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Supplemental Table 1. Characteristics of included studiesSourceASA-PSAge (protocol)SurgeryType ofanesthesiaAnesthesia agent usedRoute of study drugBolus dose of study drugContinuous dose of study drugTiming of study drug (bolus)Timing of observationUlusoy 1995 1 - 230-51non-cardiac surgeryGeneralhalothane, N2OIV60 mg · kg-1　Three min before intubationnot clearTramèr 1996 1 - 2not definedabdominal hysterectomyGeneralthiopental, fentanyl, vecuronium, N2O, isoflurane,IV3000 mg500 mg · h-1after inductionpostopKara 2002 1 - 226-65abdominal hysterectomyGeneralthiopental, fentanyl, vecuronium, N2O, IsofluraneIV30 mg · kg-1500 mg · h-1after induction of anesthesiapostop　Levaux 2003 1 - 2adultlumber arthrodesisGeneralpropofol, remifentanil, rocuronium, sevoflurane, N2OIV50 mg · kg-1　immediately before induction of anesthesiaat emergence and thereafterBhatia 2004 1 - 2not definedopen cholecystectomyGeneralthiopental, vecuronium, N2O, halothaneIV50 mg · kg-115 mg · kg-1 · h-115 min before general anesthesiapostopTramèr 2007not definedadultsilioinguinal hernia repair, or varicose vein operationGeneralfentanyl, propofol, N2O, isoflurane, 0.5% bupivacaine 20 mlIV4000 mg　after anesthetic inductionpostop　Usmani 2007 1 - 218-50surgical procedure of upper abdomenGeneralfentanyl, propofol, vecuronium, N2O, IV50 mg · kg-115 mg · kg-1 · h-115 min before anesthesia inductionpostop　Ryu 2008 1 - 230-65Total abdominal hysterectomy Generalpropofol, remifentanil, rocuroniumIV50 mg · kg-115 mg · kg-1 · h-1Immediately before anesthesia induction postopLee 2008 1 - 2not definedmajor abdominal surgeryGeneralpropofol, remifentanil, rocuronium, sevofluraneIV50 mg · kg-110 mg · kg-1 · h-1before induction of anesthesiapostopJang 2009 1 - 2not definedmajor abdominal surgeryGeneralremifentanil, propofol, rocuronium, sevofluraneIV50 mg · kg-110 mg · kg-1 · h-1intraoperativepostop Abd Elmawgoud 2009 1 - 240-60Radical mastectomy GeneralRemifentanil, propofol, rocuronium, sevoflurane, IVA. 50 mg · kg-1 B. 30 mg · kg-1A. 0 B. 10mg · kg-1 · h-1IntraoperativepostopHwang 2010 1 - 2not definedhip arthroplastySpinalhyperbaric bupivacaine 0.5%, fentanyl 20μgIV50 mg · kg-115 mg · kg-1 · h-1after spinal anesthesiapostop 30min, 4, 24, 48 hGozdemir 2010 1 - 240-70transurethral resection of prostateSpinal0.5% hyperbaric bupivacaine 3 mlIV80 mg · kg-12 g · h-1just after intrathecal injectionintraopNa 2010not reported5 - 15orthopedic osteotomy (lower extremities)Generalthiopental, rocuronium, sevoflurane, N2OIV50 mg · kg-115 mg · kg-1 · h-1during surgerypostop　Song 2011 1 - 220-65thyroidectomyGeneralthiopental, remifentanil, rocuronium, sevofluraneIV30 mg · kg-110 mg · kg-1 · h-1after inductionpostopSingh 2011 1 - 221-50elective surgery under general anesthesiaGeneralpropofol, vecuronium, isoflurane, N2OIV2.48mmol　before propofol injectionpostopKim 2012 1 - 218-65craniotomy for aneurysm clipping or superficial temporal artery-middle cerebral artery anastomosisGeneralvalproic acid, rocuronium, propofolIV50 mg · kg-115 mg · kg-1 · h-1after tracheal intubationpostopLópez 2013 1 - 218-65surgery with estimated duration of 60 to 180 min Generalpropofol, fentanyl, rocuronium, sevofluraneIV50 mg · kg-1　10 min prior to ending of surgery20 min after study drugAlipour 20131not definedcesarean sectionSpinal0.5% hyperbaric bupivacaine 3mlIV30 mg · kg-1　30 min before spinal anesthesiaintraop (for 90 min after spinal)Piplai 