The Korean Journal of Gastrointestinal Endoscopy Review 의식하진정내시경검사 : Midazolam vs Propofol 고려대학교의과대학내과학교실 Conscious Sedation During Gastrointestinal Endoscopy: Midazolam vs Propofol Ja Seol Koo, M.D. and Jai Hyun Choi, M.D. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Endoscopy is increasingly performed with the patient under conscious sedation in many countries. The majority of patients can be adequately and safely sedated during routine upper endoscopy and colonoscopy with a combination of a benzodiazepine and opioid. Midazolam is a water-soluble benzodiazepine that is characterized by a rapid onset of action and a shorter duration compared with that of the other drugs of the same class. The major side effect of midazolam is respiratory depression, which can be reversed by flumazenil, a benzodiazepine-specific antagonist. Propofol is a lipid-soluble agent that has the advantages of a more rapid onset of action and a shorter recovery time compared to that of midazolam. However, it should be used with caution since it can lead to hypotension and respiratory depression. Propofol can be safely and effectively administered by nonanesthesiology physicians and nurses provided that they have received adequate training. Two models have been proposed for the administration of propofol by endoscopists: nurse-administered propofol sedation (NAPS) and combination propofol (propofol plus other agents) sedation. In order to modify the pharmacological disadvantages of propofol, fospropofol sodium, a water-soluble prodrug of propofol, has recently been developed. In addition, new delivery systems have been devised: patient-controlled sedation and computer-assisted personalized sedation, in which the computer continuously monitors the patient s condition and adjusts the dose of propofol accordingly. Endoscopists must have a thorough understanding of the medications used for endoscopic sedation and they must acquire the skills necessary for the treatment of cardiopulmonary complications. Therefore, it is necessary to develop a practice guideline pertaining to endoscopic sedation and also training programs for physicians and nurses in Korea. (Korean J Gastrointest Endosc 2011;42:67-73) Key Words: Conscious sedation, Endoscopy, Midazolam, Propofol, Practice guideline 교신저자. 