咪唑安定＋芬太尼混合剂用于局部麻醉镇静最佳配方的研究
摘要
目的：观察不同配伍剂量的咪唑安定+芬太尼用于局部麻醉镇静，在达到相同镇静程度时镇静效果和副作用的发生情况，比较哪种药物组合能较快获得最佳的镇静效果，并且副作用较少，以确定这两种药物的最佳组合，为临床使用这种镇静方法提供依据和参考。
方法：本实验为多中心、随机、双盲、前瞻性实验，由5个中心共同完成，每个中心完成60例。300例行局部麻醉的病人，体重40-80kg、年龄18-70岁、无明显心、肺、肝、肾疾病，根据使用咪唑安定+芬太尼的配方的不同随机分为5组，每组60例。M+F_(100)组：咪唑安定10mg+芬太尼100μg；M+F_(200)组：咪唑安定10mg+芬太尼200μg；M+F_(300)组：咪唑安定10mg+芬太尼300μg；M+F_(400)组：咪唑安定10mg+芬太尼400μg：M+F_(500)组：咪唑安定10mg+芬太尼500μg。为保证盲法的实施，以上各组药物配方均用生理盐水稀释到20ml。采用小剂量分次给药(每次2ml，隔5分钟后追加2ml)的方法使各组病人达到改良Wilson镇静分级2级，观察并记录实验期内各组病人镇静药用量、达镇静级别所用的时间、呼吸循环功能变化及相关并发症的发生率、术中遗忘率和麻醉医师对镇静质量的总体评价(VAS评分)等情况，用SPSS统计软件进行统计学比较，确定咪唑安定+芬太尼的最佳配伍方法。
结果：1．各组病人一般情况无统计学差异，组间具有可比性。2．M+F_(100)组病人镇静达2级所用的时间最长为19．1±7．0min，M+F_(500)组病人镇静达2级所用的时间最短为13．0±6．1min；M+F_(200)组、M+F_(300)和M+F_(400)组病人镇静达2级所用的时间分别为17．8±7．9min、16．2±7．0min和14．2±6．0min。3．M+F_(300)组病人镇静质量的VAS评分最高为9．2±0．7，与M+F_(100)组、M+F_(400)组和M+F_(500)组比较有统计学差异；M+F_(200)组镇静质量的VAS评分为8．9±0．7，与M+F_(300)组比较无统计学差异；M+F_(100)组、M+F_(400)组和M+F_(500)组镇静质量的VAS评分较低，分别为7．8±1．5、8．4±1．4和8．3±1．2。4．各组病人术中遗忘率均较高，平均为70％，组间比较无统计学差异。5．各组病人的血流动力学变化轻微，组间变化无统计学差异，在达到改良Wilson镇静分级2级时，无明显的循环抑制发生。6．随着镇静配方中芬太尼用量的加大，药物对呼吸功能的影响趋于加重，呼吸并发症增加。M+F_(100)组病人芬太尼的用量最少为38．8±13．4μg，呼吸并发症最少：RR＜8次／min的发生率为3.3％、SpO_2＜95％的发生率为21．7％、SPO_2＜90％发生率为0、中重度呼吸道梗阻发生率为3．3％；M+F_(400)组和M+F_(500)组病人芬太尼用量较大，分别为117．3±47．0μg和140．0±57．3μg，对呼吸的影响严重，呼吸并发症多：RR＜8次／min的发生率分别为20％和30％、SpO_2＜95％的发生率分别为38．3％和50．0％、SPO_2＜90％的发生率分别为25．0％和33．3％、中重度呼吸道梗阻发生率分别为10．0％和28．3％；M+F_(200)组和M+F_(300)组芬太尼用量较少分别为66．3±31．9μg和99．6±39．1μg，呼吸并发症相对较少：RR＜8次／min的发生率分别为6．7％和11．7％、SpO_2＜95％的发生率分别为25．0％和33．3％、SPO_2＜90％的发生率两组均为11．7％、中重度呼吸道梗阻发生率两组均为8．3％。
结论：采用M+F_(200)组和M+F_(300)组配方，用小剂量分次给药的方法对局部麻醉病人进行镇静，能较快达到改良Wilson镇静分级2级，并且镇静质量较高、遗忘效果好、对循环功能无明显抑制，呼吸抑制相对较轻、呼吸并发症较少，是理想的咪唑安定和芬太尼配伍方法。
Objective: To investigate the efficacy and respiratory complications of midazolam combined with different dose fentanyl for sedation during regional anesthesia, and to determine the appropriate dosage regimen.