2013 1 - 218-40lumbar spinal fixation surgeryGeneralfentanyl, propofol, N2OIV30 mg · kg-110 mg · kg-1 · h-1immediately before induction of anesthesiapostopModir 2013 1 - 220-45laparotomyGeneralpropofol, isoflurane, N2OIV80 mg · kg-1　before surgerypostop 0, 10, 20 minDavoudi 2013 1 - 2not definedcesarean sectionSpinal0.5% bupivacaine 3 ml, fentanyl 25 μgIV50 mg · kg-110 mg · kg-1 · h-115 min before spinal anesthesiapostopIbrahim 2014 1 - 218-60lower extraperitoneal abdominal or lower limb surgerySpinalhyperbaric bupivacaine 20 mgIV50 mg · kg-12 mg · kg-1 · h-1immediately after spinal injectionuntil after 2 segment regressionBae 2015 1 - 220-70laparoscopic gastrectomyGeneralpropofol, remifentanil, vecuroniumIV50 mg · kg-120 mg · kg-1 · h-1before induction of anesthesiapostopMaulik 2015 1 - 2not definedcesarean section Spinalheavy 0.5% bupivacaineIV40 mg · kg-110 mg · kg-1 · h-1prior to surgerypostop　Abdulatif 2015 1 - 218-60arthroscopic anterior cruciate ligament reconstructionGeneral+regional0.25% bupivacaine 20 ml for fem nerve block, propofol, fentanyl, isofluraneIVIA1000 mg　at the conclusion of the surgerypostopArgawal 2015 1 - 220-40cesarean sectionSpinal 5% hyperbaric lignocaine 1.4 mlIV50 mg · kg-1　 60 min after spinal anesthesiaIntra and postop　Elsharnouby 2015 1 - 23-10adenotonsillectomyGeneralsevoflurane, fentanyl, atracuriumIV40 mg · kg-115 mg · kg-1 · h-1after induction of general anesthesiapostopGomathi 2016 1 - 218-65lower abdominal or lower limb surgerySpinalhyperbaric bupivacaine 12.5 mgIV2000 mg　 before spinal anesthesiaintraopHashemi 2016not reportednot definedabdominal surgeryGeneral　IV30mg · kg-140mg · kg-150 mg · kg-1　　Before the reverse of anesthesiaAt admission to recovery roomModanlou Jubari 2016not reported15-36orthognathic surgeryGeneralpropofol, remifentanil, N2OIV30 mg · kg-110 mg · kg-1 · h-1unclearpostopEl Shal 2017 1 - 220-60arthroscopic knee surgery requiring thigh tourniquetEpidural0.5% bupivacaineIV30 mg · kg-110 mg · kg-1 · h-1before insertion of epidural catheterpostopGoyal 2017 1 - 218-50craniotomy for nonvascular ICSOLGeneralN2O, isofluraneIV30 mg · kg-1　after skin closurepostopEl Sayed 2017 1 - 218-diagnostic or therapeutic knee arthroscopySpinal0.5% bupivacaine 15 mg IVITIAA. 30 +10 mg · kg-1B. 50 mgC. 800 mg　A. 10 min after intrathecal injectionB. with spinal injectionC. 10 min before the end of surgerypostop 　Hirmanpour 2017 1 - 2not definedcesarean sectionSpinal0.5 ml Sufentanil, 0.2 ml of 0.5% hyper-thin MarcaineIV40 mg · kg-115 mg · kg-1 · h-1before spinal anesthesianot definedGhatak 2010 1 - 218-60lower abdominal or lower limb surgeryEpidural0.5% bupivacaine 19 mlED50mg　with initial epidural injectionintra and postopYousef 2010 1 - 218-40cesarean sectionspinal +epidural0.5% hyperbaric bupivacaine 2 ml, bupivacaine, fentanylED500 mg　after spinal injectionintra and postopSun 2012 1 - 2-35cesarean sectionspinal +epidural0.5% isobaric bupivacaine, 0.1% bupivacaine10 ml, (morphine 1.5mg)ED500 mg　after delivery of fetuspostopShahi 2014 1 - 2not definedlower limb surgeryEpidural0.5% bupivacaine 14mlED50 mg　with epidural anesthesiaFor 1-2 h of drug administrationYousef 2014 1 - 21-6inguinal hernia repairGeneral+epiduralropivacaine 0.15% 1.5　ml · kg-1, N2Osevoflurane, ED50 mg　with caudal blockpostopRoy 2015 1 - 218-60subumbilical surgeryEpidural0.5% bupivacaine 19mlED50 mg　at the same time of epidural injectionNot definedLakra 2015 1 - 218-60lower limb surgeryEpidural0.5% bupivacaine 