최재현고려대학교의과대학내과학교실 (425-707), 경기안산시고잔 1 동 516 전화 : 031-412-5580 팩스 : 031-412-5582 이메일 : kumccjh@kumc.or.kr 접수. 2010 년 2 월 1 일승인. 2010 년 2 월 19 일 서론내시경검사에서진정은환자의불안과통증및불쾌한기억을줄여주고적합한시술여건을제공하는데도움을준다. 국내에내시경검사의전처치제로진정제가도입된이래로점차진정제사용이증가하고있으며, 1 미국의경우상부위장관내시 경과대장내시경검사에서내시경의사의 98% 는진정제를사용하고있다. 2 진정이란의식수준을약물로떨어뜨려통증과불안을최소화하면서안전과편안함을느끼도록하는것으로미국마취과학회는진정을정도에따라 4단계로나누고있다 (Table 1). 3 통상적으로내시경검사에필요한진정수준은 의식하진정 (conscious sedation, moderate sedation) 으로호흡및심혈관기능 Vol. 42, No. 2 February, 2011 (67-73) 67
Table 1. Levels of Sedation and Anesthesia Responsiveness Airway Spontaneous ventilation Cardiovascular function Minimal sedation (Anxiolysis) Normal response to verbal stimulation Unaffected Unaffected Unaffected Moderate sedation (Conscious sedation) Purposeful* response to verbal or tactile stimulation No intervention required Adequate Usually maintained *Reflex withdrawal from a painful stimulus is not considered a purposeful response. Deep sedation Purposeful* response after repeated or painful stimulation Intervention may be required May be inadequate Usually maintained General anesthesia Unarousable even with painful stimulus Intervention often required Frequently inadequate May be impaired Table 2. Pharmacologic Profile of Drugs Used for Endoscopic Sedation Drug Onset of action (min) Peak effect (min) Duration of effect (min) Dosing for endoscopic sedation Initial dose Maximum dose Pharmacologic antagonist Adverse effects Diazepam (mg) Fentanly (μg) Flumazenil (mg) Meperidine (mg) Midazolam (mg) Naloxone (mg) Propofol (mg) 2 3 3 6 <1 3 5 3 5 3 5 7 3 4 5 360 30 60 60 60 180 15 80 30 45 4 8 5 10 50 100 0.1 0.3 25 50 0.2 0.4 10 40 20 200 >5 150 6 >2 400 Flumazenil Naloxone Naloxone Flumazenil None chemical phlebitis vomiting Agitation, withdrawal symptoms vomiting disinhibition Narcotic withdrawal cardiovascular instability 은자발적으로유지되면서청각또는촉각자극에반응을보이는상태를의미한다. 4,5 의식하진정내시경검사에흔히사용하는약제는벤조다이아제핀 (benzodiazepine) 과아편유사제 (opioid) 로, 벤조다이아제핀계열의 midazolam은강력한선행성기억상실과불안해소, 진정효과를가지고있다. 그리고, midazolam과아편유사제의병합은진통효과를제공하며진정과기억상실효과를증가시키고환자만족도를향상시킨다. 6 그러나, midazolam은호흡억제작용, 진정유도에시간이오래걸리는점, 그리고비교적긴반감기로환자회복이늦은단점이있다. 이런이유로 midazolam보다진정유도와회복이빠른 propofol 사용이증가하고있으나 propofol은저혈압과무호흡이발생할수있다. 7 본고에서는내시경검사에서자주사용하는 midazolam과 propofol의약리학적특징, 사용방법, 부작용을정리하고새로운진정제와약물투여방법에대하여정리하고자한다. 본론 내시경검사에서진정은약제관련부작용을최소화하면서환자의만족을극대화하기위한것으로, 이를위해환자요인과시술요인을고려해야한다. 먼저환자요인으로는연령, 건강상태, 약물복용력, 불안감, 통증에대한내성이있다. 그리고, 시술요인으로는시술의침습정도, 시술로인한불편정도, 시술시간등이있다. 8 내시경의사는진정제를사용하기전에투여약물의약동학적및약력학적특성과부작용, 약물의상호작용을숙지하여야한다. 특히과도한진정을피하기위해약효가최고에이르는시간을알고있어야한다. 의식하진정내시경에흔히사용하는약물의약리학적특징을 Table 2 에정리하였다. 9,10 68 The Korean Journal of Gastrointestinal Endoscopy
