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A Multicenter, Randomized, Double-Blind, Positive-Controlled, Non-Inferiority, Phase III Clinical Trial Evaluating the Efficacy and Safety of Emulsified Isoflurane for Anesthesia Induction in Patients

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Abstract

Background

Emulsified isoflurane was designed to circumvent the deficiencies of inhalation anesthetics, which have a longer time to onset, result in a higher drug consumption, and for which a specific anesthesia machine is required for clinical use. The aim of this study was to compare the efficacy and safety of emulsified isoflurane with propofol for anesthesia induction in adults patients.

Methods

This multicenter, randomized, double-blind, positive-controlled, non-inferiority, phase III clinical trial compared the efficacy and safety of emulsified isoflurane with propofol for anesthesia induction. Each patient in the emulsified isoflurane group received a single bolus injection of 12% emulsified isoflurane at a dose of 30 mg/kg, and each patient in the propofol group received a single bolus injection of 0.8% propofol at a dose of 2 mg/kg. The primary outcome of the efficacy evaluation was the proportion of participants with successful anesthesia induction, which was regarded as a Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score of < 1 and lack of use of other sedative drugs. A number of secondary efficacy outcomes were also assessed. Safety was monitored based on (1) adverse events, (2) repeated measurement of vital signs; (3) physical examination, (4) routine laboratory examinations of hematology, biochemistry, urine, coagulation function, and (5) 12-lead electrocardiogram.

Results

A total of 416 patients were enrolled (n = 208 in each group) and 398 patients were administered study drug. The proportion of participants with successful anesthesia induction was 100% with a 95% confidence interval of − 1.9% to + 1.9% for the emulsified isoflurane and propofol groups, which met the predesigned non-inferiority criteria of 5%. The study demonstrated the non-inferiority of sedation produced by emulsified isoflurane compared to propofol. Among the secondary efficacy outcomes, emulsified isoflurane showed a better cardiovascular stability than propofol. The number of patients from the emulsified isoflurane group who experienced drug-related adverse events was significantly higher than that of patients from the propofol group. However, there was no significant difference between the two groups in terms of adverse events or drug-related adverse events of grades 3–5.

Conclusions

Emulsified isoflurane exhibited non-inferiority of anesthesia/sedation compared to propofol in patients undergoing anesthesia induction.

Clinical Trial Registration

ChiCTR2000038185, registered on 12 December, 2020 (www.chictr.org.cn).

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References

  1. Kopriva CJ, Lowenstein E. An anesthetic accident: cardiovascular collapse from liquid halothane delivery. Anesthesiology. 1969;30(2):246–7.

    Article  CAS  PubMed  Google Scholar 

  2. Sandison JW, Sivapragasam S, Hayes JA, Woo-Ming MO. An experimental study of pulmonary damage associated with intravenous injection of halothane in dogs. Br J Anaesth. 1970;42(5):419–24.

    Article  CAS  PubMed  Google Scholar 

  3. Sutton J, Harrison GA, Hickie JB. Accidental intravenous injection of halothane: case report. Br J Anaesth. 1971;43(5):513–20.

    Article  CAS  PubMed  Google Scholar 

  4. Kawamoto M, Suzuki N, Takasaki M. Acute pulmonary edema after intravenous liquid halothane in dogs. Anesth Analg. 1992;74(5):747–52.

    Article  CAS  PubMed  Google Scholar 

  5. Biber B, Johannesson G, Lennander O, Martner J, Sonander H, Werner O. Intravenous infusion of halothane dissolved in fat: haemodynamic effects in dogs. Acta Anaesthesiol Scand. 1984;28(4):385–9.

    Article  CAS  PubMed  Google Scholar 

  6. Johannesson G, Alm P, Biber B, Lennander O, Werner O. Halothane dissolved in fat as an intravenous anaesthetic to rats. Acta Anaesthesiol Scand. 1984;28(4):381–4.

    Article  CAS  PubMed  Google Scholar 

  7. Huang H, Zhang W, Liu S, Yanfang C, Li T, Liu J. Cardioprotection afforded by St Thomas solution is enhanced by emulsified isoflurane in an isolated heart ischemia reperfusion injury model in rats. J Cardiothorac Vasc Anesth. 2010;24(1):99–103.

