Brazilian Journal of Anesthesiology
Brazilian Journal of Anesthesiology
Clinical Research

Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial

Efeito da pré-administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado

Jing Ma, Mian Peng, Fei Wang, Lei Chen, Zong-Ze Zhang, Yan-Lin Wang

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Background and objectives
Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol.

Ninety-six patients (ASA I or II, aged 18–65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5, 0.75 and 1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The “up-and-down” method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 μg.mL-1-lower (or-higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation and 15 minutes after intubation.

Results The EC50 of propofol was lower in Group C (2.32 μg.mL-1, 95% Confidence Interval [95% CI] 1.85–2.75) and D (2.39 μg.mL-1, 95% CI 1.91–2.67) than in Group A (2.96 μg.mL-1, 95% CI 2.55–3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 μg.mL-1, 95% CI 2.33–2.71) and Group A (p ˃ 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05).

High-dose FA (0.75 or 1 reduces the EC50 of propofol, and 1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.


Flurbiprofen axetil;  NSAIDs;  Median effective concentration;  Propofol


Justificativa e objetivos
A administração pré-operatória de Flurbiprofeno Axetil (FA) é amplamente usada para a modulação da analgesia. No entanto, a relação entre FA e fármacos sedativos permanece obscura. Neste estudo, nosso objetivo foi investigar os efeitos de diferentes doses de FA na Concentração Efetiva mediana (CE50) do propofol.

Noventa e seis pacientes (ASA I ou II, com idades de 18–65 anos) foram alocados aleatoriamente em quatro grupos na proporção de 1:1:1:1. Dez minutos antes da indução, o Grupo A (grupo controle) recebeu 10 mL de Intralipid, enquanto os grupos B, C e D receberam FA na dose de 0,5; 0,75 e 1, respectivamente. A profundidade da anestesia foi medida pelo Índice Bispectral (BIS). O método up-and-down foi usado para calcular a CE50 do propofol. Durante o período de equilíbrio, se o valor do BIS fosse ≤ 50 ou BIS > 50, o próximo paciente tinha a infusão de propofol ajustada para uma concentração alvo-controlada 0,5 μg.mL-1 inferior ou superior, respectivamente. Os dados hemodinâmicos foram registrados no início do estudo, 10 minutos após a administração de FA, após a indução, após a intubação e 15 minutos após a intubação.

A CE50 do propofol foi menor no Grupo C (2,32 μg.mL-1, Intervalo de Confiança de 95% [95% IC] 1,85–2,75) e D (2,39 μg.mL-1, 95% IC 1,91–2,67) do que no Grupo A (2,96 μg.mL-1; 95% IC 2,55–3,33) (p = 0,023, p = 0,048, respectivamente). Não houve diferenças significantes na CE50 entre o Grupo B (2,53 μg.mL-1, 95% IC 2,33–2,71) e o Grupo A (p > 0,05). Não houve diferenças significantes na Frequência Cardíaca (FC) entre os grupos A, B e C. A FC foi significantemente menor no grupo D do que no grupo A após a intubação (66 ± 6 vs. 80 ± 10 bpm, p < 0,01) e 15 minutos após a intubação (61 ± 4 vs. 70 ± 8 bpm, p < 0,01). Não houve diferenças significantes entre os quatro grupos na Pressão Arterial Média (PAM) em qualquer momento. A PAM dos quatro grupos foi significantemente menor após a indução, após a intubação e 15 minutos após a intubação do que na linha de base (p < 0,05).

FA em altas doses (0,75 ou 1 reduz a CE50 do propofol, e 1 de FA reduz a FC durante níveis adequados de anestesia em pacientes não estimulados. Embora esse resultado deva ser investigado na presença de estimulação cirúrgica, sugerimos que a pré-administração de FA pode reduzir a necessidade de propofol durante anestesia cuja profundidade seja monitorada pelo BIS.


Flurbiprofeno axetil;  AINE;  Concentração efetiva mediana;  Propofol


[1] M.T. Roszkowski, J.Q. Swift, K.M. Hargreaves Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S)-flurbiprofen following extraction of impacted third molars Pain., 73 (1997), pp. 339-345

[2] K. Wang, J. Luo, L. Zheng, et al. Preoperative flurbiprofen axetil administration for acute postoperative pain: a meta-analysis of randomized controlled trials J Anesth., 31 (2017), pp. 852-860

[3] X. Xiang, X. Yuan, Y. Lian, et al. Effect of oxycodone hydrochloride combined with flurbiprofen axetil for intravenous patient-controlled analgesia in lower abdominal patients: A randomized trial Medicine (Baltimore)., 97 (2018), p. e9911

[4] J. Wang, H. Li, H. Ma, et al. Effect of preemptive flurbiprofen axetil and tramadol on transurethral resection of the prostate under spinal anesthesia Pain Res Treat., 2016 (2016), p. 3942040

[5] A. Wallstrom, G.H. Frisman Facilitating early recovery of bowel motility after colorectal surgery: a systematic review J Clin Nurs., 23 (2014), pp. 24-44

[6] Y. Xu, Z. Tan, J. Chen, et al. Intravenous flurbiprofen axetil accelerates restoration of bowel function after colorectal surgery Can J Anaesth., 55 (2008), pp. 414-422