1. Midazolam 벤조다이아제핀계열의 midazolam은산성 (<ph 3) 에서는수용성이지만정맥주사후체내에서는지용성이증가한다. 11 Midazolam의효과는 diazepam보다 1.5 3.5배강하고다른벤조다이아제핀계약제에비해작용발현이빠르며지속시간도짧다. 정맥주사시약제발현시간은 분이며 3 4분에최대효과가나타나고지속시간은 15 80분이다. 12 고령, 비만, 간또는신장기능이저하된환자에서 midazolam의소실이감소될수있고 11 H 2 수용체길항제를복용하는환자에서 midazolam의생체이용률은 30% 정도증가한다. 60세이하의건강한성인에서초기용량은 분에걸쳐 1 mg (0.03 mg/kg 이하 ) 이며, 진정이이루어질때까지 2분간격으로 1 mg씩 (0.02 0.03 mg/kg) 추가로투여할수있다. 13 그리고, midazolam 과아편유사제를병용투여할경우진정효과가증가하므로 midazolam을감량해야하고, 60세이상혹은심각한기저질환을가진환자에서는 midazolam을 20% 이상줄여야한다. 11 대체적으로내시경검사에 6 mg 이상은필요하지않으나장시간의내시경시술이필요한경우더많은용량을사용할수있다. 14 Midazolam의주된부작용은호흡억제로 midazolam과아편유사제를병용투여한환자에서호흡억제로인한사망이발생하였다. 15 그리고, midazolam 마지막정주후 30분동안무호흡이발생한사례가있다. 16 드물지만 midazolam 투여후부정맥이발생한경우도보고되었으며, 적대감, 분노또는공격성향등이발생할수있다. 17 Midazolam과유사한구조의 flumazenil (1,4-imidazobenzodiazepine) 은벤조다이아제핀길항제역할을한다. GABAA 수용체복합체에작용하여벤조다이아제핀의중추신경계효과를경쟁적으로억제하고진정, 정신운동장애, 기억상실, 호흡억제효과를해소시킬수있다. 18 수용성으로지속정주또는일시정주가가능하고반감기는 0.7 1.3시간이며평균작용시간은 1 시간이다. Midazolam의효과는 80분이상나타날수있으므로 flumazenil 투여후진정이다시발생하는것을주의해야한다. 19 환자와내시경검사실측면에서 flumazenil의효과는확립되지않았으나, 20,21 내시경검사후투여한경우회복시간을단축하는효과가있다. 22 2. Propofol Propofol은최소한의진통효과를가지는수면유도약물로, 수면유도보다낮은용량에서는진정과기억상실효과가있다. 23 Propofol의수면유도는 GABA 수용체해리를감소시켜 GABA 효과가증가하여나타나는데, 정맥주사후 30 45초에효과가나타나며작용시간은 4 8분이다. 24 Propofol은지용성으로간에서빠르게대사되어신장으로배설되는데, 약동학적 으로성별, 나이, 체중, 동반질환여부가약효에영향을주지만, 간경변이나신부전이약동학적으로유의한영향을주지는않는다. 25 아편유사제, barbiturate와같은다른중추신경계작용약물과병용할경우진정효과가증가한다. 26 현재사용하는 propofol 제제는 1% propofol, 10% soybean oil, 2.25% glycerol, 1.2% purified egg phosphatide를포함하고있어콩, 계란또는아황산염에알레르기가있는사람에게는사용할수없고 sulfonamide 알레르기환자에서도금기이다. 27 Propofol 일시정주환자의 30% 에서주사부위통증을호소하고, 28 심박출량, 체혈관저항및동맥압을감소시키는효과가있다. 29 이러한심혈관효과는 propofol 용량감소또는중단으로신속하게회복되지만, 심수축력감소와호흡억제가나타날수있다. 30 그리고, propofol은안정역이좁아중등도진정 (moderate sedation) 에서깊은진정 (deep sedation) 이나전신마취로신속하게진행할수있고약효를반전시키는약물이없다는단점이있다. 이런이유로초기에 propofol은마취과의사만사용할수있었으나, 최근미국소화기관련 3개학회-미국소화기학회 (American Gastroenterological Association), 미국소화기연구학회 (American College of Gastroenterology), 미국소화기내시경학회 (American Society for Gastrointestinal Endoscopy)-는내시경의사에의한 propofol 사용은효과적이고안전하다고공언하였다. 