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1 Korean J Pain Vol. 22, No. 1, 200 대한통증학회지 200; 22: 5 64 DOI: /kjp 원저 주요복강수술환자에서황산마그네슘의아편유사제내성감소에대한효과 원광대학교의과대학마취통증의학교실, * 원광대학교의과대학산본병원내과학교실, 건국대학교의과대학충주병원마취통증의학교실 장미순ㆍ손용ㆍ이철ㆍ이주환ㆍ박정현 * ㆍ이명종 Magnesium Sulfate Attenuate Opioid Tolerance in Patients undergoing Major Abdominal Surgery Mi Soon Jang, M.D., Yong Son, M.D., Ph.D., Cheol Lee, M.D., Ju Hwan Lee, M.D., Jeong Hyun Park, M.D.*, and Myeong Jong Lee, M.D. Department of Anesthesiology and Pain Medicine, College of Medicine, Wonkwang University, Iksan, *Department of Internal Medicine, Sanbon Hospital, College of Medicine, Wonkwang University, Gunpo, Department of Anesthesiology and Pain Medicine, Chungju Hospital, College of Medicine, Konkuk University, Chungju, Korea Background: Magnesium is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. Magnesium is thought to be involved in opioid tolerance by way of inhibiting calcium entry into cells. Methods: The patients were randomly assigned to three groups according to the anesthetic regimens: Group M received magnesium sulfate and Group C received saline intravenously under remifentanil-based anesthesia. Group S received saline intravenously under sevoflurane based anesthesia in place of remifentanil. The patients in the group M received 25% magnesium sulfate 50 mg/kg in 100 ml of saline, and those patients in groups C and S received an equal volume of saline before induction of anesthesia; this was followed by 10 mg/kg/h infusion of either magnesium sulfate (group M) or an equal volume of saline (groups C and S) until the end of surgery. Pain was assessed on a visual analog scale at 1, 6, 12, 24, and 36 hours after the operation. The time to the first postoperative analgesic requirement and the cumulative analgesic consumption were evaluated in the three groups. Results: The visual analog scales for pain and the cumulative analgesic consumption were significantly greater in group C than in other groups. The time to first postoperative analgesic requirement was significantly shorter in group C than that in the other groups. There were no differences between group M and S for side effects. Conclusions: A relatively high dose and continuous remifentanil infusion is associated with clinically relevant evidence of acute opioid tolerance. NMDA-receptor antagonist, magnesium sulfate as an adjuvant analgesic prevents opioid tolerance in patients who are undergoing major abdominal surgery under high dose and continuous remifentanil infusion-based anesthesia. (Korean J Pain 200; 22: 5-64) Key Words: magnesium sulfate, NMDA receptor, opioid tolerance, remifentanil. 접수일 :200 년 2 월 12 일, 승인일 :200 년 4 월 1 일책임저자 : 이철, (50-4) 전북익산시신용동 원광대학교의과대학마취통증의학교실 Tel: , Fax: ironyii@wonkwang.ac.kr 200 년도원광대학교교내연구비지원에의함. Received February 12, 200, Accepted April 1, 200 Correspondence to: Cheol Lee Department of Anesthesiology and Pain Medicine, School of Medicine, Wonkwang University, 344-2, Sinyong-dong, Iksan 50-4, Korea Tel: , Fax: ironyii@wonkwang.ac.kr This study was supported by Wonkwang University in 200.

