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1 pissn X / eissn J Vet Clin 34(2) : (2017) 호흡마취유도제로서 alfaxalone 의후향적평가 : 150 례 장민 손원균 조상민 이인형 1 서울대학교수의과대학, BK21 수의과학연구소 (Received: February 23, 2015 / Accepted: April 14, 2015) Retrospective Evaluation of Alfaxalone as an Induction Agent of Inhalation Anesthesia: 150 Cases Min Jang, Won-gyun Son, Sang-min Jo and Inhyung Lee 1 Department of Veterinary Clinical Sciences, BK21 and Research Institute of Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea Abstract : This study was performed to evaluate the clinical efficacy of alfaxalone for induction of inhalation anesthesia in small animal practice. Patient data were collected according to anesthetic records (136 dogs and 14 cats) presented to the Veterinary Medical Teaching Hospital of Seoul National University for surgeries and diagnostic imaging from July 2013 to March Anesthetic results included signalment, American Society of Anesthesiologists (ASA) grade, premedicated drugs, procedures, induction quality, and recovery after anesthesia. One hundred fifty anesthetic events were classified according to the ASA grade. Three patients were ASA grade I, 52 patients grade II, 86 patients grade III, and 9 patients grade IV, respectively. The most common premedication was midazolam and hydromorphone combination (n = 59, 39.3%) follow by acepromazine and hydromorphone combination (n = 22, 14.7%). The majority of anesthesia procedures were diagnostic imaging (n = 33, 22.0%) and ophthalmic surgeries (n = 31, 20.7%), followed by soft tissue surgeries (n = 27, 18.0%), and orthopedic surgeries (n = 20, 13.3%). Intravenous alfaxalone provided smooth induction for inhalation anesthesia in almost cases, but transient apnea and twitching/paddling were observed after induction and during recovery, respectively. In addition, alfaxalone did not show pain response during intravenous administration. Alfaxalone showed smooth induction of inhalation anesthesia in dogs and cats with mild to severe systemic disease (ASA 2-4). Alfaxalone was considered as an acceptable induction agent for patients with higher risk in small animal practice. Key words : alfaxalone, induction, ASA grade, dogs, cats. 서론 Alfaxalone 은 gamma-aminobutyric acid (GABA) 수용체에작용하여마취와근이완효과를일으키는합성스테로이드성마취제이다 (7). 역사적으로스테로이드성마취제인 alphadolone 이 Cremophor EL 용매제에유화되어시판되었으나개와고양이, 사람에서과민반응을유발하였다 (9). 이러한 Cremophor EL 의과민반응을이유로, 인의에서허가된 Althesin 과수의학에서사용되었던 Saffan 은시장에서철회되었다 (9,21) 년이래로 alfaxalone 은 histamine 유리반응을유발하지않는 cyclodextrin 을기반으로한 2-hydroxypropyl-β-cyclodextrin (HPCD) 용액으로새롭게시장에출시되어유럽과북미에서널리사용중이다 (19). 수의학에서마취제로서의 alfaxalone 의특징은정맥주사시 1 Corresponding author. inhyunglee@snu.ac.kr 빠르고부드러운유도와조용한회복을보이는것이다 (1,7,9). 이외에도다른마취유도제에비하여정맥외투여시낮은조직자극성, 넓은안전역, 좋은근이완효과등의여러장점을가진다 (1,11,13). 