2 전세계적으로내시경의사의감독하에 propofol 을투여한 646,080예의분석에서사망률은벤조다이아제핀 / 아편유사제병합요법보다낮고마취과의사에의한전신마취의사망률과비슷하였다. 31 현재 propofol을이용한진정방법은두가지가제안되고있는데, 먼저간호사가환자를감시하면서 propofol을투약하는 nurse-administered propofol sedation (NAPS) 과두번째로 propofol을다른약제와병용해서투약하는 propofol 병합요법 (combination propofol) 이있다. 8 전자의경우환자상태를감시하고 propofol 투약을담당할훈련된간호사가필요한데, 처음에 propofol 10 60 mg을일시정주한뒤최소 20 30초간격을두고추가로 10 20 mg씩투약하는방식이다. 32-36 Propofol은진통효과가적기때문에, NAPS의경우대부분의환자들에서깊은진정이필요하고결과적으로저혈압, 호흡저하, 서맥등의부작용이빈번하게나타날수있다. 37 따라서, 심박수, 혈압, 산소포화도의감시와함께경비캐뉼라를통한산소공급이필요하다. 미국과스위스에서 NAPS를시행한 36,000예의후향분석에서앰부마스크와같은보조환기가필요한무호흡이나기도관련문제는 500 1,000 검사마다한예에서발생하였다. 37 그러나, 기도삽관이필요하거나사망또는영구적후유증이남은경우는없었다. Propofol 병합요법은 propofol과아편유사제또는벤조다이아제핀계약물을병용투여하여용량관련부작용을최소화하면서각약물의효과를극대화하기위한것으로, 보다적은용 Vol. 42, No. 2 February, 2011 (67-73) 69
량 (5 15 mg) 의 propofol을사용하여진통과기억상실효과를얻을수있다. 일반적으로 propofol 병합요법은아편유사제 (fentanyl 25 75 μg, meperidine 25 50 mg), midazolam (0.5 2.5 mg), 또는두약제에 propofol 5 15 mg을투여하고추가적으로 5 15 mg씩투여하면서용량을조정한다. 7,38,39 Propofol 병합요법에서는대체로중등도진정으로내시경을마칠수있어깊은진정에따르는부작용발생빈도가적고부작용이발생하더라도 naloxone이나 flumazenil과같은약물사용으로가역적이기때문에안전하다. 그리고, NAPS보다추가로사용하는 propofol 용량이적기때문에더욱세밀한조정이가능하다. 30,40 중등도진정을목표로하는 propofol 병합요법에서 propofol 평균용량은상부위장관내시경에서 35 70 mg, 대장내시경에서 65 100 mg 이었다. 41-43 Propofol 병합요법에서 propofol 투약은의사와간호사모두에게책임이있으며모든환자에서호흡및신경학적상태와맥박, 혈압, 산소포화도모니터링이필요하다. Propofol 병합요법을위하여내시경의사는적절한훈련이필요하고, 이러한내시경의사에의한 propofol 병합요법은효과적이고안전하다. 7 대장내시경환자를대상으로 propofol과 midazolam 병합요법과 midazolam과 pethidine 병합요법의비교에서 propofol 투여환자들은 pethidine 투여환자보다검사중불편감을호소하는비율이낮고빠른회복을보였다. 44 그리고, 대장내시경에서저용량 midazolam (0.03 mg/kg) 또는고용량 midazolam (0.07 mg/kg) 과 propofol (0.3 mg/kg) 병합요법과 midazolam (0.07 mg/kg) 단독요법을비교한연구에서안전성과환자만족도는세군모두에서차이가없어발생가능한부작용을고려하면저용량 midazolam과 propofol 병합요법이안전하고유용하였다. 45 일반적인상부위장관내시경과대장내시경검사에서미국소화기내시경학회는벤조다이아제핀 / 아편유사제병합요법을표준방법으로권장하는데, 5 내시경의사에의한 propofol 진정과벤조다이아제핀 / 아편유사제병합요법은저산소증, 저혈압, 서맥같은부작용발생에서유사하고안전성에차이가없다. 46 그리고, 전세계적인임상경험이부족하여단정할수없으나역행성췌담도조영술과내시경초음파검사에서 propofol 진정은 midazolam/ 아편유사제병합요법과안전성에서유사하다. 47,48 역행성췌담도조영술, 내시경초음파검사, 소장내시경검사와같은내시경시술 799예에서경험이풍부한마취과의사에의한 propofol 진정은안전하게사용할수있었다. 49 내시경의사에의한 propofol 진정은벤조다이아제핀 / 아편유사제병합요법보다진정유도가빠르고회복시간이짧은장점이있다. 50 그리고, 환자만족도에서도 propofol 진정이벤조다이제핀 / 아편유사제병합요법보다우수하거나유사하여, 46 내시경의사에의한 propofol 진정은유용할것으로생각한다. 3. 새로운약물과진정방법 의식하진정내시경검사에이상적인약제는진정, 진통및기억상실효과를가지면서약효가빠르게나타나고지속시간이짧으면서의식회복이빠른특성이있어야한다. 