小剂量氯胺酮对临床浓度瑞芬太尼诱发痛觉过敏的影响
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摘要
目的：观察小剂量氯胺酮对临床相关浓度瑞芬太尼诱发术后痛觉过敏的预防作用。方法：40例择期行腹部手术患者,ASAⅠ～Ⅲ级,年龄29～83岁,随机均分为两组。KG组：诱导时予氯胺酮0.5mg/Kg,持续泵注5μg. kg-1. min-1至手术结束；CG组：予等容量的生理盐水泵注至手术结束。两组麻醉诱导采用咪达唑仑0.03mg/kg、芬太尼2.0μg/kg、维库溴铵0.1mg/kg和异丙酚1-2mg/kg;瑞芬太尼和七氟烷维持麻醉至关腹时停用,术后采用曲马多持续静脉自控镇痛(PCIA)。记录和评价指标：入室诱导前、诱导后、气管插管、切皮、关腹和拔管时血流动力学变化和脑电双频谱指数(BIS)值；入室后、手术两小时、术后第12小时和24小时血浆P物质(SP)浓度；术毕睁眼时间和拔管时间；术后不同时间点镇痛镇静评分；麻醉恢复室(PACU)曲马多使用情况；病房24小时内PCIA泵自控按压总次数及术后并发症的发生率。结果：KG组在气管插管时血流动力学反应较平稳(P<0.01)。KG组在拔管后第10、15分钟的口述描绘疼痛评分(VRS)低于CG组(P＜0.01), Ramsay评分高于CG组(P<0.01)。KG组术后1小时至20小时视觉模拟(VAS)评分低于CG组(P<0.01)。SP浓度两组在术后第12小时和24小时均较基础值显著增高(P<0.01),其中CG组在术后第12小时和24小时SP浓度明显高于KG组(P<0.01)。CG组患者在PACU首次要求追加曲马多的时间明显提前(P<0.05),反复要求镇痛次数增多(P<0.01),两组曲马多累积用量比较具有统计学意义(P<0.01)。KG组患者在病房24小时内PCIA泵自控按压总次数显著较CG组少(P<0.01)。两组患者术毕睁眼时间、拔管时间以及并发症的发生率相比无明显差异。结论：术中持续使用小剂量氯胺酮,能减轻病人术后疼痛评分,减少曲马多用量,降低SP浓度,提示小剂量氯胺酮对临床相关浓度瑞芬太尼所诱发的术后痛觉过敏具有预防作用；术中持续使用小剂量氯胺酮并不影响患者术后苏醒,亦不增加术后不良反应的发生,可以安全复合于全身麻醉中。
Objective:To observe the effect of clinically relevant concentrations of remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Methods:Fourty patients aged 29-83 yr (ASA I-III) scheduled for abdominal surgery were randomly assigned to receive intraoperative low-dose ketamine(bolus dose of 0.5mg/Kg followed by continuous infusion of 5μg.kg-1.min-1) or an equal volume of saline during remifentanil/sevoflurane anesthesia.Then anesthesia was induced with midazolam 0.03mg/Kg, fentanyl 2μg/Kg, vecuronium 0.1mg/Kg and propofol 1-2mg/Kg, and patient-controlled intravenous analgesia (PCIA) with tramadol after operations. The index of hemodynamics and bispectral index of the electroencephalogram (BIS) were recorded at following time points:before induction、after induction、orotracheal intubation、piece、skin closure and extubation.The concentration of substance P (SP) was measured after entering the operating room、two hours after starting the surgery、12 and 24h postoperative. Pain scores、sedation scores and tramodal consumption in post anesthesia care unit (PACU) were recored. The total times that patients pressed the PCIA control key was observed in the first postoperative 24 h. Awakening time、extubation time and anesthetic-related complications were recorded as well. Results:Intraoperative hemodynamic responses at orotracheal intubation were more stable in KG group (P＜0.01). Verbal rating scales (VRS) in 15 minutes after extubation were lower in KG group (P<0.01); Ramsay sedation score were higher than CG group (P<0.01). The visual analog pain scores (VAS) during 20 postoperative hours were significantly greater in CG group (P<0.01). The concentration of SP at the time of 12 and 24 h postoperative, both two groups were higher than baseline values (P <0.01); compared with the same point of CG group, there were significant difference (P<0.01). Patients in CG group required tramadol for the first time earlier than in KG group (P<0.05); Tramadol comsumption in PACU were much more than KG group (P<0.01). The total times that patients pressed PCIA control key in KG group was less than CG group in the first postoperative 24h (P<0.01). Awakening time、extubation time and anesthetic-related complications were similar in each group. Conclusion:Intraoperative low-dose ketamine could lighten postoperative pain and sedation score、decrease tramadol consumption and the concentration of SP. These data suggest that small-dose ketamine could prevent clinically relevant concentrations of remifentanil-induced postoperative hyperalgesia; Intraoperative low-dose ketamine had no effect on awakening time、extubation time and anesthetic-related complications, which suggest that it could be safety compounded in general anesthesia.