Methods: Three hundred patients undergoing surgery with regional anesthesia were enrolled in this multicenter, double-blind, randomized study. Patients were randomly assigned to five groups of 60 patients each according to the dosage of midazolam and fentanyl in a bolus. (groupM+F_(100): midazolam 1mg/ fentanyl 10μg; groupM+F_(200): midazolam 1mg/ fentanyl 20μg; groupM+F_(300): midazolam 1mg/ fentanyl 30μg; groupM+F_(400): midazolam 1mg/ fentanyl 40μg; groupM+F_(500): midazolam 1mg/ fentanyl 50μg).Patients received 2 ml mixture (a bolus) of midazolam and fentanyl every 5min until a Modified Wilson Sedation Scale of 2 was achieved. BP,HR,RR,SpO_2,and PetCO_2 were measured every 5min for 45min. Intraoperative amnesia effects was assessed using picture recall test. The time required to achieve Modified Wilson sedation scale of 2, total dose of midazolam and fentanyl, and perioperative complications were recorded. The investigator's overall satisfaction with the sedation protocol was assessed using the visual analog scale (VAS). Data was analyzed using SPSS program.
Results: The groups were comparable in terms of sex, age, height and weight. The time to achieve Modified Wilson sedation scale score of 2 in groupM+F_(100), groupM+F_(200), groupM+F_(300), groupM+F_(400), and groupM+F_(500) were 19.1±7.0min, 17.8±7.9min, 16.2±7.0min, 14.2±6.0min, and 13.0±6.1 min, respectively. The overall amnesia effects among 5 groups was 70.0%, there were no significant differences in the amnesia effects between 5 groups. The investigator's overall satisfaction with the sedation protocol in groupM+F_(300) was 9.2±0.7 which was significantly higher than that in groupM+F_(100), groupM+F_(400),and groupM+F_(500), there were no significant differences in the investigator's overall satisfaction with the sedation protocol between groupM+F_(200) and groupM+F_(300)(8.9±0.7). Each group had a stable hemodynamics, there were no significant differences in the hemodynamic variables between 5 groups. With increasing the doses of fentanyl, respiratory complications progressively increased. Patients in groupM+F_(100) received smaller doses fentanyl (38.8±13.4μg), resulted in fewer respiratory complications: 3.3% patients experienced bradypnea (＜8 breaths/min), 21.7% patients experienced moderate oxygen desaturation (SpO_2＜95%), and 3.3% patients experienced upper respiratory obstruction. Respiratory complications occurred more often in group M+F_(400) and group M+F500 due to their relatively more fentanyl doses (117.3±41.7μg and 140.0±57.3μg, respectively),23.3% patients in group M+F_(400) and 35.0% patients in group M+F_(500) experienced severe oxygen desaturation (SpO_2＜90%), 38.3% patients in group M+F_(400) and 50.0% patients in group M+F_(500) experienced moderate oxygen desaturation (SpO_2＜95%), 20.0% patients in group M+F_(400) and 30.0% patients in group M+F_(500) experienced bradypnea (＜8 breaths/min), 10.0% patients in group M+F_(400) and 28.3% patients in group M+F_(500) experienced upper respiratory obstruction. A moderate dose of fentanyl (66.3±31.9μg and 99.6±39.1μg) was administered to the patients in group M+F_(200) and groupM+F_(300) respectively.25.0% patients in group M+F_(200) and 33.3% patients in group M+F_(300) experienced moderate oxygen desaturation ((SpO_2＜95%),11.7% patients and 8.3% patients in both groups experienced severe oxygen desaturation ((SpO_2＜90%) and upper airway obstruction, respectively; 6.7% patients in group M+F_(200) and 11.7% patients in group M+F_(300) experienced bradypnea (＜8 breaths/min).
Conclusion: Intravenous sedation with intermittent midazolam 1mg combined with fentany 20μg or 30ug was a safe and effective dosage regimen for regional anesthesia, provided adequate sedation and amnesia with a stable hemodynamics, and resulted in fewer respiratory complications.