8 그리고, 중등도진정에서약동학적반응을예측할수있고순환기또는호흡기계부작용을최소화하고길항제가있어야한다. 또한, 내시경의사나간호사가투여할수있고진정방법은비용효과적이어야한다. 의식하진정을향상시키기위하여신약개발과기존약제의재평가, 그리고새로운투약방법이연구되고있다. 1) Fospropofol disodium: Propofol의수용성전구물질인 fospropofol disodium (Lusedra TM, Eisai Co, Inc., NJ, USA) 은미국에서마취과의사만사용하는약제로승인되었으나, 현재내시경검사에서임상연구가진행되고있다. 51,52 정맥주사후 fospropofol 은알칼리성인산분해효소 (alkaline phosphatase) 에의해대사되어 propofol이생성된다. 53,54 대장내시경환자에서다양한농도의 fospropofol (2, 5, 6.5 또는 8 mg/kg) 과 midazolam (0.02 mg/kg) 을비교한연구에서 fospropofol 용량이증가하면서진정성공률이증가하여, fospropofol 6.5, 8 mg/kg은 2 mg/kg 보다우월한진정효과를보였다. 51 Fospropofol 6.5 mg/kg을투여한환자에서중등도진정성공률이높았으며진정정도와관련하여의사와환자만족도가높았다. 52 2) Patient-controlled sedation: Patient-controlled sedation (PCS) 은환자가직접약물투여시기를조절하는것으로장벽의신전이나팽창으로통증이발생할수있는대장내시경검사에적합할것으로보인다. 대부분 PCS에서는 propofol 단독또는 propofol과아편유사제를병합하여사용하며스위치를누르면정해진용량을투여하는특수펌프를사용한다. 8 PCS을이용한내시경에서환자들은시술관련만족도가높았으며일부에서는벤조다이아제핀과아편유사제를이용한진정보다만족도가좋았다. 55,56 그리고, PCS에서는투여하는약물총량이감소하므로회복이더빠른장점이있다. 그러나, 기기에대한교육과참여가필요하므로나이어린환자, 여성, 검사전불안이증가된환자에서는사용이어렵다. 3) Computer-assisted personalized sedation: Computer-assisted personalized sedation (CAPS) 은정해진 propofol 농도를유지하기위하여컴퓨터보조투약장치를이용하는것으로 Sedasys R System (Ethicon Endo-surgery, OH, USA) 이최초로개발되었다. 57,58 이기기는 propofol 주입장치에환자모니터링과자동화된반응감시를추가한것으로과진정으로인한저산소증, 저호흡과같은생리학적지표의변화가나타나거나청각 / 촉각반응이소실되면약물투여를줄이거나중단하도록프로그램되어있다. 57 임상연구에서일반적인상부위장관내시경및대장내시경환자에서과진정을예방하면서효과 70 The Korean Journal of Gastrointestinal Endoscopy
적인진정을제공하였다. 59 결론 여러가지진정약물과방법이지역과나라에따라사용되고있다. 57 Midazolam과아편유사제병합요법은상부위장관내시경과대장내시경검사에서대체로적절하고안전한진정을유도할수있어미국소화기내시경학회는이러한병합요법을권장하고있으나, 5 최근내시경의사에의한 propofol 진정이벤조다이아제핀 / 아편유사제병합보다환자만족도에서유사하거나우월하고사망률이낮다는연구결과와함께점차사용이증가하고있으며일부에서는보편적인진정방법으로사용하기도한다. 57 그러나, propofol은저혈압과호흡억제를초래할수있으므로내시경의사와간호사는안전한약물사용과발생가능한심폐합병증에신속한대처를위하여적절한교육과훈련을받아야하다. 5,8 우리나라의경우의식하진정내시경검사가증가하고있으나진정제사용정도와실제임상에서사용하고있는진정방법은잘알려져있지않다. 국내에서 midazolam과 propofol의적정용량과안전성에대한연구는있으나, 의식하진정내시경검사의사전준비, 사용가능한진정제와효과적인사용법, 환자모니터링, 내시경의사및간호사교육등국내실정에맞는권고사항또는지침이마련되어있지않은실정이다. 보다안전하고효과적인내시경검사를위하여의식하진정을위한진정제사용현황을명확히파악하고다양한연구를통하여우리나라에적합한의식하진정내시경검사지침이마련되어야할것이다. 요약 내시경검사에진정제를사용하는의식하진정내시경검사는점차증가하고있으며벤조다이아제핀과아편유사제가흔히사용되었다. Midazolam은다른벤조다이아제핀계약물보다효과가빠르게나타나고지속시간이짧은장점이있으나부작용으로호흡억제가발생할수있다. 그러나, 벤조다이아제핀길항제인 flumazenil을사용하여 midazolam의호흡억제효과를감소시킬수있다. Midazolam과아편유사제의병합은효과적이며안전한진정방법으로일반적인상부위장관내시경과대장내시경검사에적합하다. Propofol은지용성으로 midazolam보다진정유도와회복이빠른장점이있으나저혈압과일시적무호흡이보고되어주의가필요하다. 