Objective:To observe the effect of clinically relevant concentrations of remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Methods:Fourty patients aged 29-83 yr (ASA I-III) scheduled for abdominal surgery were randomly assigned to receive intraoperative low-dose ketamine(bolus dose of 0.5mg/Kg followed by continuous infusion of 5μg.kg-1.min-1) or an equal volume of saline during remifentanil/sevoflurane anesthesia.Then anesthesia was induced with midazolam 0.03mg/Kg, fentanyl 2μg/Kg, vecuronium 0.1mg/Kg and propofol 1-2mg/Kg, and patient-controlled intravenous analgesia (PCIA) with tramadol after operations. The index of hemodynamics and bispectral index of the electroencephalogram (BIS) were recorded at following time points:before induction、after induction、orotracheal intubation、piece、skin closure and extubation.The concentration of substance P (SP) was measured after entering the operating room、two hours after starting the surgery、12 and 24h postoperative. Pain scores、sedation scores and tramodal consumption in post anesthesia care unit (PACU) were recored. The total times that patients pressed the PCIA control key was observed in the first postoperative 24 h. Awakening time、extubation time and anesthetic-related complications were recorded as well. Results:Intraoperative hemodynamic responses at orotracheal intubation were more stable in KG group (P＜0.01). Verbal rating scales (VRS) in 15 minutes after extubation were lower in KG group (P<0.01); Ramsay sedation score were higher than CG group (P<0.01). The visual analog pain scores (VAS) during 20 postoperative hours were significantly greater in CG group (P<0.01). The concentration of SP at the time of 12 and 24 h postoperative, both two groups were higher than baseline values (P <0.01); compared with the same point of CG group, there were significant difference (P<0.01). Patients in CG group required tramadol for the first time earlier than in KG group (P<0.05); Tramadol comsumption in PACU were much more than KG group (P<0.01). The total times that patients pressed PCIA control key in KG group was less than CG group in the first postoperative 24h (P<0.01). Awakening time、extubation time and anesthetic-related complications were similar in each group. Conclusion:Intraoperative low-dose ketamine could lighten postoperative pain and sedation score、decrease tramadol consumption and the concentration of SP. These data suggest that small-dose ketamine could prevent clinically relevant concentrations of remifentanil-induced postoperative hyperalgesia; Intraoperative low-dose ketamine had no effect on awakening time、extubation time and anesthetic-related complications, which suggest that it could be safety compounded in general anesthesia.
引文
[1]Rosow CE. An overview of remifentanil [J].Anesth Analg,1999,89(4 suppl):S1-3.
[2]Scott LJ, Perry CM. Remifentanil:A review of its use during the induction and maintenance of general anaesthesia [J]. Drugs,2005,65(13):1793-1823.
[3]Towett PK, Kanui TI, Juma FD. Stimulation of mu and delta opioid receptors induces hyperalgesia while stimulation of kappa receptors induces antinociception in the hot plate test in the naked mole-rat (Heterocephalus glaber) [J].Brain Res Bull,2006,71(1-3):60-68.
[4]Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance [J]. Anesthesiology,2008,109(2):308-317.
