Anesth Pain Med 2016; 11: 264-268 http://dx.doi.org/10.17085/apm.2016.11.3.264 임상연구 http://crossmark.crossref.org/dialog/?doi=10.17085/apm.2016.11.3.264&domain=pdf&date_stamp=2016-07-25 pissn 1975-5171 ㆍ eissn 2383-7977 부인종양수술환자에서수술후오심구토예방효과에관한 ramosetron 과 palonosetron 의비교 단국대학교의과대학제일병원마취통증의학교실 윤희조ㆍ지영석ㆍ김영득 Comparison of the efficacy of ramosetron and palonosetron for prevention of postoperative nausea and vomiting in patients undergoing gynecologic oncology surgery Hea-Jo Yoon, Young Seok Jee, and Young-deuk Kim Department of Anesthesiology and Pain Medicine, Cheil General Hospital & Women Healthcare Center, Dankook University College of Medicine, Seoul, Korea Background: Postoperative nausea and vomiting (PONV) is a major concern during the post-surgical period. 5-hydroxy-tryptamine (5-HT 3) receptor antagonists may be useful for the prevention of PONV. The recently developed 5-HT 3 receptor antagonists, ramosetron and palonosetron, have a greater receptor affinity and a longer elimination half-life. This study was designed to assess the efficacy of palonosetron and ramosetron for prevention of PONV in patients receiving intravenous patient-controlled analgesia (IV-PCA) with opioids after gynecological oncology surgery. Methods: In this prospective trial, 290 female patients scheduled for elective gynecologic oncology surgery with IV-PCA with opioids were randomized to receive either 0.3 mg ramosetron or 0.075 mg palonosetron intravenously. The occurrence of nausea and vomiting and the use of rescue antiemetics were recorded immediately after the end of surgery, and,, and postoperatively. Results: The total incidence of PONV was similar between the Received: February 1, 2016. Revised: 1st, March 4, 2016; 2nd, March 25, 2016; 3rd, April 22, 2016. Accepted: May 12, 2016. Corresponding author: Young Seok Jee, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Cheil General Hospital & Women Healthcare Center, Dankook University College of Medicine, 17 Seoae-ro 1 gil, Jung-gu 04619, Korea. Tel: 82-2-2000-7628, Fax: 82-2-2000-7784, E-mail: jisaac@naver.com This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. two groups 0 48 h after surgery, but the incidence of nausea was significantly lower in the ramosetron group postoperatively (11.5% vs. 22.0%, P = 0.036). The incidence of vomiting and the use of rescue antiemetics