하지만 alfaxalone 은용량의존적으로심혈관계와호흡기계억압을일으키며 (13), 고용량 (20 mg/kg) 의 alfaxalone 에서저혈압과마취유도용량 (2 mg/kg) 에서호흡억제가보고되어있다 (2,13). 임상적으로건강한개에서의마취사망률은 1/1800 이며, 반면에 American Society of Anesthesiologist (ASA) 3-5 단계의질환이있는환자에서는마취위험도가거의 1/75 가지증가한다 (19). 이러한마취사망률의 6% 는마취도입기또는초기마취기간동안발생하므로, 다양한질환을가진환자에서마취유도제의안전성은매우중요하다 (3,19). 최근연구에서건강한개와고양이에서 alfaxalone 의심혈관계와호흡기계에미치는연구들이보고되고있으나 (1,13,14), 질환이있는환자에서의안정성에대해서는보고가적다 (19). 본조사에서는 ASA 2-4 단계의마취위험군환자에서 alfaxalone 의마취유도제로서의임상적평가를보고하고자한다. 135

2 136 장민 손원균 조상민 이인형 Table 1. American Society of Anesthesiologists (ASA) physical status classification system (4) ASA Grade Category 1 Category 2 Category 3 Category 4 Category 5 Definition Normal healthy patient A patient with mild systemic disease A patient with severe systemic disease A patient with severe systemic disease that is a constant threat to life A moribund patient who is not expected to survive without the operation 재료및방법 환자기록 2013 년 7 월부터 2014 년 3 월까지서울대학교부속동물병원에내원하여마취를실시한 461 증례의환자중 alfaxalone 을유도제로투여한 150 증례를대상으로의무기록조사를실시하였다. 환자의수술전검사로신체검사, 흉부또는복부영상검사, 혈액검사, 요검사를실시하였으며, 품종, 연령, 체중, 시술법, 마취기록등을조사하였다. 환자의 ASA 단계 (4) 는환자의병력, 기저질환, 내원시실시한신체검사결과와수술전검사결과를고려하여 3 명의마취의가평가하였다 (Table 1). 각환자는개별적으로평가하여수술전안정화를위하여수액및투약이필요시처치하였다. 마취과정각환자는마취 12 시간전부터음식섭취를제한하였다. 마취유도에앞서환자에결정질용액, 진정제및진통제를환자의상태및예상되는통증정도에따라투여하였다. 진정제로는 acepromazine ( 세다젝트, 삼우메디안, 예산, 대한민국 ), diazepam ( 디아제팜, 삼진제약, 서울, 대한민국 ), midazolam ( 미다졸람, 부광약품, 서울, 대한민국 ) 중의선택된약제를정맥투여하였으며, 진통제로는 hydromorphone ( 딜리드, 하나제약, 화성, 대한민국 ), fentanyl ( 펜타닐, 하나제약, 화성, 대한민국 ), butorphanol ( 부토판주사, 명문제약, 서울, 대한민국 ), tramadol ( 트라마돌염산염, 한올바이오파마, 대전, 대한민국 ) 중의선택된약제를투여하였다. 마취유도전 5 분동안 4 L/min 의산소를공급하였으며, 마취의유도는개에서 alfaxalone (Alfaxan, Jurox, Rutherford, Australia) 2-3 mg/kg, 고양이에서 5 mg/kg 을천천히 (60 초이상 ) 정맥내로주사하여실시하였다. 마취의유지는 isoflurane ( 아이프란, 하나제약, 화성, 대한민국 ) 과산소를이용하여실시하였다. 마취중환자감시는환자감시장치 (Datex-Ohmeda S/5, GE healthcare, Helsinki, Finland) 를이용하여실시하였으며, 마취제의최소폐포농도, 심전도, 직접또는간접동맥혈압, 산소포화도, 호기말이산화탄소분압을감시하였다. 정형외과수술환자는예상되는통증에따라 bupivacaine ( 염산부피바카인, 명문제약, 화성, 대한민국 ) 과보존제가없는 morphine ( 황몰핀, 하나제약, 화성, 대한민국 ) 을이용하여경막외마취와상완신경얼기차단술을추가로실시하였다. 마취유도평가 Alfaxalone 을개에서 2 mg/kg, 고양이에서 5 mg/kg 의정맥투여후환자의안검반사, 눈동자위치및턱근긴장도를통하여기관내튜브의장착을시도하였다. 환자의연하반사, 턱근긴장도의유지로삽관이불가능한경우 alfaxalone 1 mg/ kg 를추가투여하였다. 마취유도의평가는삽관의용이성과마취제의주입시통증반응의유무를기준으로평가하였다 (Table 2) (10,11). 결과 마취를실시한총 150 례의환자중개는 136 두, 고양이는 14 두였으며, 개에서품종별로는 Shih Tzu 가 24 두 (16.0%) 로가장높은빈도를보였으며, Maltese 와 Cocker Spaniel 이 23 두 (15.3%), Yorkshire Terrier 15 두 (10.0%) 등으로조사되었다 (Table 3). 환자의평균연령은 8.4 ± 4.0 년, 평균체중은 7.1 ± 5.8 kg 였으며, 환자의 ASA 단계는 ASA 3 단계가 86 두 (57.3%) 로가장높은빈도를보였으며, ASA 2 단계는 52 두 (34.7%), ASA 4 단계는 9 두 (6.0%) 의빈도를보였다 (Table 4). 환자의임상증상에따라다양한시술을위한마취가실시되었다 (Table 5). 진단영상검사가 33 례 (22.0%) 로가장높은빈도를보였으며, 안과수술 31 례 (20.7%), 연조직수술 27 례 (18.0%) 의빈도를보였다. 