[7] L. Zhang, J. Zhu, L. Xu, et al. Efficacy and safety of flurbiprofen axetil in the prevention of pain on propofol injection: a systematic review and meta-analysis Med Sci Monit., 20 (2014), pp. 995-1002

[8] R. Ueki, M. Tanimoto, T. Tatara, et al. Emulsion of flurbiprofen axetil reduces propofol injection pain due to a decrease in free propofol concentration J Anesth., 21 (2007), pp. 325-329

[9] G. Kobal, C. Hummel, B. Nuernberg, et al. Effects of pentazocine and acetylsalicylic acid on pain-rating, pain-related evoked potentials and vigilance in relationship to pharmacokinetic parameters Agents Actions., 29 (1990), pp. 342-359

[10] J. Lotsch, P. Mohammadian, T. Hummel, et al. Effects of azapropazone on pain-related brain activity in human subjects Br J Clin Pharmacol., 40 (1995), pp. 545-552

[11] J.A. Horne Aspirin and nonfebrile waking oral temperature in healthy men and women: links with SWS changes? Sleep., 12 (1989), pp. 516-521

[12] M.C. Wallenstein Differential effects of prostaglandin synthetase inhibitors on EEG in rat Eur J Pharmacol., 111 (1985), pp. 201-209

[13] W. Geng, W. Hong, J. Wang, et al. Flurbiprofen Axetil Enhances Analgesic Effects of Sufentanil and Attenuates Postoperative Emergence Agitation and Systemic Proinflammation in Patients Undergoing Tangential Excision Surgery Mediators Inflamm., 2015 (2015), p. 601083

[14] Y.G. Yang, L.H. Hu, H. Chen, et al. Target-controlled infusion of remifentanil with or without flurbiprofen axetil in sedation for extracorporeal shock wave lithotripsy of pancreatic stones: a prospective, open-label, randomized controlled trial BMC Anesthesiol., 15 (2015), p. 161

[15] A.E. Ibrahim, J.K. Taraday, E.D. Kharasch Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol Anesthesiology., 95 (2001), pp. 1151-1159

[16] P.S. Glass, M. Bloom, L. Kearse, et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers Anesthesiology., 86 (1997), pp. 836-847

[17] W.J. Dixon Staircase bioassay: the up-and-down method Neurosci Biobehav Rev., 15 (1991), pp. 47-50

[18] L.P. Wang, P. McLoughlin, M.J. Paech, et al. Low and moderate remifentanil infusion rates do not alter target-controlled infusion propofol concentrations necessary to maintain anesthesia as assessed by bispectral index monitoring Anesth Analg., 104 (2007), pp. 325-331

[19] P. Tang, R. Eckenhoff Recent progress on the molecular pharmacology of propofol F1000Res., 7 (2018), p. 123

[20] I.J. Jang, A.J. Davies, N. Akimoto, et al. Acute inflammation reveals GABAA receptor-mediated nociception in mouse dorsal root ganglion neurons via PGE2 receptor 4 signaling Physiol Rep. (2017), pp. 5-8

[21] H.T. Ton, T.X. Phan, A.M. Abramyan, et al. Identification of a putative binding site critical for general anesthetic activation of TRPA1 Proc Natl Acad Sci U S A., 114 (2017), pp. 3762-3767

[22] K.A. Woll, K.A. Skinner, E. Gianti, et al. Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling Biophys J., 113 (2017), pp. 2168-2172

[23] H. Hu, J. Tian, Y. Zhu, et al. Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs Pflugers Arch., 459 (2010), pp. 579-592

[24] M.M. Sahinovic, M. Struys, A.R. Absalom Clinical Pharmacokinetics and Pharmacodynamics of Propofol Clin Pharmacokinet. July (2018), p. 18

[25] K. Ogata, N. Takamura, J. Tokunaga, et al. Dosage plan of a flurbiprofen injection product using inhibition of protein binding by lipid emulsion in rats J Pharm Pharmacol., 60 (2008), pp. 15-20

[26] J.X. Mazoit, K. Samii Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics Br J Clin Pharmacol., 47 (1999), pp. 35-42

[27] K.R. Sweeney, D.J. Chapron, E.J. Antal, et al. Differential effects of flurbiprofen and aspirin on acetazolamide disposition in humans Br J Clin Pharmacol., 27 (1989), pp. 866-869

[28] X. Chi, J. Pan, J. Cai, et al. Pharmacokinetic Analysis of Propofol Target-Controlled Infusion Models in Chinese Patients with Hepatic Insufficiency Med Sci Monit., 24 (2018), pp. 6925-6933

[29] Y.H. Li, J.H. Xu, J.J. Yang, et al. Predictive performance of ‘Diprifusor’ TCI system in patients during upper abdominal surgery under propofol/fentanyl anesthesia J Zhejiang Univ Sci B., 6 (2005), pp. 43-48

[30] S. Aggarwal, V.K. Goyal, S.K. Chaturvedi, et al. A comparative study between propofol and etomidate in patients under general anesthesia Braz J Anesthesiol., 66 (2016), pp. 237-241

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