were not significantly different between the two groups during any of the time intervals. Pain intensity scores and total fentanyl consumption were significantly lower in the ramosetron group postoperatively compared to the palonosetron group (P = 0.021, P = 0.041, respectively). Conclusions: The prophylactic effects of ramosetron and palonosetron on PONV incidence in the postoperative 48 h were similar in patients undergoing gynecologic oncology surgery and those receiving opioid-based IV-PCA. (Anesth Pain Med 2016; 11: 264-268) Key Words:, PONV,. 서 정맥내자가조절진통을이용한아편유사제의투여는수술후급성통증을조절하는효과적인방법중하나이다 [1]. 그러나고용량의아편유사제를사용하므로수술후오심구토 (PONV: postoperative nausea and vomiting) 의주요한요인이되기도한다 [2]. 특히부인과수술에서수술후정맥내자가조절진통으로다량의아편유사제를투여할경우수술후오심구토의비율은아편유사제에용량의존적으로상승한다 [3]. 이에수술후오심구토를줄이려는다양한노력이있었는데그중예방적항구토제투여가비교적효과가있다. 현재항구토제로 5-hydroxytryptamine (5-HT 3) 수용체길항제가널리쓰여지고있으며가장최근에개발된 5-HT 3 수용체길항제인 ramosetron과 palonosetron은수용체와친화력이매우높아서이전의 5-HT 3 수용체길항제보다효과가강하고작용시간도길다 [4-8]. 고용량의아편유사제를정맥내자가조절진통으로투여받는부인과수술환자는수술후오심구토의고위험군으로예방적항구토제가필요하며, 최근널리사용되는 ramosetron과 palonosetron, 두약물의효과에관한비교우위는논란이있다 [9-12]. 따라서본연구는수술후통증조절을위해다량의아편유사제를정맥자가조절장치로투여받는부인과종양수술이예정된 론 264
윤희조외 2 인 :Effect of ramosetron and palonosetron on PONV 265 환자를대상으로 ramosetron과 palonosetron의항오심구토효과를비교하기위해시행되었다. 대상및방법임상연구심의위원회의승인을얻은후연구에대한설명을하고동의를받았으며, 전신마취하정규부인종양수술이예정된미국마취과학회신체상태분류 1, 2등급에해당하며정맥내통증자가조절을신청한 20세이상의여성환자를대상으로전향적연구를시행하였다. 약물남용의과거력이있거나, 약물에과민반응이있는경우, 위장관계, 심혈관계, 호흡기계, 뇌질환, 신장또는간장질환, 수술전 24 시간내에항구토제를투여받은환자, 임부, 수유부는대상에서제외하였다. 환자들은 Random allocation software (version 2.0) 를사용하여무작위로 ramosetron 0.3 mg을수술종료전에정맥투여한군, palonosetron 0.075 mg을마취유도직후에정맥투여한군으로나누었다. 모든환자들은수술전 8시간이상금식하였고, 마취전처치로 glycopyrrolate 0.2 mg, midazolam 2 mg을수술 30분전에근주하였다. 마취는 propofol 2 mg/kg 정주로유도하였으며의식이소실되면펜타닐 1 mg/kg과 rocuronium 0.6 mg/kg 정주한후기관내삽관하였고, 마취유지는산소 2 L/min, 아산화질소 2 L/min, sevoflurane 2 vol% 로호기말이산화탄소분압이 35 40 mmhg로유지되도록기계적환기를하였다, 수술종료후 100% 산소로용수환기하며자발호흡을유도하고 atropine 0.02 mg/kg, neostigmine 0.04 mg/kg 정주로근이완제효과를가역한다음충분히자발호흡이돌아온후발관하였다. 수술후통증조절을위해서펜타닐 1000 g, nefopam 120 mg 그리고생리식염수 70 ml를혼합하여수술직후시간당 2 ml의속도로일시주입량 0.5 ml, 폐쇄간격을 15분으로하여일회용주입기 (ANAPA R, Ewha, Siheung, Korea) 를이용하여정맥내자가조절진통을실시하였다. 예방적항구토제투여에도불구하고오심, 구토가발생한경우에는 metoclopramide 10 mg을정주하였고, 수술후통증에대해추가적인치료를원하는경우에는 ketorolac 30 mg 을정주하였다. 마취전환자와면담하여수술후오심, 구토혹은멀미의과거력, 흡연여부를조사하였다. 수술후 3 시간, 24시간, 48시간에환자를방문하여오심, 구토의발생유무, metoclopamide의사용, 통증의정도, 일회용자가조절진통에포함된펜타닐의사용량, 항구토제의부작용에대하여조사하였다. 