The use of ketamine on emergence agitation in
children: a systematic review and meta-analysis

Ka Ting Ng; Jun Chuen Hui; Wan Yi Teoh; Ina Ismiarti Shariffuddin; Mohd Fitry Zainal Abidin

doi:10.1016/j.bjane.2025.844675

Revisão Sistemática

The use of ketamine on emergence agitation in children: a systematic review and meta-analysis

Uso da cetamina no delírio ao despertar em crianças: revisão sistemática e meta-análise

Ka Ting Ng, Jun Chuen Hui, Wan Yi Teoh, Ina Ismiarti Shariffuddin, Mohd Fitry Zainal Abidin

http://dx.doi.org/10.1016/j.bjane.2025.844675 Braz J Anesthesiol, vol.75, n6, 844675, 2025

PDF

Downloads: 0

Abstract

Background

Ketamine is believed to reduce the incidence of emergence agitation in children after surgery. However, recent studies reported contradictory ﬁndings. Thus, the primary objective of this review and meta-analysis was to investigate the use of ketamine in the reduction of emergence agitation in children undergoing surgery or procedure.

Methods

MEDLINE, EMBASE and CENTRAL were systematically searched from their inception date until March 2024. Randomized controlled trials comparing intravenous ketamine and placebo in children were sought. Observational studies, editorial letters or case reports were excluded.

Results

Seventeen studies (1515 patients) were included. Children who received ketamine were reported to have a signiﬁcantly lower incidence of emergence agitation (OR = 0.27, 95% Conﬁdence Interval: 0.16 to 0.45, p < 0.00001, I² = 61%, certainty of evidence: very low). As compared to placebo, the ketamine group had a signiﬁcantly lower postoperative pain score (MD = -2.28, 95% Conﬁdence Interval -3.68 to -0.87, p = 0.001, I² = 91%, certainty of evidence: very low). However, no signiﬁcant differences were observed in the incidence of postoperative nausea and vomiting, desaturation, and laryngospasm.

Conclusion

This meta-analysis highlights the potential beneﬁts of ketamine in the reduction of emergence agitation in children undergoing surgery or diagnostic procedures. However, high degrees of heterogeneity and low certainty of evidence limit the recommendations of the routine use of ketamine in the prevention of emergence agitation in children. Further high-quality randomized controlled trials are warranted before routine use can be recommended.

PROSPERO registration
CRD42024523680.

Keywords

Emergence agitation; Emergence delirium; Ketamine; Meta-analysis; Pain; Systematic review

Resumo

Introdução

Acredita-se que a cetamina reduza a incidência de delírio ao despertar (ED) em crianças após cirurgias. No entanto, estudos recentes têm apresentado resultados contraditórios. Assim, o objetivo principal desta revisão e meta-análise foi investigar o uso da cetamina na redução do ED em crianças submetidas a procedimentos cirúrgicos ou diagnósticos.

Métodos

As bases de dados MEDLINE, EMBASE e CENTRAL foram pesquisadas sistematicamente desde sua criação até março de 2024. Foram incluídos ensaios clínicos randomizados que compararam cetamina intravenosa com placebo em crianças. Estudos observacionais, cartas ao editor e relatos de caso foram excluídos.

Resultados

Dezessete estudos (1515 pacientes) foram incluídos. As crianças que receberam cetamina apresentaram uma incidência significativamente menor de ED (OR = 0,27; Intervalo de Confiança [IC] 95%: 0,16–0,45; p < 0,00001; I² = 61%; certeza da evidência: muito baixa). Em comparação ao placebo, o grupo cetamina apresentou um escore de dor pós-operatória significativamente menor (Diferença Média [MD] = -2,28; IC 95%: -3,68 a -0,87; p = 0,001; I² = 91%; certeza da evidência: muito baixa). No entanto, não houve diferenças significativas na incidência de náusea e vômito pós-operatórios, dessaturação e laringoespasmo.

Conclusão

Esta meta-análise destaca os potenciais benefícios da cetamina na redução do delírio ao despertar em crianças submetidas a cirurgias ou procedimentos diagnósticos. Entretanto, o alto grau de heterogeneidade e a baixa certeza das evidências limitam a recomendação do uso rotineiro da cetamina para prevenção do ED em crianças. São necessários ensaios clínicos randomizados de alta qualidade antes que seu uso sistemático possa ser recomendado.