2 장미순외 5 인 : 마그네슘과아편유사제내성 5 서론아편유사제내성을유발하는기전은아직까지명확히밝혀지지않았으나아마도다양한기전들이관여하는것으로보인다. 1) 이러한잠재적기전들로는형질도입체계로부터분리, 항진통체계, NMDA 수용체와세포내이차전령계의변화가있다. 2,3) 예를들면마그네슘이나케타민과같은비선택적 NMDA 수용체길항제는모르핀내성을차단할수있는것으로알려져있다. 4,5) 마그네슘보충없이주요수술을받는환자들은저마그네슘혈증이발생할위험이크다. 6,) 또한감소된혈중마그네슘은주술기이환율과연관되어있다.,) 이전의저자들의연구에서 remifentnail을기반으로하는주요복강수술에서 magnesium sulfate가수술후통증을감소시키고아편유사제소모량을감소시켰다. 10) 이에저자들은선택적주요복강수술에서혈중마그네슘의농도에서 rocuronium 투여량, 저혈압, 서맥, 오심과전율과같은반응을평가하고 sevoflurane을기반으로하는마취와비교할때 remifentanil을기반으로마취에서수술후통증의증가나아편유사제요구량증가를급성아편유사제내성이라가설을정하고이와관련이있는지알아보기위해연구를시행하였다. 대상및방법선택적주요복강수술을받는환자중미국마취과학회신체등급분류 1 또는 2에해당하는 0명 ( 각각 30명 ) 을대상으로시행하였다. 본연구는본원임상연구윤리위원회의허가를받고수술전대상환자들에게연구의목적과방법에대해충분히설명한후서면동의를얻은후연구를시행하였다. 수술전간질환, 신장질환과심장질환이나만성폐쇄성폐질환, 마그네슘이나그외다른약물들에알레르기반응을보이거나칼슘통로차단제, 아편유사제, 항응고제를투여받는환자들은연구대상에서제외하였다. 환자들을무작위로선택하여세군으로나눈후 M군과 C군은 remifentanil을기반으로하는마취하에 M군은생리식염수 100 ml에 25% magnesium sulfate 50 mg/kg 을투여받은후 10 mg/kg/h의속도로지속주입하였으며, C군은황산마그네슘대신같은용적의생리식염수를투여하였다. S군은 sevoflurane을기반으로하는마취하에 C군과마찬가지로같은용적의생리식염수를수술 이끝날때까지투여하였다. 약물의제제는이연구의코디네이터에의해준비되었으며수술동안환자를담당하고있는마취통증의학과의사들은연구약물을알지못하였다. 환자들은마취도입전에마취전투약이이루어지지않았다. 모든환자들은동맥카테터와요도카테터는일상적인관리의부분으로서거치하였고정질액으로는 lactated Ringer씨용액을투여받았다. 수술전과수술후혈중마그네슘, 알부민, 적혈구용적률치를측정하기위해전신마취도입후와수술종료직전에 4 ml의동맥혈을채혈하여즉시임상병리실로보내분석하였다. 마취도입은 remifentanil 1μg/kg을 60 0초에걸쳐서서히정주한후 propofol 2 mg/kg을투여하여의식소실을확인후기관내삽관을위해 rocurounium 0. mg/kg을투여하였다. 기관내삽관후마취유지는흡입산소분율이 40% 가되도록산소와공기를투여하였으며, remifentanil을기반으로하는 M군과 C군은호기말 sevoflurane 농도는 0. minimum alveolar concentration (MAC) 으로일정하게유지하였다. 이때 remifentanil의주입은 0.25μg/kg/min의속도로주입하였으며불충한마취가의심이되면점차 0.05μg/kg/min씩증량하였다. Sevoflurane을기반으로하는 S군은 remifentanil을 0.05 μg/kg/min을일정하게주입하고불충분한마취가의심이되면자율신경반응에따라 sevoflurane 농도를적정화하였다. 마취도입전에비해심박수가 15% 증가하거나수축기동맥압이 20% 초과될때를불충분한마취의기준으로삼았다. 이중분광계수감시장치 (BIS XP, A-2000, Aspect Medical Systems, USA) 를이용하여이중분광계수가 범위내로유지하도록 M군과 C군은 remifentanil의농도를 S군에서는 sevoflurane의농도를적정화하였다. 근육이완은말초신경자극기 (TOF Watch R, Organon, Ireland) 를이용하여감시하였으며사연속자극을매 10 15분마다시행하였다. 사연속자극수가 2 또는이상인경우 rocuronium 0.2 mg/kg을투여하였다. 수술중평균동맥압이마취도입전에비해 20% 이상감소하면 ephedrine 10 mg을투여하거나심박수가분당 45회이하인경우 atropine 0.5 mg을투여하였다. 수술종료시신경근차단은사연속자극이 25% 로되었을때 neostigmine 0.05 mg/kg과 atropine 0.02 mg/kg을투여하여회복시켰다. 이중분광계수가 0 이상이고자발적호흡이이루어졌을때기관발관을시행하였다. 마지막수술바늘한땀이행해질때 remifentanil과 magne-