통증정도는시각통증등급 (Visual analogue scale: VAS, 0 10 cm) 로기록하였다. 표본수는 G-POWER 3.1 통계적검정력분석을이용하여산출하였으며, 유의수준 0.05, 통계적검정력 0.8인경우수술후오심구토발생률 30% 차이 (60% 에서 42%) 를검정하기위해서는각군당 129명의환자가필요하였고, 중도탈락을고려하여각군당 145명의환자를배정하였다 [13]. 모든측정치는평균 ± 표준편차, 중앙값 (1사분위수-3사분위수), 환자의수 (%) 로표시하였으며, 연속형변수는 Shapiro Wilk normality test후 Student t test나 Mann-Whitney test, 범주형변수는 χ 2 test를하였다. P값이 0.05 미만인경우통계적으로유의한있는것으로간주하였다. 통계분석은 SigmaStat version 4.0 (San Jose, CA, USA) 을사용하였다. Table 1. Demographic Data Age (yr) Weight (kg) Height (cm) BMI Surgery time (min) Anesthesia time (min) Laparotomy/Laparoscopy Cervical ca/ovarian ca/ Endometrial ca History of postoperative nausea/vomiting Motion sickness Nonsmoking Simplified risk score 결 각군 145명, 총 290명의환자가연구에참여하였으며, 완전한데이터를얻을수없었던환자를제외하고 palonosetron군은 132명, ramosetron군은 130명의환자를분석하였다. 대상환자의평균연령, 체중, 신장, 수술시간, 개복술과복강경수술의비율, 진단된암의종류, 수술후오심구토와차멀미의과거력, 흡연여부, 수술후오심구토의위험점수 (simplified risk score) 는군간의차이가없었다 (Table 1). 수술후 48시간내전체수술후오심구토발생률과오심발생률, 구토발생률, 항구토제의사용빈도는두군간에의미있는차이가없었다 (Table 2). 그러나수술후 24 48시간사이에는 palonosetron군에비해 ramosetron군에서수술후오심구토와오심의발생률이통계적으로의미있게낮았다 (22.0% vs 11.5%, P = 0.036) (Table 2). 또한시각통증등급과펜타닐의사용량도수술후 24 48시간사이에 palonosetron군에비해 ramosetron군에서통계적으로의미있 51.2 ± 11.1 60.1 ± 7.1 158.2 ± 5.7 24.0 ± 3.5 129.0 ± 73.6 150.4 ± 76.2 42/90 (32/68) 56/51/25 (42/39/19) 16 (12) 73 (55) 120 (91) 4.0 [3 4] 49.8 ± 10.5 61.4 ± 9.9 159.3 ± 5.4 24.2 ± 3.8 123.0 ± 66.9 142.8 ± 67.2 36/94 (28/72) 61/38/31 (47/29/24) 9 (7) 70 (54) 115 (88) 3.5 [3 4] 0.298 0.223 0.110 0.857 0.491 0.147 0.552 0.254 0.222 0.910 0.654 0.814 Values are mean ± SD, number of patients (%) or median [interquartile range]. There are no significant differences between two groups. Simplified risk score is the final simple sum of female gender, prior history of motion sickness or history of postoperative nausea/vomiting, nonsmoking, and the use of postoperative opioids. 과
266 Anesth Pain Med Vol. 11, No. 3, 2016 Table 2. Incidence of Nausea, Vomiting and Requirement for Rescue Antiemetic Treatment Table 3. The VAS Scores for Pain and Nausea, and Fentanyl Consumption Nausea Vomiting Postoperative nausea/vomiting Use of rescue antiemetic 60 (45) 58 (44) 29 (22)* 22 (17) 0 (0) 22 (17) 1 (1) 60 (45) 58 (44) 29 (22)* 26 (20) 20 (15) 51 (39) 49 (38) 15 (12) 13 (10) 0 (0) 13 (10) 2 (2) 51 (39) 49 (38) 15 (12) 16 (12) 3 (2) 10 (8) 0.371 0.367 0.036 0.160 1.000 0.160 0.989 0.371 0.367 0.036 0.144 0.512 0.089 Values are number of patients (%). *P < 0.05 vs. the ramosetron group. 