[5]Chatterton JE, Awobuluyi M, Premkumar LS, et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits [J]. Nature,2002,415(6873):793-798.
[6]Dirks J, Moiniche S, Hilsted KL, et al. Mechanisms of postoperative pain:clinical indications for a contribution of central neuronal sensitization [J]. Anesthesiology,2002,97(6):1591-1596.
[7]Hahnenkamp K, Nollet J, Van Aken HK, et al. Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes [J].Anesthesiology,2004, 100(6):1531-1537.
[8]Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation:respiration, postoperative mood, perception, cognition, and pain [J]. Anesth Analg, 2001,92:1465-1469.
[9]Schmid RL, Sandler AN, Katz J.Use and efficacy of low-dose ketamine in the management of acute postoperative pain:a review of current techniques and outcomes [J].Pain,1999, 82(2):111-125.
[10]江澄川,赵志奇,蒋豪.疼痛的基础与临床[M].上海：复旦大学出版社,2001,89.
[11]Massari VJ, Tizabi Y, Park CH, et al. Distribution and origin of bombesin substance P and somatostatin in cat spinal cord [J].Peptides,1983,4(5):673-681.
[12]O'Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome [J]. Neurogastroenterol Motil,2000,12(5):449-457.
[13]Ibrahim Andra E, Taraday JK, Kharasch ED. Bispectral index monitoring during sedation with sevoflurane, midazolam and propofol [J]. Anesthesiology,2001,95(5):1151-1159.
[14]Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance:Intraoperative remifentanil increases postoperative pain and morphine requirement [J]. Anesthesiology,2000, 93(2):409-417.
[15]Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine [J]. Anesthesiology,2000,92(2):465-472.
[16]Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance:can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? [J]. Anesth Analg,2000,91(6):1483-1488.
[17]Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain [J]. Anesth Analg,2001,93(1):204-209.
[18]Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans [J]. Anesth Analg,1998,86(6):1307-1311.
[19]Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia [J]. Anesth Analg,2003, 97(3):810-815
[20]Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine [J]. Anesthesiology,2005,103(1):147-155.
[21]Koppert W, Sittl R, Scheuber K, et al. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans[J]. Anesthesiology,2003,99(1):152-159.
[22]Servin F. Remifentanil:when and how to use it. Eur J Anaesthesiol Suppl,1997 May, 15:41-44.
[23]Egan TD.Remifentanil Pharmacokinetics and pharmacodynamics.A preliminary appraisal [J].Clin Pharmacokinet,1995,29(2):80-94.
[24]Sear JW. Recent advances and developments in the clinical use of i.v. opioids during the peroperative period [J].Br J Anaesth,1998,81(1):38-50.
[25]Camu F, Royston D. Inpatient experience with Remifentanil [J].Anesth Analg,1999, 89:S15-21.
[26]Trafton JA, Abbadie C, Marek K, et al. Postsynaptic signaling via the [mu]-opioid receptor: Responses of dorsal horn neurons to exogenous opioids and noxious stimulation [J]. J Neurosci, 2000,20(23):8578-8584.
[27]Borgland SL. Acute opioid receptor desensitization and tolerance:Is there a link? [J]. Clin Exp Pharmacol Physiol,2001,28(3):147-154.
[28]Vanderah TW, Gardell LR, Burgess SE, et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance [J]. J Neurosci,2000,20(18):7074-7079.
[29]Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance:a current view of their possible interactions. Pain,1995,62(3):259-274.
[30]Laulin JP, Maurette P, Corcuff JB, et al. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance[J]. Anesth Analg,2002,94(5):1263-1269.
[31]Herrero JF, Laird JM, Lopez Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol,2000,61(2):169-203.
[32]刘月江,李秋兰,祖翠华,等.氟比洛芬酯或小剂量氯胺酮有效预防雷米芬太尼麻醉术后痛觉过敏.临床麻醉学杂志,2008,24(10)：856-858.
[33]宋青,张宏,宋运琴,等.冠状动脉架桥术麻醉及围手术期处理.军医进修学院学报,2000,21(4)：282-284.