3 60 MS Jang, et al / Korean J Pain Vol. 22, No. 1, 200 sium sulfate의주입을중단하였다. 수술종료 30분전에모든환자들은생리식염수, morphine 60 mg, ketorolac 10 mg과 ondansetron 16 mg이포함된총용적 100 ml의혼합용액을폐쇄간격 15분, 부하용량 0.5 ml, 지속주입용량 2 ml/hr으로설정된자가통증조절장치 (Accufusor R, WooYoung medical, Korea) 를통해진통제를투여받았다. 이번연구에서약물투여군에대해모르는마취통증의학과의사에의해수술후 1시간, 6시간, 12시간, 24시간, 36시간에움직임이있을때나타나는통증을수치통증등급을이용하여통증이없는경우를 0점으로, 참을수없는아픈통증을 10점으로하여평가하였다. 또한 36시간내에사용된진통제종류및양, 진통제처음투여한시간, 수술후오심, 저혈압, 전율발생여부를기록하였다. 모든환자는첫 1시간동안회복실에서비침습적혈압, 심박수, 말초산소포화도가관찰되었다. 오심은정맥내 metoclopromide 10 mg으로, 수술후전율은공기가온장치 (forced air warming blanket) 로치료되었다. 모든측정치는평균 ± 표준편차또는표준오차와환자수로표시되었다. 수술전과수술후혈중마그네슘, 알부민, 적혈구용적률치의변화는 paired t-test로분석되었고, 연령, 체중, 수술후첫진통제요구시점비교에있어서, 통증에대한시각통증등급, 각군간수액투여량이 one-way ANOVA를통하여비교되었다. 성별, 진전의 빈도수, 저혈압, 서맥, 오심과같은비모수자료는카이제곱검정이시행되었다. 결과환자의연령, 체중, 성별, 마취시간, 수술종류, 수액투여량은각군간에유의한차가없었다. 수술후진통제를처음투여한시기는다른두군보다 C군에서통계학적으로유의하게짧았다. M군의환자들은다른군에비해총 rocuronium 투여량이통계학적으로유의하게적었고, 저혈압, 서맥, 오심오심의빈도는각군간에서유사했다. 전율의빈도는다른두군보다 M군에서통계학적으로유의하게적었다 (Table 1). 세군의환자들은수술전에비해수술후혈중알부민, 적혈구용적률치는통계적으로유의하게감소하였다. C군과 S군은혈중총마그네슘농도가수술전에비해수술후통계적으로유의하게감소하였으나, M군에서는수술전에비해수술후혈중마그네슘의농도가통계학적으로유의하게증가했으며또한다른두군에비해서수술후마그네슘의농도가유의하게증가되었다 (Table 2). 수술후통증에대한수치통증등급은수술후 24시간동안다른군보다 C군에서현저히높았다 (Table 3). 수술후 1시간, 6시간, 12시간, 24시간에자가통증조절장치를 Table 1. Demographic Data, Anesthetic Characteristics and Postoperative Events Age (yr) Weight (kg) Gender (M/F) Duration of anesthesia (min) Procedure Whipple's operation PPPD Colectomy with colorectal anastomosis Colectomy with coloanal anastomosis Administered crystalloid (ml) Time weighted mean remifentanil dose (μg/kg/min) Total rocuronium consumption (mg/kg/h) The time to the first postoperatvie analgesic requirement (min) Hypotension Bradycardia Nausea Shivering 61.1 ± ± 4. 1/ ± ,121.5 ± ± ± ± ± ± / ± ,0.6 ± ± ± ± ± ± / ± ,232.6 ± ± 0.00* 0.60 ± ± Values are mean ± SD or number of patients. *P < 0.05 compared with the other groups. P < 0.05 compared with the other groups. P < 0.05 compared with the other groups. PPPD: pylorus preserving pancreaticoduodenectomy.