    Article  PubMed  Google Scholar 

  8. Zhou C, Wu W, Liu J, Liao DQ, Kang Y, Chen XD. Inhibition of voltage-gated sodium channels by emulsified isoflurane may contribute to its subarachnoid anesthetic effect in beagle dogs. Reg Anesth Pain Med. 2011;36(6):553–9.

    Article  CAS  PubMed  Google Scholar 

  9. Huang H, Zhou C, Liu J, Song H, Qiu Y. Adding emulsified isoflurane to cardioplegia solution produces cardiac protection in a dog cardiopulmonary bypass model. Sci Rep. 2016;28(6):23572.

    Article  Google Scholar 

  10. Yang XL, Ma HX, Yang ZB, Liu AJ, Luo NF, Zhang WS, et al. Comparison of minimum alveolar concentration between intravenous isoflurane lipid emulsion and inhaled isoflurane in dogs. Anesthesiology. 2006;104(3):482–7.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou JX, Luo NF, Liang XM, Liu J. The efficacy and safety of intravenous emulsified isoflurane in rats. Anesth Analg. 2006;102(1):129–34.

    Article  CAS  PubMed  Google Scholar 

  12. Zhou C, Liu J. A novel intravenous general anesthetic–emulsified isoflurane: from bench to bedside. Front Med. 2012;6(4):381–7.

    Article  PubMed  Google Scholar 

  13. Huang H, Li R, Liu J, Zhang W, Liao T, Yi X. A phase I, dose-escalation trial evaluating the safety and efficacy of emulsified isoflurane in healthy human volunteers. Anesthesiology. 2014;120(3):614–25.

    Article  CAS  PubMed  Google Scholar 

  14. Doyle DJ, Goyal A, Bansal P, Garmon EH. American Society of Anesthesiologists classification. Treasure Island: StatPearls; 2020.

    Google Scholar 

  15. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990;10(4):244–51.

    CAS  PubMed  Google Scholar 

  16. Fast JP, Perkins MG, Pearce RA, Mecozzi S. Fluoropolymer-based emulsions for the intravenous delivery of sevoflurane. Anesthesiology. 2008;109(4):651–6.

    Article  CAS  PubMed  Google Scholar 

  17. Yang H, Yin Q, Huang L, Zhang M, Zhang X, Sun Q, et al. The bioequivalence of emulsified isoflurane with a new formulation of emulsion: a single-center, single-dose, double-blinded, randomized, two-period crossover study. Front Pharmacol. 2021;12: 626307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jiajun ZHU, Jindong LIU, Daliang W, Yongwan W, Hailong XU. Effect of isoflurane treatment on myocardial ischemia-reperfusion injury of rats. J Clin Med Pract. 2016;17:4–7.

    Google Scholar 

  19. Tsikas D, Jordan J, Engeli S. Blood pressure-lowering effects of propofol or sevoflurane anaesthesia are not due to enhanced nitric oxide formation or bioavailability. Br J Clin Pharmacol. 2015;79(6):1030–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sneyd JR, Absalom AR, Barends CRM, Jones JB. Hypotension during propofol sedation for colonoscopy: an exploratory analysis. Br J Anaesth. 2021;128(4):610–22.

  21. Hilton P, Dev VJ, Major E. Intravenous anaesthesia with propofol and alfentanil: the influence of age and weight. Anaesthesia. 1986;41(6):640–3.

    Article  CAS  PubMed  Google Scholar 

  22. Ebert TJ, Muzi M, Berens R, Goff D, Kampine JP. Sympathetic responses to induction of anesthesia in humans with propofol or etomidate. Anesthesiology. 1992;76(5):725–33.

    Article  CAS  PubMed  Google Scholar 

  23. Tan CH, Onsiong MK. Pain on injection of propofol. Anaesthesia. 1998;53(5):468–76.

    Article  CAS  PubMed  Google Scholar 

  24. Doenicke AW, Roizen MF, Hoernecke R, Lorenz W, Ostwald P. Solvent for etomidate may cause pain and adverse effects. Br J Anaesth. 1999;83(3):464–6.

    Article  CAS  PubMed  Google Scholar 

  25. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011;15(342): d1110.