方法：本实验为多中心、随机、双盲、前瞻性实验，由5个中心共同完成，每个中心完成60例。300例行局部麻醉的病人，体重40-80kg、年龄18-70岁、无明显心、肺、肝、肾疾病，根据使用咪唑安定+芬太尼的配方的不同随机分为5组，每组60例。M+F_(100)组：咪唑安定10mg+芬太尼100μg；M+F_(200)组：咪唑安定10mg+芬太尼200μg；M+F_(300)组：咪唑安定10mg+芬太尼300μg；M+F_(400)组：咪唑安定10mg+芬太尼400μg：M+F_(500)组：咪唑安定10mg+芬太尼500μg。为保证盲法的实施，以上各组药物配方均用生理盐水稀释到20ml。采用小剂量分次给药(每次2ml，隔5分钟后追加2ml)的方法使各组病人达到改良Wilson镇静分级2级，观察并记录实验期内各组病人镇静药用量、达镇静级别所用的时间、呼吸循环功能变化及相关并发症的发生率、术中遗忘率和麻醉医师对镇静质量的总体评价(VAS评分)等情况，用SPSS统计软件进行统计学比较，确定咪唑安定+芬太尼的最佳配伍方法。
结果：1．各组病人一般情况无统计学差异，组间具有可比性。2．M+F_(100)组病人镇静达2级所用的时间最长为19．1±7．0min，M+F_(500)组病人镇静达2级所用的时间最短为13．0±6．1min；M+F_(200)组、M+F_(300)和M+F_(400)组病人镇静达2级所用的时间分别为17．8±7．9min、16．2±7．0min和14．2±6．0min。3．M+F_(300)组病人镇静质量的VAS评分最高为9．2±0．7，与M+F_(100)组、M+F_(400)组和M+F_(500)组比较有统计学差异；M+F_(200)组镇静质量的VAS评分为8．9±0．7，与M+F_(300)组比较无统计学差异；M+F_(100)组、M+F_(400)组和M+F_(500)组镇静质量的VAS评分较低，分别为7．8±1．5、8．4±1．4和8．3±1．2。4．各组病人术中遗忘率均较高，平均为70％，组间比较无统计学差异。5．各组病人的血流动力学变化轻微，组间变化无统计学差异，在达到改良Wilson镇静分级2级时，无明显的循环抑制发生。6．随着镇静配方中芬太尼用量的加大，药物对呼吸功能的影响趋于加重，呼吸并发症增加。M+F_(100)组病人芬太尼的用量最少为38．8±13．4μg，呼吸并发症最少：RR＜8次／min的发生率为3.3％、SpO_2＜95％的发生率为21．7％、SPO_2＜90％发生率为0、中重度呼吸道梗阻发生率为3．3％；M+F_(400)组和M+F_(500)组病人芬太尼用量较大，分别为117．3±47．0μg和140．0±57．3μg，对呼吸的影响严重，呼吸并发症多：RR＜8次／min的发生率分别为20％和30％、SpO_2＜95％的发生率分别为38．3％和50．0％、SPO_2＜90％的发生率分别为25．0％和33．3％、中重度呼吸道梗阻发生率分别为10．0％和28．3％；M+F_(200)组和M+F_(300)组芬太尼用量较少分别为66．3±31．9μg和99．6±39．1μg，呼吸并发症相对较少：RR＜8次／min的发生率分别为6．7％和11．7％、SpO_2＜95％的发生率分别为25．0％和33．3％、SPO_2＜90％的发生率两组均为11．7％、中重度呼吸道梗阻发生率两组均为8．3％。
结论：采用M+F_(200)组和M+F_(300)组配方，用小剂量分次给药的方法对局部麻醉病人进行镇静，能较快达到改良Wilson镇静分级2级，并且镇静质量较高、遗忘效果好、对循环功能无明显抑制，呼吸抑制相对较轻、呼吸并发症较少，是理想的咪唑安定和芬太尼配伍方法。
Objective: To investigate the efficacy and respiratory complications of midazolam combined with different dose fentanyl for sedation during regional anesthesia, and to determine the appropriate dosage regimen.