Registro PROSPERO
CRD42024523680.

Palavras-chave

Delírio ao despertar; Agitação ao despertar; Cetamina; Meta-análise; Dor; Revisão sistemática

Referências

1. Urits I, Peck J, Giacomazzi S, et al. Emergence Delirium in Perioperative Pediatric Care: a Review of Current Evidence and New Directions. Adv Ther. 2020;37(5):1897−909.

2. Eckenhoff JE, Kneale DH. Dripps RD. The incidence and etiology of postanesthetic excitement A Clinical Survey. Anesthesiology. 1961;22(5):667−73.

3. Nair S, Wolf A. Emergence delirium after paediatric anaesthesia: new strategies in avoidance and treatment. BJA Educ. 2018;18:30−3.

4. Hudek K. Emergence Delirium: a Nursing Perspective. AORN J. 2009;89:509−20.

5. Lee SJ, Sung TY. Emergence agitation: current knowledge and unresolved questions. Korean J Anesthesiol. 2020;73:471−85.

6. Aniley HT, Mekuria ST, Kebede MA, Gebreanania AH, Muleta MB, Aniley TT. Magnitude of emergence agitation, its interventions and associated factors among paediatric surgical patients. BMC Anesthesiol. 2024;24:236.

7. Sikich N, Lerman J. Development and Psychometric Evaluation of the Pediatric Anesthesia Emergence Delirium Scale. Anesthesiology. 2004;100:1138−45.

8. Gao Z, Zhang J, Nie X, Cui X. Effectiveness of Intravenous Ibuprofen on Emergence Agitation in Children Undergoing Tonsillectomy with Propofol and Remifentanil Anesthesia: a Randomized Controlled Trial. J Pain Res. 2022;15:1401−10.

9. Chen JY, Jia JE, Liu TJ, Qin MJ, Li WX. Comparison of the effects of dexmedetomidine, ketamine, and placebo on emergence agitation after strabismus surgery in children. Can J Anaesth J Can Anesth. 2013;60:385−92.

10. Eghbal MH, Taregh S, Amin A, Sahmeddini MA. Ketamine improves postoperative pain and emergence agitation following adenotonsillectomy in children. A randomized clinical trial. Middle East J Anaesthesiol. 2013;22:155−60.

11. Zorumski CF, Izumi Y, Ketamine Mennerick S. NMDA Receptors and Beyond. J Neurosci Off J Soc Neurosci. 2016;36:11158−64.

12. Abu-Shahwan I, Chowdary K. Ketamine is effective in decreasing the incidence of emergence agitation in children undergoing dental repair under sevoflurane general anesthesia. Paediatr Anaesth. 2007;17:846−50.

13. Demir CY, Yuzkat N. Prevention of Emergence Agitation with Ketamine in Rhinoplasty. Aesthetic Plast Surg. 2018;42:847−53.

14. Lee YS, Kim WY, Choi JH, Son JH, Kim JH, Park YC. The effect of ketamine on the incidence of emergence agitation in children undergoing tonsillectomy and adenoidectomy under sevoflurane general anesthesia. Korean J Anesthesiol. 2010;58:440.

15. Ng KT, Sarode D, Lai YS, Teoh WY, Wang CY. The effect of ketamine on emergence agitation in children: a systematic review and meta-analysis. Paediatr Anaesth. 2019;29:1163−72.

16. Higgins J, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024) [Internet]. Cochrane; 2024. Available from: www. training.cochrane.org/handbook.

17. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

18. Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.. -d5928.

19. Russell PSS, Mammen PM, Shankar SR, et al. Pediatric Anesthesia Emergence Delirium Scale: a diagnostic meta-analysis. World J Clin Pediatr. 2022;11:196−205.

20. Simonsen BY, Skovby P, Lisby M. An evaluation of the Danish version of the Pediatric Anesthesia Emergence Delirium scale. Acta Anaesthesiol Scand. 2020;64:613−9.