    Article  Google Scholar 

  26. Liu X, Nakano M, Yamaguchi A, Bush B, Akiyoshi K, Lee JK, et al. The association of bispectral index values and metrics of cerebral perfusion during cardiopulmonary bypass. J Clin Anesth. 2021;74: 110395.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, et al. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc. 2010;85(1):18–26.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Radtke FM, Franck M, Lendner J, Kruger S, Wernecke KD, Spies CD. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth. 2013;110(Suppl. 1):i98-105.

    Article  CAS  PubMed  Google Scholar 

  29. Chan MT, Cheng BC, Lee TM, Gin T, Group CT. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol. 2013;25(1):33–42.

    Article  PubMed  Google Scholar 

  30. Wildes TS, Mickle AM, Ben Abdallah A, Maybrier HR, Oberhaus J, Budelier TP, et al. Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial. JAMA. 2019;321(5):473–83.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sieber FE, Neufeld KJ, Gottschalk A, Bigelow GE, Oh ES, Rosenberg PB, et al. Effect of depth of sedation in older patients undergoing hip fracture repair on postoperative delirium: the STRIDE randomized clinical trial. JAMA Surg. 2018;153(11):987–95.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Short TG, Campbell D, Frampton C, Chan MTV, Myles PS, Corcoran TB, et al. Anaesthetic depth and complications after major surgery: an international, randomised controlled trial. Lancet. 2019;394(10212):1907–14.

    Article  PubMed  Google Scholar 

  33. Morohashi T, Itakura S, Shimokawa KI, Ishii F, Ikeda T, Kazama T. The effectiveness and stability of a 20% emulsified sevoflurane formulation for intravenous use in rats. Anesth Analg. 2016;122(3):712–8.

    Article  CAS  PubMed  Google Scholar 

  34. Morohashi T, Itakura S, Shimokawa KI, Ishii F, Sanjo Y, Kazama T. Anesthetic potency of intravenous infusion of 20% emulsified sevoflurane and effect on the blood-gas partition coefficient in dogs. Anesth Analg. 2021;132(2):575–83.

    Article  CAS  PubMed  Google Scholar 

  35. Karlsen KL, Persson E, Wennberg E, Stenqvist O. Anaesthesia, recovery and postoperative nausea and vomiting after breast surgery: a comparison between desflurane, sevoflurane and isoflurane anaesthesia. Acta Anaesthesiol Scand. 2000;44(4):489–93.

    Article  CAS  PubMed  Google Scholar 

  36. Valanne JV, Korttila K. Recovery following general anesthesia with isoflurane or enflurane for outpatient dentistry and oral surgery. Anesth Prog. 1988;35(2):48–52.

  37. Chiari PC, Pagel PS, Tanaka K, Krolikowski JG, Ludwig LM, Trillo RA Jr, et al. Intravenous emulsified halogenated anesthetics produce acute and delayed preconditioning against myocardial infarction in rabbits. Anesthesiology. 2004;101(5):1160–6.

    Article  CAS  Google Scholar 

  38. Liu S-l, Liu J. Cadioprotective effects of emulsified isoflurane and intralipid on ischemia-reperfusion injury in isolated rat heart. West China J Pharm Sci. 2007;22(5):525.

    CAS  Google Scholar 

  39. Hu Q, Wang J, Chang X, Long C. Cardioprotective effects of emulsified isoflurane strengthened cardioplegia on ischemia-reperfusion injury in isolated rat hearts. J Clin Med Pract. 2009;13:5–8.

    Google Scholar 

  40. Liu SL, Liu J. Apoptosis mechanism of intralipid postconditioning to reduce ischemia reperfusion injury of islated rat hearts. Sichuan da Xue Xue Bao Yi Xue Ban. 2007;38(4):663–6.

    CAS  PubMed  Google Scholar 

  41. Yan R, Wang YL, Chen YQ, Zhang WS, Liu J. Protective effects of emulsified isoflurane after myocardial ischemia-reperfusion injury and its mechanism in rabbits. Chin J Traumatol. 2009;12(1):18–21.