4 장미순외 5 인 : 마그네슘과아편유사제내성 61 Table 2. Preoperative and Postoperative Laboratory Data Preoperative Postoperative Preoperative Postoperative Preoperative Postoperative Total magnesium (mg/l) Albumine (g/dl) Hematocrit (%) 1.0 ± ± ± ± 0.15* 3.36 ± 0.22* ± 1.5* 1.1 ± ± ± ± 0.1*, 3.3 ± 0.23* ± 1.* 1.1 ± ± ± ± 0.13* 3.36 ± 0.25* ± 1.2* Values are mean ± SD. *P < 0.05 compared with preoperative concentration. P < 0.05 compared with postoperative concentration of the other groups. Table 3. Numeric Rating Scale Scores for Pain 1 h after operation 6 h after operation 12 h after operation 24 h after operation 36 h after operation 6.3 ± 1.12* 6.04 ± 0.2* 5.2 ± 0.5* 3.1 ± 0.* 2.1 ± ± ± ± ± ± ± ± ± ± ± 0.45 Values are median and SEM. *P < 0.05 compared with the other groups. Table 4. Postoperative Cumulative Injected Volume through PCA Pump (ml) 1 h after operation 6 h after operation 12 h after operation 24 h after operation 36 h after operation 2.1 ± 0.26* ± 2.1* ± 3.1* ± 3.1* 0.06 ± ± ± ± ± 1.3. ± ± ± ± ± ± 2. Values are mean ± SD or number of patients. PCA: patients controlled analgesia. *P < 0.05 compared with the other groups. 통하여투여된진통제누적소모량은다른군보다 C군에서통계학적으로유의하게많았고, M군과 S군간에통계적으로유의한차이가없었다 (Table 4). 고찰아편유사제에대한급성내성은동물실험에서는일관되게증명되었을지라도인간의임상적연구에서는상충되는결과를보여주고있다. 11,12) Crawford 등은 11) 비교적짧은시간의수술보다는고용량의아편유사제투여나장시간수술에서는아편유사제내성이발생한다고보고하고있다. 본연구에서수술후통증증가와수술중 remifentanil 사용량의증가는수술중 remifentanil 주입이급성아편유사제발달과관련이있다는가설과일치하게된다. 최근의몇가지연구에서수술중고용량의 fentanyl 13) 또는 remifentanil 14) 에대한급성아편유사제노출이아편유사제진통제에대한임상적으로중요한내성과관련될수있다고제안하였다. 내성의정도는사용된아편유사제의역가와관련이없어보이고, 특히작용시간이짧을수록내성은빨리발생한다. 15) 그래서작용시간이긴아편유사제보다 remifentanil처럼작용시간이짧은약제가내성이더잘발생하는것으로보여진다. 일부연구에서비교적고용량, 또는반복적투여와장시간아편유사제를투여했을때아편유사제내성이발생한다고보고하고있다. 13,14,16) 그러나 Ho 등은 1) 아편유사제내성의크기는아편유사제의다른항정상태의혈중농도보다는투여시간에보다연관이있다고보고하였다. 아편유사제내성의중요한임상적관점은아편유사제를투여한기간이상으로내성이잘지속된다는것이다. 예를들어, Célèrier 등은 1) rats에서 fentanyl 투여후에통증민감도가오래지속되고강화되었음을보고하였

5 62 MS Jang, et al / Korean J Pain Vol. 22, No. 1, 200 다. 본연구에서도수술후기간동안비교적아편유사제에내성을보였던우리환자들에게서도유사하게지속되었다. 아편유사제내성기전은여전히잘이해되지않은채남아있고, 다양한기전이기여하는것으로보여진다. 1) 잠재적기전들로는형질도입체계로부터분리, 2) 항진통체계, 3) N-methyl-D-aspartate 수용체와이것의세포내이차전령계의변화가있다. 3,5) 즉 μ- 아편유사제수용체의활성은 protein kinase C를세포막으로이동시켜전압의존성 Mg 2+ 차단을제거하여 NMDA 수용체가리간드작동통로로서기능을하게된다. NMDA 수용체로부터 Mg 2+ 차단제거는세포내로칼슘의유입이증가하고이러한증가는다양한작용을하게된다. 