[34]Hayakawa Fujii Y, Takada M, Ohta S, et al. Hemodynamic stability during induction of anesthesia and tracheal intubation with propofol plus fentanyl, ketamine, and fentanyl-ketamine [J]. J Anesth,2001,15(4):191-196.
[35]王贤裕,田玉科.小剂量氯胺酮镇痛的临床研究进展.《国外医学》麻醉学与复苏分册,2004,25(5)：295-298.
[36]Engelhardt T, Zaarour C, Naser B, et al. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery [J]. Anesth Analg,2008,107(4):1170-1175.
[37]Gonzales JM, Loeb AL, Reichard PS, et al.Ketamine inhibits glutamate-, N-methyl-D-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons [J]. Anesthesiology,1995,82(1):205-213.
[38]Engelhardt T, Lowe PR, Galley HF, et al. Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wide-type and nNOS knockout mice [J]. Eur J Anaesthesiol, 2006,23(3):197-201.
[39]Wu ZZ, Guan BC, Li ZW, et al. Sustained potentiation by substance P of NMDA-activated current in rat primary sensory neurons [J].Brain Res,2004,1010(1-2):117-126.
[40]Bradesi S, Eutamene H, Fioramonti J, et al. Acute restraint stress activates functional NK1 receptor in the colon of female rats:involvement of steroids [J]. Gut,2002,50(3):349-354.
[41]Weinstein J. The dorsal root ganglion and its role as a mediator of low-back pain [J]. Spine, 1986,11(10):999-1001.
[42]石欣,高乃荣,霍明东,等.P物质及其受体在慢性胰腺炎组织的表达和临床意义[J].中华肝胆外科杂志,2003,9(3)：172-176.
[2]Scott LJ, Perry CM. Remifentanil:A review of its use during the induction and maintenance of general anaesthesia [J]. Drugs,2005,65(13):1793-1823.
[3]Towett PK, Kanui TI, Juma FD. Stimulation of mu and delta opioid receptors induces hyperalgesia while stimulation of kappa receptors induces antinociception in the hot plate test in the naked mole-rat (Heterocephalus glaber) [J].Brain Res Bull,2006,71(1-3):60-68.
[4]Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance [J]. Anesthesiology,2008,109(2):308-317.
[5]Chatterton JE, Awobuluyi M, Premkumar LS, et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits [J]. Nature,2002,415(6873):793-798.
[6]Dirks J, Moiniche S, Hilsted KL, et al. Mechanisms of postoperative pain:clinical indications for a contribution of central neuronal sensitization [J]. Anesthesiology,2002,97(6):1591-1596.
[7]Hahnenkamp K, Nollet J, Van Aken HK, et al. Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes [J].Anesthesiology,2004, 100(6):1531-1537.
[8]Mortero RF, Clark LD, Tolan MM, et al. The effects of small-dose ketamine on propofol sedation:respiration, postoperative mood, perception, cognition, and pain [J]. Anesth Analg, 2001,92:1465-1469.
[9]Schmid RL, Sandler AN, Katz J.Use and efficacy of low-dose ketamine in the management of acute postoperative pain:a review of current techniques and outcomes [J].Pain,1999, 82(2):111-125.
[10]江澄川,赵志奇,蒋豪.疼痛的基础与临床[M].上海：复旦大学出版社,2001,89.
[11]Massari VJ, Tizabi Y, Park CH, et al. Distribution and origin of bombesin substance P and somatostatin in cat spinal cord [J].Peptides,1983,4(5):673-681.
[12]O'Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome [J]. Neurogastroenterol Motil,2000,12(5):449-457.
[13]Ibrahim Andra E, Taraday JK, Kharasch ED. Bispectral index monitoring during sedation with sevoflurane, midazolam and propofol [J]. Anesthesiology,2001,95(5):1151-1159.
[14]Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance:Intraoperative remifentanil increases postoperative pain and morphine requirement [J]. Anesthesiology,2000, 93(2):409-417.
[15]Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine [J]. Anesthesiology,2000,92(2):465-472.
[16]Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance:can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? [J]. Anesth Analg,2000,91(6):1483-1488.
