macrophage migration inhibitory factor to inhibit T cell immunosuppression in the tumor microenvironment and improve cancer outcomes in head and neck squamous cell carcinoma. Oral Oncol. 2025;160:107126.
28. Hanahan D, Michielin O, Pittet MJ. Convergent inducers and effectors of T cell paralysis in the tumour microenvironment. Nat Rev Cancer. 2025;25(1):41-58.
29. Wu W, Li Y, Wu X, Liang J, You W, He X, et al. Carnosic acid nanocluster-based framework combined with PD-1 inhibitors impeded tumorigenesis and enhanced immunotherapy in hepatocellular carcinoma. Funct Integr Genomics. 2024;24(1):5.
30. Qing X, Fengting Y, Liting Y, Xiaojie L, Xuelei L, Hongxin Z, et al. The CD4/CD8 ratio is associated with T lymphocyte functions in long-term virally suppressed patients with HIV. BMC Infectious Diseases. 2025;25(1).
31. Han J, Zhao L, Wu J, Diao Y, Guo Q, Yang J, et al. Role of CD4(+)T, CD8(+)T Cells, and CD4(+)T/CD8(+)T Cell Ratio in Gastric Cancer and Its Clinical Significance. Appl Bionics Biomech. 2022;2022:1094607.
32. Husien HM, Peng W, Essa MOA, Adam SY, Ur Rehman S, Ali R, et al. The Anti-Inflammatory Properties of Polysaccharides Extracted from Moringa oleifera Leaves on IEC6 Cells Stimulated with Lipopolysaccharide In Vitro. Animals (Basel). 2024;14(23).
33. Zhou X, Li Q, Luo Q, Wang L, Chen J, Xiong Y, et al. A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons. Drug Discov Ther. 2023;17(4):279-88.
34. Chen H, Zhi J, Wang L, Jin Z, Xu J, Xing F, et al. Subanesthetic Dose of Esketamine Improves the Sedative and Analgesic Effects of Dexmedetomidine and Remifentanil in Liposuction Anesthesia: A Prospective, Double-Blinded, Randomized Controlled Trial. Drug design, development and therapy. 2024;18:3645-58.
35. Ren YL, Yuan JJ, Xing F, Zhu LN, Zhang W. Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial. Pain Therapy. 2023;12(3):739-50.
36. He J, Lian X, Luo T. Evaluating dexmedetomidine in mitigating emergence agitation and perioperative complications in pediatric tonsillectomy and/or adenoidectomy: a systematic review and meta-analysis. Front Pharmacol. 2025;16:1681936.
37. Shen F, Zhang L, Wang X, Li B, Liu W, Xue Y, et al. Effect of Intravenous, Inhalational, or Combined Anesthesia Maintenance on Postoperative Respiratory Adverse Events in Children Undergoing Adenotonsillectomy (AmPRAEC): A Multicenter Randomized Clinical Trial. Anesthesiology. 2025;143(6):1484-96.
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| Issue | Articles in Press | |
| Section | Brief Communication | |
| Keywords | ||
| Adenoidectomy Child Esketamine Immunomodulation Inflammation Tonsillectomy | ||
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How to Cite
1.
Guan X, He H. Dose-dependent Immunomodulatory Effects of Esketamine in Pediatric Adenotonsillectomy. Iran J Allergy Asthma Immunol. 2026;:1-14.