Methods: Three hundred patients undergoing surgery with regional anesthesia were enrolled in this multicenter, double-blind, randomized study. Patients were randomly assigned to five groups of 60 patients each according to the dosage of midazolam and fentanyl in a bolus. (groupM+F_(100): midazolam 1mg/ fentanyl 10μg; groupM+F_(200): midazolam 1mg/ fentanyl 20μg; groupM+F_(300): midazolam 1mg/ fentanyl 30μg; groupM+F_(400): midazolam 1mg/ fentanyl 40μg; groupM+F_(500): midazolam 1mg/ fentanyl 50μg).Patients received 2 ml mixture (a bolus) of midazolam and fentanyl every 5min until a Modified Wilson Sedation Scale of 2 was achieved. BP,HR,RR,SpO_2,and PetCO_2 were measured every 5min for 45min. Intraoperative amnesia effects was assessed using picture recall test. The time required to achieve Modified Wilson sedation scale of 2, total dose of midazolam and fentanyl, and perioperative complications were recorded. The investigator's overall satisfaction with the sedation protocol was assessed using the visual analog scale (VAS). Data was analyzed using SPSS program.
Results: The groups were comparable in terms of sex, age, height and weight. The time to achieve Modified Wilson sedation scale score of 2 in groupM+F_(100), groupM+F_(200), groupM+F_(300), groupM+F_(400), and groupM+F_(500) were 19.1±7.0min, 17.8±7.9min, 16.2±7.0min, 14.2±6.0min, and 13.0±6.1 min, respectively. The overall amnesia effects among 5 groups was 70.0%, there were no significant differences in the amnesia effects between 5 groups. The investigator's overall satisfaction with the sedation protocol in groupM+F_(300) was 9.2±0.7 which was significantly higher than that in groupM+F_(100), groupM+F_(400),and groupM+F_(500), there were no significant differences in the investigator's overall satisfaction with the sedation protocol between groupM+F_(200) and groupM+F_(300)(8.9±0.7). Each group had a stable hemodynamics, there were no significant differences in the hemodynamic variables between 5 groups. With increasing the doses of fentanyl, respiratory complications progressively increased. Patients in groupM+F_(100) received smaller doses fentanyl (38.8±13.4μg), resulted in fewer respiratory complications: 3.3% patients experienced bradypnea (＜8 breaths/min), 21.7% patients experienced moderate oxygen desaturation (SpO_2＜95%), and 3.3% patients experienced upper respiratory obstruction. Respiratory complications occurred more often in group M+F_(400) and group M+F500 due to their relatively more fentanyl doses (117.3±41.7μg and 140.0±57.3μg, respectively),23.3% patients in group M+F_(400) and 35.0% patients in group M+F_(500) experienced severe oxygen desaturation (SpO_2＜90%), 38.3% patients in group M+F_(400) and 50.0% patients in group M+F_(500) experienced moderate oxygen desaturation (SpO_2＜95%), 20.0% patients in group M+F_(400) and 30.0% patients in group M+F_(500) experienced bradypnea (＜8 breaths/min), 10.0% patients in group M+F_(400) and 28.3% patients in group M+F_(500) experienced upper respiratory obstruction. A moderate dose of fentanyl (66.3±31.9μg and 99.6±39.1μg) was administered to the patients in group M+F_(200) and groupM+F_(300) respectively.25.0% patients in group M+F_(200) and 33.3% patients in group M+F_(300) experienced moderate oxygen desaturation ((SpO_2＜95%),11.7% patients and 8.3% patients in both groups experienced severe oxygen desaturation ((SpO_2＜90%) and upper airway obstruction, respectively; 6.7% patients in group M+F_(200) and 11.7% patients in group M+F_(300) experienced bradypnea (＜8 breaths/min).
Conclusion: Intravenous sedation with intermittent midazolam 1mg combined with fentany 20μg or 30ug was a safe and effective dosage regimen for regional anesthesia, provided adequate sedation and amnesia with a stable hemodynamics, and resulted in fewer respiratory complications.
引文
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2. Helgesen KG, Ellingsen O, Ilebekk A. Inotropic effect of meperidine: Influence of receptor and ion channel blockers in the rat atrium [J]. Anesth Analg, 1990, 70(5):499-506.
3. Nancy Chang, Arthur Simone, Lester Schultheis,et al. Reviewing case reports and the droperidol warning: FDA response[J]. Anesth Analg, 2003, 97(5) : 1542.