게낮았다 (P = 0.021, P = 0.041) (Table 3). 군과 ramosetron군간의부작용발생률은두군간의미있는차이는없었고양군모두부작용중현기증의발생률이가장높았다 (Table 4). Pain (VAS 0 10 cm) Nausea (VAS 0 10 cm) Fentanyl consumption ( g) 4.9 ± 1.6 3.8 ± 1.5 2.1 ± 1.3 1.3 ± 1.4 4.0 ± 2.8 2.4 ± 1.7 128.4 ± 65.7 603.6 ± 160.5 460.0 ± 190.9* 1144.4 ± 287.8 4.6 ± 1.9 3.4 ± 2.0 1.8 ± 0.7 1.0 ± 0.2 3.1 ± 2.4 1.6 ± 1.4 126.0 ± 53.6 598.2 ± 129.9 413.1 ± 180.3 1101.0 ± 314.8 0.168 0.069 0.021* 0.407 0.250 0.125 0.894 0.905 0.041 0.248 Values are mean ± SD. *P < 0.05 vs. the ramosetron group. VAS: visual analogue scale. Table 4. Incidence of Adverse Events Dizziness Constipation Headache Diarrhea 53 (40) 11 (8) 22 (167) 3 (2) 62 (48) 7 (5) 12 (9) 7 (5) 0.269 0.484 0.108 0.321 Values are number of patients (%). There are no significant differences between two groups. 고찰본전향적연구는수술후아편유사제를포함한약제로정맥내자가조절진통을하는부인종양 ( 자궁경부암, 난소암, 자궁내막암 ) 수술환자를대상으로하였다. 수술후 48시간동안오심구토전체적인발생률은두약물간의차이는없었으나, 수술후 24시간에서 48시간사이에오심의발생률이 ramosetron군에서 palonosetron군에비해의미있게낮았다. 두군의구토의발생률과 metoclopamide 처방률은차이가없었다. 본연구의오심구토의발생률은 ramosetron이나 palonosetron을사용하고, 수술후정맥내자가조절진통으로아편유사제를투여받은부인과비종양복강경수술환자를대상으로한연구의발생률과유사했다 [10]. 최근, 수술후오심구토예방을목적으로 5-HT 3 수용체길항제가널리사용되고있는데, 이들의작용기전은비슷하나화학적구조나수용체와의친화력, 작용시간, 치료용량등은다양하다. 이약제중 ramosetron과 palonosetron이 5-HT 3 수용체에친화력이강하고혈장반감기가길어서다른 5-HT 3 수용체길항제에비해작용시간이길고역가가더크다 [10,14]. 이두약물의효과를비교한연구를살펴보면, Roh 등은 [9] 수술후오심구토의예방효과가 ramosetron이우세하다고보고한반면, Park 등은 [10] 본연구처럼수술후 48시간동안, 오심구토의예방효과가 palonosetron군과 ramosetron군에서차이가없다고하였으나, 본연구와는달리수술후 0 6시간에 palonosetron군이수술후오심구토의발생률이낮았다고보고하였다. Kim 등은 [11] palonosetron 0.75 mg 정맥투여군, ramosetron 0.3 mg 정맥투여군그리고 ramosetron 0.3 mg을정주하고정맥자가통증조절기구에 ramosetron 0.6 mg을혼합한군등 3군으로나누어연구하였는데, 수술후오심구토의예방효과가 palonosetron군과 ramosetron군은차이가없고, ramosetron 0.3 mg을정주한후정맥자가통증조절기구에 ramosetron 0.6 mg 을혼합하여주입한군은 palonosetron 0.075 mg 정맥투여군, ramosetron 0.3 mg 정맥투여군보다수술후오심구토의예
윤희조외 2 인 :Effect of ramosetron and palonosetron on PONV 267 방효과가우수하였다. 이수술후오심구토의예방효과가 ramosetron에비해의미있게우수하였다는 Kim 등의 [12] 연구도있어서두약물의비교우위는아직논란이있다. 본연구에서는수술후 48시간동안오심구토의발생률은두약제간에통계적인차이가없었으나, ramosetron 군이 palonosetron군에비해수술후 24시간에서 48시간사이에오심의발생률이의미있게낮은것으로보아이기간동안 ramosetron의수술후오심예방효과가우세한것으로보인다. 그러나, 이는 5-HT 3 수용체와친화력이우수하고더긴작용시간을갖고있는 palonosetron의약리학적특성에반하는결과로 [15], 이기간동안 palonosetron군에서통증의정도와펜타닐의사용량이높은것이혼란변수로작용했을수가있다. 