21. Stamper MJ, Hawks SJ, Taicher BM, Bonta J, Brandon DH. Identifying pediatric emergence delirium by using the PAED Scale: a quality improvement project. AORN J. 2014;99:480−94.

22. Bong CL, Ng ASB. Evaluation of emergence delirium in Asian children using the Pediatric Anesthesia Emergence Delirium Scale. Paediatr Anaesth. 2009;19:593−600.

23. RevMan 2014 [Internet]. The Cochrane Collaboration; 2014. (Review Manager (RevMan)). Available from: revman.cochrane.org.

24. GRADEpro GDT [Internet]. McMaster University and Evidence Prime. (GRADEpro Guideline Development Tool)Available from: gradepro.org.

25. Schunemann H, Bro € zek J, Guyatt G, Oxman A. GRADE handbook _ for grading quality of evidence and strength of recommendations [Internet]. The GRADE Working Group; Available from: guidelinedevelopment.org/handbook.

26. Jeong WJ, Kim WY, Moon MG, et al. The effect of ketamine on the separation anxiety and emergence agitation in children undergoing brief ophthalmic surgery under desflurane general anesthesia. Korean J Anesthesiol. 2012;63:203−8.

27. Abdelhalim AA, Alarfaj AM. The effect of ketamine versus fentanyl on the incidence of emergence agitation after sevoflurane anesthesia in pediatric patients undergoing tonsillectomy with or without adenoidectomy. Saudi J Anaesth. 2013;7:392.

28. Ozcan A, Kaya AG, Ozcan N, et al. Effects of ketamine and midazolam on emergence agitation after sevoflurane anaesthesia in children receiving caudal block: a randomized trial]. Rev Bras Anestesiol. 2014;64:377−81.

29. Rashad MM, Soud DEM. The effect of different drugs on sevoflurane emergence agitation in pediatric patients undergoing hypospadias repair surgery. Egypt J Anaesth. 2014;30:123−7.

30. Rizk SN, Samir EM. Use of ketofol to control emergence agitation in children undergoing adenotonsillectomy. Egypt J Anaesth. 2014;30:13−9.

31. Ozturk T, Ac{kel A, Y{lmaz O, Topcu I, ¸ Cev ¸ {kkalp E, Yuksel H. Effects of low-dose propofol vs ketamine on emergence cough in children undergoing flexible bronchoscopy with sevofluraneremifentanil anesthesia: a randomized, double-blind, placebocontrolled trial. J Clin Anesth. 2016;35:90−5.

32. Jalili S, Esmaeeili A, Kamali K, Rashtchi V. Comparison of effects of propofol and ketofol (Ketamine-Propofol mixture) on emergence agitation in children undergoing tonsillectomy. Afr Health Sci. 2019;19:1736.

33. Ibrahim DMHA, Mostafa ZA, Ismail YAA, Ashoor TMA. The effect of low dose nalbuphine or ketamine in the prevention of emergence agitation after sevoflurane anesthesia in children undergoing tonsillectomy with or without adenoidectomy. Egypt J Anaesth. 2023;39:894−9.

34. Chen Y, Ru F, Ye Q, et al. Effect of S-ketamine administered at the end of anesthesia on emergence delirium in preschool children undergoing tonsillectomy and/or adenoidectomy. Front Pharmacol. 2023;14:1044558.

35. Qiu J, Cao H, Zhu Z, Jin H. Effects of S-ketamine on emergence agitation during general anesthesia of pediatric ambulatory laparoscopy. J Clin Pediatr Surg. 2023;22:447−53.

36. Dalens BJ, Pinard AM, Letourneau DR, Albert NT, Truchon RJY. Prevention of emergence agitation after sevoflurane anesthesia for pediatric cerebral magnetic resonance imaging by small doses of ketamine or nalbuphine administered just before discontinuing anesthesia. Anesth Analg. 2006;102:1056−61.

37. Moawad HES, El-Diasty T. Efficacy of ketamine in prevention of agitation in children undergoing magnetic resonance imaging under face mask sevoflurane: a randomized trial. Egypt J Anaesth. 2015;31:121−5.

38. Schmitz A, Weiss M, Kellenberger C, et al. Sedation for magnetic resonance imaging using propofol with or without ketamine at induction in pediatrics-A prospective randomized double-blinded study. Paediatr Anaesth. 2018;28:264−74.