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8. White PF, Negus JB. Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. J Clin Anesth 1991;3:32-9
9．米卫东，靳冰．阈下氯胺酮对呼吸、循环功能的影响．中华麻醉学杂志，1994．14(3)：206-208
10．杜光生，屠文龙．阈下剂量氯胺酮复合硬膜外麻醉用于剖宫产术．chin J Anesthesia 1997，17(4)：244．
11. Green SM, Hummel CB, Wittlake WA, et al What is the optimal dose of intramuscular ketamine for pediatric sedation?Acad Emerg Med 1999;6:21-6.
12. McGlone RG, Howes MC,Joshi M. The Lancaster experience of 2.0 to 2.5 mg/kg intramuscular ketamine for paediatric sedation: 501 cases and analysis. Emerg Med J 2004,21(3):290-295.
13. Sherwin TS, Green SM, Khan A, et al. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized double blind placebo controlled trial. Ann Emerg Med 2000;35:229-38.
14. Heinz P,Geelhoed GC ,'Wee C,Pascoe EM. Is atropine needed with ketamine sedation? A prospective, randomised, double blind study. Emerg Med J 2006,23(3): 206-209
15. MacKenzie N, Grant IS. Propofol for intravenous sedation. Anaesthesia 1987;42:3-6.
16. Taylor E, Ghouri AF, White PF. Midazolam in combination with propofol for sedation during local anesthesia. J Clin Anesth 1992;4:213-6.
17. Yoon, Hee-Dong; Yoon, Eul-Sik; Dhong, Eun-Sang; et al. Low-Dose Propofol Infusion for Sedation during Local Anesthesia. American Society of Plastic Surgeons 2002,109(3):956-963
18. White PF, Negus JB. Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. J Clin Anesth 1991;3:32-9.
19. Watcha MF, Simeon RM, White PF, Stevens JL. Effect of propofol on the incidence of postoperative vomiting after strabismus surgery in pediatric outpatients. Anesthesiology 1991;75:204-9.
20. Hui TW ,Short TG ,Hong W, et al. Additive Interactions between Propofol and Ketamine When Used for Anesthesia Induction in Female Patients.Anesthesiology,1995,82(3):641-648
21. Smith I, Avramov MN, White PF. A comparison of propofol and remifentanil during monitored anesthesia care. J Clin Anesth 1997;9:148-54.
22. Rigg JR, Goldsmith CH. Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man. Can Anaesth Soc J 1976;23:370-82.
23. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993;79:881-92.
24. Kapila A, Glass PS, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83:968-75.
25. Rosow C. Remifentanil: a unique opioid analgesic. Anesthesiology 1993;79:875-6.
26. Avramov MN, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology 1996;85:1283-9.
27. Sa Rego MM, Inagaki Y, White PF. Use of remifentanil during lithotripsy: intermittent boluses vs continuous infusion [abstract]. Anesth Analg 1997;84:S541.
28. Ramirez-Ruiz M, Smith I, White PF. Use of analgesics during propofol sedation: a comparison of ketorolac, dezocine, and fentanyl. J Clin Anesth 1995;7:481-5.
29. Higgins MS, Givogre JL, Marco AP, et al. Recovery from outpatient laparoscopic tubal ligation is not improved by preoperative administration of ketorolac or ibuprofen. Anesth Analg 1994;79:274-80.
30. Torjman M, Mora CT, White PF. Does flumazenil antagonize midazolam-induced depression of ventilatory response to hypoxia? Anesthesiology 1994;80:233-5.
31. Mora CT, Torjman M, White PF. Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal. Can J Anaesth 1995;42:677-84.
32. Ghouri AF, Ruiz MA, White PF. Effect of flumazenil on recovery after midazolam and propofol sedation. Anesthesiology 1994;81:333-9.
33. Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action. Anesthesiology 1976;44:398-401.
2. Nancy Chang, Arthur Simone, Lester Schultheis,et al. Reviewing case reports and the droperidol warning: FDA response[J]. Anesth Analg, 2003; 97(5): 1542.
3. Helgesen KG, Ellingsen O, Ilebekk A.Inotropic effect of meperidine: Influence of receptor and ion channel blockers in the rat atrium[J]. Anesth Analg, 1990; 70(5):499-506.
4. 张雄,曹春梅,王琳琳.哌替啶对心室收缩的抑制作用及其机制 [J].生理学报, 2003, 55(2): 197-200.