통증자체가수술후오심구토의위험인자이며 [16], 수술후에투여되는아편유사제가용량의존적으로수술후오심구토를증가시키기때문이다 [3]. 또 ramosetron군이 palonosetron군보다이기간동안우세한항오심효과를보인것은 ramosetron의수술후오심구토 (PONV) 예방용량이항암제유발오심구토 (CINV) 치료용량과동일한용량인데반해 [16], palonosetron은수술후오심구토예방용량 (0.075 mg) 이항암제유발오심구토치료용량 (0.25 mg) 의 30% 수준인것도원인일수있다 [17]. 이기간동안 ( 수술후 24시간에서 48시간 ) 오심의발생률이 palonosetron 군에서높았음에도 metoclopramide의처방률에차이를보이지않는것은 metoclopramide 처방을요구하지않을정도로오심의정도가낮으며, 두군간에차이가없었기때문일수있다 (Table 3). 오심은구토를인식하는주관적인불쾌한감각이고, 구역은위내용물의분출없이부자연스러운경련성의주기적인호흡근의수축, 구토는입을통하여위내용물의강제적인분출로정의할수있다 [10]. 수술후오심구토의마취와연관된위험인자로는흡입마취제 [18-21] 와수술후통증조절을위해투여되는아편유사제이고 [22,23] 마취와연관되지않은위험인자로는여성, 수술후오심구토나멀미의과거력, 비흡연, 젊은나이등이다 [23]. 흡입마취제와야편유사제가수술후오심구토에미치는기전은아직명확하게밝혀지지않았으나, 전뇌 (forebrain) 는오심에마름뇌 (hindbrain) 는구토에관여한다고알려져있다 [24]. 수술후오심구토는환자에게불편감을주고외과적창상파열 (wound disruption), 탈수, 전해질불균형이나흡인성폐렴까지일으킬수있다 [25]. 본연구에서 5-HT 3 수용체길항제의예방적투여에도불구하고, 수술후오심구토의발생률이 palonosetron군에서 45.4%, ramosetron군에서 39.2% 로비교적높은비율을보이는것은, 대상환자들이수술후오심구토의위험점수 (simplified risk score) 가 3점이넘는고위험군이기때문이라생각된다. 수술후오심구토의위험점수는 Apfel 등이 [2] 여성, 멀미나수술후오심구토의과거력, 비흡연, 수술후아편유사제사용등 4가지인자의합으로만든수치이다. 이들위험요인이 0개, 1개, 2개, 3개, 4개이면수술후오심구토의발생률이각각 10%, 21%, 39%, 61%, 79% 로예측할수있다 [2]. 수술후오심수치가 3이면수술후오심구토의발생률이 61% 이고, 특히수술후정맥내자가조절진통으로아편유사제를투여받은다양한위험인자를갖는환자군에서는수술후오심구토의발생률이 80% 까지보고되었다 [3]. 본연구에서는예방적항구토제를투여한결과, 두군모두발생률이 40% 내외로감소되어어느정도효과가있었다고볼수있다. 대상환자들이대부분수술후오심구토에영향을끼치는아산화질소를사용한것도영향을끼쳤다고생각된다 [26]. 흡입마취제는화학수용체방아쇠영역 (chemoreceptor trigger zone) 을자극하여수술후오심구토발생률을증가시킨다 [27]. 5-HT 3 receptor antagonists의부작용은다양한데그중두통와어지러움증이가장흔한것으로보고되었다 [9,10,28]. 본연구에서 palonosetron군과 ramosetron군간의부작용발생률은의미있는차이는없었고양군모두부작용중어지러움증발생률이가장높았다. 본연구의제한점으로는첫째, 대조군이없는것인데이는수술후오심구토의고위험군에게예방적중재를하지않는것은비윤리적이기때문이다. 둘째, 의경우 FDA는수술후오심구토의예방에효과적인최소용량으로 palonosetron 0.075 mg을승인하였으나, 아편유사제와관련된수술후오심구토의적절한용량은알려져있지않지않다. 동일한상황에서 ramosetron과 palonosetron의동일역가의용량이알려진바없어서두약물의효능을비교하기위하여각약물의동일역가보다는현재알려진수술후오심구토를예방할수있는추천용량을사용한점이다. 셋째, 두군에서수술방법이개복수술혹은복강경수술만을대상으로하지않고두가지수술방법이혼재하고있다는것이다. 개복수술과복강경수술의비율이두군간통계적인차이는없었으나, palonosetron군에서 ramosetron 군에비해상대적으로개복수술의비율이높았고 (32% vs. 28%), 이로인해수술후 24 48시간에통증점수와펜타닐사용량이증가하여, 그기간동안오심및수술후오심구토의발생률의차이를유발했을수가있다. 결론적으로전신마취하부인종양수술및술후아편유사제를기반으로한정맥내자가통증조절장치를사용한환자들에서수술후오심구토예방을위해투여한 palonosetron과 ramosetron의약물효과는수술후 0 48시간동안비슷하였다. 다만, 오심의여러유발인자와항구토제용량과의복잡성에견주어볼때, 앞으로수술후오심구토의고위험군환자에서항구토제의적절한용량을찾는연구가필요할것으로생각된다.
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