내시경의사의감독하에적절하게훈련받은의료인에의한 propofol 투여는효과적이고안전하며, propofol 투여방법으로는간호사가환자를감시하면서 propofol을투약하는 nurse-administered propofol sedation (NAPS) 과 propofol과다른약물을병용하는 propofol 병 합요법이있다. 새로운진정제로 propofol 전구물질인 fospropofol이개발되었으며새로운약물투여방법으로 propofol 주입을환자스스로조절하는 patient-controlled sedation과환자상태에따라자동으로약물을조절하는 computer-assisted personalized sedation이연구중에있다. 안전하고효과적인의식하진정내시경검사를위하여내시경의사는사용약물에대한충분한지식을갖춰야하고발생할수있는부작용에대처할수있어야한다. 이를위해국내실정에적합한내시경검사지침과의사및간호사를위한교육훈련프로그램이개발되어야할것이다. 색인단어 : 의식하진정, 내시경검사, 미다졸람, 프로포폴, 실행지침 참고문헌 1. Rim KS, Hong SP, Won WH, Park PW, Cha YS. Midazolam as premedication for upper gastrointestinal endoscopy. Korean J Gastrointest Endosc 1996;16:181-190. 2. Cohen LB, Wecsler JS, Gaetano JN, et al. Endoscopic sedation in the United States: results from a nationwide survey. Am J Gastroenterol 2006;101:967-974. 3. Gross JB, Bailey PL, Connis RT, et al. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004-1017. 4. Thomson A, Andrew G, Jones DB. Optimal sedation for gastrointestinal endoscopy: review and recommendations. J Gastroenterol Hepatol 2010;25:469-478. 5. Lichtenstein DR, Jagannath S, Baron TH, et al. Sedation and anesthesia in GI endoscopy. Gastrointest Endosc 2008;68: 815-826. 6. Chokhavatia S, Nguyen L, Williams R, Kao J, Heavner JE. Sedation and analgesia for gastrointestinal endoscopy. Am J Gastroenterol 1993;88:393-396. 7. Cohen LB, Dubovsky AN, Aisenberg J, Miller KM. Propofol for endoscopic sedation: a protocol for safe and effective administration by the gastroenterologist. Gastrointest Endosc 2003;58:725-732. 8. Cohen LB, Delegge MH, Aisenberg J, et al. AGA Institute review of endoscopic sedation. Gastroenterology 2007;133: 675-701. 9. Springhouse. Physician's drug handbook. 11th ed. Philadelphia: Lippincott Williams & Wilkins, 2005. 10. Omoigui S. The anesthesia drugs handbook. 2nd ed. St. Louis: Mosby, 1995. 11. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985;62:310-324. 12. Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy 1985;5:138-155. 13. Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 1997;15:357-365. 14. Robb ND, Hargrave SA. Tolerance to intravenous midazolam as a result of oral benzodiazepine therapy: a potential Vol. 42, No. 2 February, 2011 (67-73) 71
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