5. Rigg JR, Goldsmith CH. Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man. Can Anaesth Soc J 1976, 23:370-382.
6. Nemethy, Maria BA; Paroli, Leonardo MD, PhD; Williams-Russo, Pamela G MD, MPH; Blanck, Thomas J. Assessing Sedation with Regional Anesthesia: Inter-Rater Agreement on a Modified Wilson Sedation Scale. Anesth Analg,2002,94(3): 723-728
7. Richards A, Griffiths M, Scully C. Wide variation in patient response tomidazolam sedation for outpatient oral surgery. Oral Surg Oral Med Oral Pathol. 1993 ;76:408-411
8. White PF, Vasconez LO, Mathes SA, et al. Comparison of midazolam and diazepam for sedation during plastic surgery. Plast Reconstr Surg 1988;81:703-12.
9. Ronald D. Miller. Anesthesia. Fifth. Harcairt Asia:Churchill livingstone,2001,2908
10. Mora CT, Torjman M, White PF: Sedative and ventilatory effects of midazolam infusion: Effect of flumazenil reversal. Can J Anaesth 42:677, 1995.
11. ADSA: ADSA guidelines for intraoperative monitoring of patients undergoing conscious sedation. ADSA Newsletter 20(2):1988.
12. Scamman FL, Klein SL, Choi WW: Conscious sedation for procedures under local or topical anesthesia. Ann Otol Rhinol Laryngol 94:21, 1985.
13. Ramsay MAE, Savege TM, Simpson BRJ, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974; 2: 656-9.
14. Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990; 10:244-51.
15．肖红，张兰，徐宏伟，等．局麻术中咪唑安定顺行性遗忘与镇静深度的关系．临床麻醉学杂志,2003，19：694-695．
16. Veselis Robert, Reinsel Ruth, Feshchenko, Vladimir, et al. The Comparative Amnestic Effects of Midazolam, Propofol, Thiopental, and Fentanyl at Equisedative Concentrations. Anesthesiology 1997; 87(4):749-764
17．徐迎阳，岳云．咪唑安定镇静期顺行性遗忘的中枢神经电生理研究．解放军医学杂志,2006,31(10)：982
18．庄心良，曾因明，陈伯銮．现代麻醉学[M]．第3版，北京：人民卫生出版社，2003．500．
19. Bailey PL, Pace NL, Ashbum MA, Moll JW, East KA, Stanley TH: Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73:826-30.
20. Poirier MP, Gonzalez Del-Rey JA, McAneney CM, DiGiulio GA. Utility of monitoring capnography, pulse oximetry, and vital signs in the detection of airway mishaps: a hyperoxemic animal model. Am J Emerg Med 1998; 16:350-352.
21. Moller Jt,Wittrup Mand Johansen SH.Hypoxemia in the psotanesthesia care unit., an observer study. Anesthesiology, 1990,73:890
22. Montravers p, Dureuil B, Desmons JM. Effect of iv Midazolam on upper airway resistance. British Joumal of Anesthesia 1992;68:27-31.
23. Litchfield NB. Complications of intravenous diazepam adverse psychological reactions. (An assessment of 16,000 cases). Anesth Prog 1980; 28: 175-183.
24．王玲玲，王秋石，王俊科，等．咪达唑仑与芬太尼用于椎管内麻醉镇静的临床观察[J]．中国医科大学学报,2005，34(4)：373-374．
25．张兰，王泉云，刘进，等．麻醉镇静术中咪唑安定剂量范围的初步探讨[J]．华西医学，2002，17(4)：474-475．
1．庄心良，曾因明，陈伯銮．现代麻醉学[M]．第3版，北京：人民卫生出版社．2003．521．
2. Helgesen KG, Ellingsen O, Ilebekk A. Inotropic effect of meperidine: Influence of receptor and ion channel blockers in the rat atrium [J]. Anesth Analg, 1990, 70(5):499-506.
3. Nancy Chang, Arthur Simone, Lester Schultheis,et al. Reviewing case reports and the droperidol warning: FDA response[J]. Anesth Analg, 2003, 97(5) : 1542.