예를들어마그네슘과케타민과같은비선택적 NMDA 수용체길항체는모르핀내성을차단하는것으로보여진다. 저마그네슘혈증은가장흔한진단되지않은전해질결핍으로알려져있고, 심장부정맥이발생할수있는고위험군환자에서필수감시로추천되고있다. 1) 저마그네슘혈증의발생은수술후환자와중환자에서보고되고있다.,20,21) 수술후저마그네슘혈증의자세한기전은아직밝혀지지않았다. 그러나총혈중마그네슘농도의저하는저알부민혈증의정도와일치하고, 이는마그네슘분획물이부착할수있는단백질의감소를나타낸다. 수술중혈중총단백질과알부민농도는감소한다. 총단백질과알부민농도감소는수액주입과크게상응하고, 평균약 40% 까지알부민이감소한다. 이연구에서주입된수액의양은총마그네슘감소와크게상응했다 (P = ). 20,21) 우리는혈중마그네슘농도가수술전에비해수술후더낮아져있음을알수있었다. 이감소가현저했음에도불구하고, 이것이임상적으로중요하지않다고생각되는이유는저마그네슘혈증의임상적징후가우리환자들에서관찰되지않았기때문이다. 그러나, 생리학적수준이하로세포외마그네슘농도감소에의한 NMDA 수용체의반응이크게강화된증거가있었다. 22) 마그네슘은 NMDA 수용체길항제와칼슘채널을차단하기때문에진통효과가있고수술후진통제요구량을감소시키는것으로보여졌다. 4,5,23,24) 그러나어떤연구자들은혈관내로주입된마그네슘의오직적은부분만이혈관-뇌장벽을통과하기때문에마그네슘주입이수술후진통에효과가없다고제안하고있다. 25-2) 몇가지임상연구에서보여진강화기전은척수강내약물주입에서보여진것과는다른기전으로보인다. 왜냐하면고용량의혈중농도라할지라도오직적은용량의마그네슘만이혈관-뇌장벽을통과하기때문이다. McCarthy 등은 5) 역으로 rats에서지속적척수강내주입이이뤄진후에도혈중농도는증가하지않는다고보고하였다. 그래서, 마그네슘이중추와말초기전둘다에의해아편유사제진통제효과를증진시키는것으로보여진다. 통증에대한매우낮은농도에서의흡입마취제 (i.e., MAC) 의효과에관한상반된연구결과들이있다. 어떤연구에서는통증역치가상승한다고보고하였지만, 2,2) 다른연구에서는흡입마취제의마취밑농도에서는통각저하또는통각과민효과가없다고보고하였다. 30,31) 실제통상적으로하는임상마취에서는위와같은매우낮은농도의흡입마취제를사용하지않기때문에흡입마취제가본연구의아편유사제내성에큰영향을미치지않았으리라생각한다. 본연구에서지속적 magnesium sulfate 주입이통계적으로 rocuronium 소모량의유의한감소를보였는데이는마그네슘이운동신경말단에서아세틸콜린의분비를억제하며근섬유막의흥분성을감소시키기때문이다. 32) 본연구에서 magnesium sulfate 50 mg/kg을투여후 10 mg/kg/h의속도로지속주입하였던 M군에서전율의발생빈도가다른두군에비해유의하게적었다. Wadhwa 등은 33) 건강한실험자에게황산마그네슘 0 mg/kg을투여한후 2 g/h의속도로지속주입은전율역치를감소시킨다고보고하였다. 임상실험에서마그네슘의전율에대한효과는 meperidine이나 clonidine에서보고된효과에비하면미미하다. 34) 마그네슘투여군으로인한저혈압이나서맥과같은심혈관계반응이나오심과같은부작용은마그네슘을투여하지군과차이를보이지않았다. 결론적으로, 본연구에서수술중고용량의 remifentanil 투여는수술후통증과진통제사용량증가를급성아편유사제내성이라정의했던가설을지지하였다. 또한수술중마그네슘투여는아편유사제내성을약화시켜수술후통증강도와진통제요구량을감소시키고, 더불어신경근차단및전율감소효과가있었다. 마그네슘은값싸고, 상대적으로덜위험하며, 생물학적기초인잠재적인항침해성효과가있기때문에수술후진통제투여에대한마그네슘의역할에대한연구가더이루어져야할것이다. 참고문헌 1. Jordan B, Devi LA: Molecular mechanisms of opioid receptor signal transduction. Br J Anaesth 1; 1: 12-.

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충북의대학술지 Chungbuk Med. J. Vol. 27. No. 1. 1~ Charcot-Marie-Tooth Disease 환자의마취 : 증례보고 신일동 1, 이진희 1, 박상희 1,2 * 책임저자 : 박상희, 충북청주시서원구충대로 1 번지, 충북대학교

충북의대학술지 Chungbuk Med. J. Vol. 27. No. 1. 1~5 2017 Charcot-Marie-Tooth Disease 환자의마취 : 증례보고 신일동 1, 이진희 1, 박상희 1,2 * 책임저자 : 박상희, 충북청주시서원구충대로 1 번지, 충북대학교의과대학마취통증의학교실, 의학연구소 (28644), happycat19@hanmail.net