[17]Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain [J]. Anesth Analg,2001,93(1):204-209.
[18]Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans [J]. Anesth Analg,1998,86(6):1307-1311.
[19]Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia [J]. Anesth Analg,2003, 97(3):810-815
[20]Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine [J]. Anesthesiology,2005,103(1):147-155.
[21]Koppert W, Sittl R, Scheuber K, et al. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans[J]. Anesthesiology,2003,99(1):152-159.
[22]Servin F. Remifentanil:when and how to use it. Eur J Anaesthesiol Suppl,1997 May, 15:41-44.
[23]Egan TD.Remifentanil Pharmacokinetics and pharmacodynamics.A preliminary appraisal [J].Clin Pharmacokinet,1995,29(2):80-94.
[24]Sear JW. Recent advances and developments in the clinical use of i.v. opioids during the peroperative period [J].Br J Anaesth,1998,81(1):38-50.
[25]Camu F, Royston D. Inpatient experience with Remifentanil [J].Anesth Analg,1999, 89:S15-21.
[26]Trafton JA, Abbadie C, Marek K, et al. Postsynaptic signaling via the [mu]-opioid receptor: Responses of dorsal horn neurons to exogenous opioids and noxious stimulation [J]. J Neurosci, 2000,20(23):8578-8584.
[27]Borgland SL. Acute opioid receptor desensitization and tolerance:Is there a link? [J]. Clin Exp Pharmacol Physiol,2001,28(3):147-154.
[28]Vanderah TW, Gardell LR, Burgess SE, et al. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance [J]. J Neurosci,2000,20(18):7074-7079.
[29]Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance:a current view of their possible interactions. Pain,1995,62(3):259-274.
[30]Laulin JP, Maurette P, Corcuff JB, et al. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance[J]. Anesth Analg,2002,94(5):1263-1269.
[31]Herrero JF, Laird JM, Lopez Garcia JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol,2000,61(2):169-203.
[32]刘月江,李秋兰,祖翠华,等.氟比洛芬酯或小剂量氯胺酮有效预防雷米芬太尼麻醉术后痛觉过敏.临床麻醉学杂志,2008,24(10)：856-858.
[33]宋青,张宏,宋运琴,等.冠状动脉架桥术麻醉及围手术期处理.军医进修学院学报,2000,21(4)：282-284.
[34]Hayakawa Fujii Y, Takada M, Ohta S, et al. Hemodynamic stability during induction of anesthesia and tracheal intubation with propofol plus fentanyl, ketamine, and fentanyl-ketamine [J]. J Anesth,2001,15(4):191-196.
[35]王贤裕,田玉科.小剂量氯胺酮镇痛的临床研究进展.《国外医学》麻醉学与复苏分册,2004,25(5)：295-298.
[36]Engelhardt T, Zaarour C, Naser B, et al. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery [J]. Anesth Analg,2008,107(4):1170-1175.
[37]Gonzales JM, Loeb AL, Reichard PS, et al.Ketamine inhibits glutamate-, N-methyl-D-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons [J]. Anesthesiology,1995,82(1):205-213.
[38]Engelhardt T, Lowe PR, Galley HF, et al. Inhibition of neuronal nitric oxide synthase reduces the propofol requirements in wide-type and nNOS knockout mice [J]. Eur J Anaesthesiol, 2006,23(3):197-201.
[39]Wu ZZ, Guan BC, Li ZW, et al. Sustained potentiation by substance P of NMDA-activated current in rat primary sensory neurons [J].Brain Res,2004,1010(1-2):117-126.
[40]Bradesi S, Eutamene H, Fioramonti J, et al. Acute restraint stress activates functional NK1 receptor in the colon of female rats:involvement of steroids [J]. Gut,2002,50(3):349-354.
[41]Weinstein J. The dorsal root ganglion and its role as a mediator of low-back pain [J]. Spine, 1986,11(10):999-1001.
[42]石欣,高乃荣,霍明东,等.P物质及其受体在慢性胰腺炎组织的表达和临床意义[J].中华肝胆外科杂志,2003,9(3)：172-176.