4．张雄，曹春梅，王琳琳，等．哌替啶对心室肌收缩的抑制作用及其机制[J]．生理学报，2003，55(2)：197-200．
5．王玲玲，王秋石，王俊科，等．咪达唑仑与芬太尼用于椎管内麻醉镇静的临床观察[J]．中国医科大学学报,2005,34(4)：373—374．
6. Richards A, Griffiths M, Scully C. Wide variation in patient response to midazolam sedation for outpatient oral surgery. Oral Surg Oral MedOral Pathol. 1993;76:408-411
7. Nishiyama T, Yokoyama T, Hanaoka K. Sedation guidelines for midazolam infusion during combined spinal and epidural anesthesia. Joumal of Clinical Anesthesia. 2004,16(8):568-72.
8. White PF, Negus JB. Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. J Clin Anesth 1991;3:32-9
9．米卫东，靳冰．阈下氯胺酮对呼吸、循环功能的影响．中华麻醉学杂志，1994．14(3)：206-208
10．杜光生，屠文龙．阈下剂量氯胺酮复合硬膜外麻醉用于剖宫产术．chin J Anesthesia 1997，17(4)：244．
11. Green SM, Hummel CB, Wittlake WA, et al What is the optimal dose of intramuscular ketamine for pediatric sedation?Acad Emerg Med 1999;6:21-6.
12. McGlone RG, Howes MC,Joshi M. The Lancaster experience of 2.0 to 2.5 mg/kg intramuscular ketamine for paediatric sedation: 501 cases and analysis. Emerg Med J 2004,21(3):290-295.
13. Sherwin TS, Green SM, Khan A, et al. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized double blind placebo controlled trial. Ann Emerg Med 2000;35:229-38.
14. Heinz P,Geelhoed GC ,'Wee C,Pascoe EM. Is atropine needed with ketamine sedation? A prospective, randomised, double blind study. Emerg Med J 2006,23(3): 206-209
15. MacKenzie N, Grant IS. Propofol for intravenous sedation. Anaesthesia 1987;42:3-6.
16. Taylor E, Ghouri AF, White PF. Midazolam in combination with propofol for sedation during local anesthesia. J Clin Anesth 1992;4:213-6.
17. Yoon, Hee-Dong; Yoon, Eul-Sik; Dhong, Eun-Sang; et al. Low-Dose Propofol Infusion for Sedation during Local Anesthesia. American Society of Plastic Surgeons 2002,109(3):956-963
18. White PF, Negus JB. Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol. J Clin Anesth 1991;3:32-9.
19. Watcha MF, Simeon RM, White PF, Stevens JL. Effect of propofol on the incidence of postoperative vomiting after strabismus surgery in pediatric outpatients. Anesthesiology 1991;75:204-9.
20. Hui TW ,Short TG ,Hong W, et al. Additive Interactions between Propofol and Ketamine When Used for Anesthesia Induction in Female Patients.Anesthesiology,1995,82(3):641-648
21. Smith I, Avramov MN, White PF. A comparison of propofol and remifentanil during monitored anesthesia care. J Clin Anesth 1997;9:148-54.
22. Rigg JR, Goldsmith CH. Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man. Can Anaesth Soc J 1976;23:370-82.
23. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993;79:881-92.
24. Kapila A, Glass PS, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83:968-75.
25. Rosow C. Remifentanil: a unique opioid analgesic. Anesthesiology 1993;79:875-6.
26. Avramov MN, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology 1996;85:1283-9.
27. Sa Rego MM, Inagaki Y, White PF. Use of remifentanil during lithotripsy: intermittent boluses vs continuous infusion [abstract]. Anesth Analg 1997;84:S541.
28. Ramirez-Ruiz M, Smith I, White PF. Use of analgesics during propofol sedation: a comparison of ketorolac, dezocine, and fentanyl. J Clin Anesth 1995;7:481-5.
29. Higgins MS, Givogre JL, Marco AP, et al. Recovery from outpatient laparoscopic tubal ligation is not improved by preoperative administration of ketorolac or ibuprofen. Anesth Analg 1994;79:274-80.
30. Torjman M, Mora CT, White PF. Does flumazenil antagonize midazolam-induced depression of ventilatory response to hypoxia? Anesthesiology 1994;80:233-5.
31. Mora CT, Torjman M, White PF. Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal. Can J Anaesth 1995;42:677-84.
32. Ghouri AF, Ruiz MA, White PF. Effect of flumazenil on recovery after midazolam and propofol sedation. Anesthesiology 1994;81:333-9.
33. Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action. Anesthesiology 1976;44:398-401.