39. Zhang Y, Ye F, Zhang T, et al. Structural basis of ketamine action on human NMDA receptors. Nature. 2021;596:301−5.

40. Ramírez D, Zuniga R, Concha G, Z ~ uniga L. HCN Channels: new ~ Therapeutic Targets for Pain Treatment. Mol Basel Switz. 2018;23:2094.

41. Omidvar S, Ebrahimi F, Amini N, et al. Comparing the effect of ketamine and lidocaine on agitation and pain in rhinoplasty: a randomized clinical trial. J Cutan Aesthetic Surg. 2023;16:107−13.

42. Dwivedi P, Patel TK, Bajpai V, Singh Y, Tripathi A, Kishore S. Efficacy and safety of intranasal ketamine compared with intranasal dexmedetomidine as a premedication before general anesthesia in pediatric patients: a systematic review and metaanalysis of randomized controlled trials. Can J Anesth Can Anesth. 2022;69:1405−18.

43. Tan D, Xia H, Sun S, Wang F. Effect of ancillary drugs on sevoflurane related emergence agitation in children undergoing ophthalmic surgery: a Bayesian network meta-analysis. BMC Anesthesiol. 2019;19:138.

44. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: insights into Therapeutic Mechanisms. Pharmacol Rev. 2018;70:621−60.

45. Roytblat L, Korotkoruchko A, Katz J, Glazer M, Greemberg L, Fisher A. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg. 1993;77:1161−5.

46. Backonja M, Arndt G, Gombar KA, Check B, Zimmermann M. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain. 1994;56:51−7.

47. Eide PK, Jørum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain. 1994;58:347−54.

48. Fu Y., Gao Y., Zou J., et al. The side effect of long-term lowdose ketamine: anxiety and relatedmetabolomics characteristics change in rat [Internet]. In Review; 2024 [cited 2025 Jan 8]. Available from: https://www.researchsquare.com/article/rs4739679/v1.

49. Ji D, Karlik J. Neurotoxic Impact of Individual Anesthetic Agents on the Developing Brain. Children. 2022;9:1779.

50. Haas DA, Harper DG. Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog. 1992;39:61−8.

51. Conway A, Rolley J, Sutherland JR. Midazolam for sedation before procedures. Cochrane Emergency and Critical Care Group, editor. Cochrane Database Syst Rev. 2016;2018: CD009491.

52. Fang XZ, Gao J, Ge YL, Zhou LJ, Zhang Y. Network Meta-Analysis on the Efficacy of Dexmedetomidine, Midazolam, Ketamine, Propofol, and Fentanyl for the Prevention of SevofluraneRelated Emergence Agitation in Children. Am J Ther. 2016;23: e1032−42.

53. Dahlem C, Monteiro C, Mendes E, et al. Modulating Influence of State Anxiety on the Effect of Midazolam on Postsurgical Pain. J Clin Med. 2023;12:2669.

54. Coursin DB, Coursin DB, Maccioli GA. Dexmedetomidine. Curr Opin Crit Care. 2001;7:221−6.

55. Bi X, Wei J, Zhang X. Effects of dexmedetomidine on neurocognitive disturbance after elective non-cardiac surgery in senile patients: a systematic review and meta-analysis. J Int Med Res. 2021;49:03000605211014294.

56. Ni J, Wei J, Yao Y, Jiang X, Luo L, Luo D. Effect of Dexmedetomidine on Preventing Postoperative Agitation in Children: a MetaAnalysis Gemma M, editor Plos One. 2015;10:e0128450.

57. Zhu M, Wang H, Zhu A, Niu K, Wang G. Meta-Analysis of Dexmedetomidine on Emergence Agitation and Recovery Profiles in Children after Sevoflurane Anesthesia: different Administration and Different Dosage editor Gao CQ, editor. Meta-Analysis of Dexmedetomidine on Emergence Agitation and Recovery Profiles in Children after Sevoflurane Anesthesia: different Administration and Different Dosage. Plos One. 2015;10:e0123728.

Submetido em:
13/02/2025

Aceito em:
19/08/2025