19mlED50 mg　with epidural anesthesiapostopMohammad 2015 1 - 320-60unilateral thoracic surgeryGeneral+epiduralpropofol, fentanyl, rocuronium, isoflurane, bupivacaineED50 mg　approximately 20 min prior to anticipated extubationPACU to postop 24hShruthi 2016 1 - 218-50elective infraumbilical surgery (orthopedic, gynecologic)Epidural0.5% bupivacaine 15 mlED50 mg　with epidural injectionpostopKogler 2016 1 - 3not definedthoracic surgeryGeneral+epidural0.5% levobupivacaine, sufentanil, midazolam, rocuronium, propofolED50 mg10mg · h-1 during surgery postop 1mg · h-115 min before general anesthesia inductionpostop (48 h)Rashmi 2016 1 - 235-45lower limb orthopedic surgerySpinalhyperbaric bupivacaine 0.5% 2.5 ml, fentanyl 50 μgED50mg　after regression of sensory block to L1postop Nagre 2017340-65femoral popliteal bypassEpidural0.25% bupivacaine 10 ml, fentanyl 50 μg, ED100 mg　With inititial epidural boluspostop?zalevli 2005 1 - 2not definedlower extremity surgerySpinal0.5% bupivacaine 10 mg, fentanyl 25 μgIT50mg　immediately following intrathecal injectionpostopSaid-Ahmed, 2008 1 - 2adultrepair of femur fractureSpinal0.75% ropivacaine 2ml, sufentanil 5μg IT50 mgwith spinal anesthesianot clearEl Samahy 2008 1 - 2not definedtransurethral prostatectomySpinal0.5% bupivacaine 2 ml, fentanyl 25μgIT50mg　immediately before intrathecal injectionThroughout periop periodUnlugenc 2009 1 - 2not definedcesarean sectionspinal +epidural0.5% isobaric bupivacaine 2 mlIT50mg　immediately after intrathecal bupivacaineintra and postopOkojie 2012 1 - 2not definedtransurethral resection of prostateSpinal0.5% hyperbaric bupivacaine 3mlIT100mg　with spinal anesthesiaintraopNath 2012 1 - 218-60total abdominal hysterectomySpinal0.5% hyperbaric bupivacaine 2.5ml, fentanyl 25μgIT100mg　with spinal anesthesiapostopAhmed Sayed 2012 1 - 218-50cesarean sectionSpinal0.5% hyperbaric bupivacaine 2ml, fentanyl 25μgIT50mg100mg　with spinal anesthesiaintraop and postop (24 h)Jabalameli 2012 1 - 218-45cesarean sectionSpinal0.5% hyperbaric bupivacaine 2.5 mlITA 50 mgB 75 mgC 100 mg　with spinal anesthesiapostopJaiswal 2013 1 - 220-60lower limb orthopedic surgerySpinal0.5% hyperbaric bupivacaine 2.5mlITA 50mg B 100mg　with spinal anesthesiapostopFaiz 2013 1 - 218-37cesarean sectionSpinal0.5% bupivacaine 2mlIT25 mg　with spinal anesthesia90 min after spinal anesthesia.Joshi-Khadke 2015 1 - 220-60gynecological surgerySpinalhyperbaric bupivacaine 17.5mgIT50 mg　with spinal anesthesiapostopXiao 2016not reportednot definedcesarean sectionSpinal0.5% bupivacaine 1.2 ml, sufentanil 2.5μgIT50 mg　with spinal anesthesiaintraop and postop (24 h)Vasure 2016 1 - 220-50Lower limb orthopedic surgerySpinal0.5% bupivacaine 2.5 ml, fentanyl 25 μgIT50 mg　with spinal anesthesiapostopXiao 2017 1 - 2not definedcesarean sectionspinal +epidural0.5% bupivacaine, sufentanil 5 μgIT50 mg　with spinal anesthesiaintraop and postop (24 h)Khandelwal 2017 1 - 220-60lower abdominal surgerySpinal0.5% hyperbaric bupivacaine 3 mlIT50 mg　with spinal anesthesiapostop (24 h)Lee 2011 1 - 2not definedrobot-assisted laparoscopic prostatectomyGeneraldesflurane, remifentanil, rocuronium,infiltration80 mg · kg-1　after pneumoperitoneumpostopSun 2017not reported50-70toe amputationregional0.25% ropivacaine 15mlperineural200 mg　popliteal sciatic nerve blockintraop and postop (48h)IV, intravenous; IA, intra-articular; ED, epidural; IT, intrathecal. ................
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