    Google Scholar 

  42. Yang MC, Chen YP, Cao DJ, Qian XU. The optimal concentration for the protective effect of emulsified isoflurane on the neonatal rat cardiac myocytes hypoxia/reoxygenation injury of primary culture. Sichuan Da Xue Xue Bao Yi Xue Ban. 2009;40(6):1075–7.

    CAS  PubMed  Google Scholar 

  43. Tan X, Chen Y, Zhang W, Liu J. Effect of emulsified isoflurane on myocardial apoptosis and expressions of and induced by hypoxia-reoxygenation. Acta Acad Med Mil Tert. 2008;30(17):1611–4.

  44. Xing-Qin T, Yu-Pei C. Emulsified isoflurane protects hypoxia/reoxgenation injury in cultured neonatal rat myocardial cells by suppressing caspase-3 expression. Acta Academiae Medicinae Mil Tert. 2009;31(14):1341–4.

  45. Hu ZY, Luo NF, Liu J. The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats. Can J Anaesth. 2009;56(2):115–25.

    Article  PubMed  Google Scholar 

  46. Yang Z, Wu S, Zhao J, Wang Z, Yao M, Lu P, et al. Emulsified isoflurane protects beta cells against high glucose-induced apoptosis via inhibiting endoplasmic reticulum stress. Ann Palliat Med. 2020;9(1):90–7.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors sincerely thank all participants in the clinical studies.

Author information

Author notes

  1. Hui Yang and YuJun Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Hui Yang, YuJun Zhang, Jin Liu & WenSheng Zhang

  2. Laboratory of Anaesthesia and Critical Care Medicine, Department of Anesthesiology, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Sichuan, 610041, Chengdu, P. R. China

    YuJun Zhang, Jin Liu & WenSheng Zhang

  3. National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    YuJun Zhang, Jin Liu & WenSheng Zhang

  4. Department of Anesthesiology, Chancheng District Central Hospital of Foshan City, Foshan, Fujian, China

    ChuiLiang Liu

  5. Department of Anesthesiology, The Third Xiangya Hospital of Central South University, Xiangya, Hunan, China

    YangWen Ou

  6. Department of Anesthesiology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China

    YuHang Zhu

  7. Department of Anesthesiology, Chongqing University Fuling Hospital, Fuling, Chongqing, China

    Yun Xue

  8. Department of Anesthesiology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, China

    GaoFeng Zhao

  9. Department of Anesthesiology, Guangdong Hospital of Traditional Chinese Medicine, University City Branch, Guangzhou, Guangdong, China

    GaoFeng Zhao

  10. Department of Anesthesiology, Zhangzhou Affiliated Hospital of FuJian Medical University, Zhangzhou, Fujian, China

    YuShuang Lin

  11. Department of Anesthesiology, Yichang Central People’s Hospital, Yichang, Hubei, China

    Chun Chen

  12. Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    GuoHai Xu

  13. Department of Anesthesiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    KaiMing Yuan

  14. Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xian, Shanxi, China

    Qiang Wang

  15. Humanwell Healthcare (Group) Co., Ltd, Yichang, Hubei, China

    Min Zhang & LiE Li

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  1. Hui Yang
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Corresponding author

Correspondence to WenSheng Zhang.

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Funding

The study received funding from Humanwell Healthcare (Group) Co., Ltd.

Conflicts of Interest/Competing Interests

No sources of funding were received for the conduct of this study or the preparation of this article.

Ethics Approval

The study was approved by the ethics committee of each participating hospital.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

Not applicable.

Availability of Data and Material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Authors’ Contributions

HY and YJZ wrote the manuscript; HY YJZ, JL, and WSZ designed the research; HY, CLL, YWO, YHZ, YX, GFZ, YSL, CC, GHX, KMY, and QW performed the research; HY, YJZ, JL, and WSZ analyzed the data; MZ and LEL funded the study; and WSZ revised the manuscript.

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Yang, H., Zhang, Y., Liu, C. et al. A Multicenter, Randomized, Double-Blind, Positive-Controlled, Non-Inferiority, Phase III Clinical Trial Evaluating the Efficacy and Safety of Emulsified Isoflurane for Anesthesia Induction in Patients. CNS Drugs 36, 1301–1311 (2022). https://doi.org/10.1007/s40263-022-00970-w

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