환자의시술법과기대되는통증에따라다양한진정제와진통제가병용투여되었다 (Table 6). Midazolam 과 hydromorphone 의조합이 59 례 (39.3%) 로가장높은빈도를보였으며, acepromazine 과 hydromorphone 이 22 례 (14.7%), midazolam 과 fentanyl 이 14 례 (9.3%) 의빈도를 Table 2. Behavior of pain and quality of induction assigned to each dog in response to intravenous injection of alfaxalone (10,11) Quality Evaluation Num/tot % Behavior of pain No pain No change from sedation state 150/ Pain response Withdrawal of leg, Attempting to bite at injection site 0/150 0 Quality of induction Very smooth Gradual relaxation of the patient, No movement or vocalization, Intubation at first attempt 143/ Smooth Some physical movement, Swallowing or coughing 3/ Poor Swallowing and coughing, Some distress and excitement 4/ Very poor Major distress or excitement 0/150 0

3 호흡마취유도제로서 alfaxalone 의후향적평가 : 150 례 137 Table 3. Species in dogs and cats treated with alfaxalone for induction of anesthesia Species Num/tot % Shih Tzu 24/ Maltese 23/ Cocker spaniel 23/ Yorkshire terrier 15/ Mongrel 12/ Domestic short hair 9/ Poodle 8/ Schnauzer 5/ Pekingese 5/ Labrado retriever 4/ Dachshund 3/ Siamese cat 3/ Chihuahua 3/ German shepherd 3/ Alaskan malamute 2/ Scottish fold cat 2/ Spitz 1/ Bichon frise 1/ Persian cat 1/ Scottish terrier 1/ Cavalier kings charles spaniel 1/ Jindo 1/ Total 150/ Table 4. Age, body weight, and anesthetic risks in dogs and cats treated with alfaxalone for induction of anesthesia Group Alfaxalone Parameter Age years (years) 8.4 ± 4.0 ( ) Body weight (kg) 7.1 ± 5.8 ( ) Anesthetic risks Num/tot % ASA I 3/ ASA II 52/ ASA III 86/ ASA IV 9/ ASA V 0/150 0 ASA: American Society of Anesthesiologist 보였다. Alfaxalone 의마취유도평가시정맥내투여한대부분의환자 (97.3%) 에서부드러운마취유도를보였으나, 4 증례 (2.7%) 에서기침, 부분적인근육단일수축및사지강직등의흥분증상을관찰할수있었다 (Table 2). 모든증례에서 alfaxalone 의정맥내주입시통증반응은없었다 (Table 2). 고찰 2013 년 9 월 Alfaxan 이국내에시판된이래로임상에서마취유도제로서의 alfaxalone 의사용빈도가증가하고있다. 2 Table 5. Surgical and diagnostic procedures performed in dogs and cats after induction of anesthesia with alfaxalone Section Internal medicine Theriogenology Ophthalmology Diagnostic imaging Soft tissue surgery Procedure Alfaxalone Num/tot 차진료기관인서울대학교동물병원에서는복합질환이있는환자가내원하게되며, 높은마취위험도를가진환자의시술이이루어진다. 이번연구의목적은높은마취위험도를가진환자에서 alfaxalone 의품종, ASA 단계, 병용진정제및진통제의조합에따른마취유도제로서의임상적유용성을평가하는것이었다. 본연구에서는개의비율이 136 례 (90.7%) 로높은빈도를보였으며, 고양이는 14 례 (9.3%) 의비율을보였다. 이는서울대학교동물병원에 2 차로의뢰되는품종이개가다수를차지하기때문으로판단되며, 세부품종으로는 Shih Tzu, Maltese, Yorkshire Terrier 등의소형견이높은비율을보였다. 품종은약물의선택과예상되는부작용에영향을주는데, 예로 Boxer 종은 acepromazine 에매우민감함을보인다 (6). 개와고양이에서 alfaxalone 의품종간특이성은보고된바가없으며, 본연구에서도다양한종에서 alfaxalone 의사용시특이점을발견할수없었다. 하지만단두종에서는상부호흡기계의장애와체중에비해적은기관내경으로기관삽관이다른종에비하여어려우므로 (6), alfaxalone 의투여후발생할수일시적인무호흡을주의하도록하여야한다. 마취의위험도에영향을주는것은환자의신체상태, 이용할수있는장비, 마취의의경험이있다 (4). 본연구에서는 3 명의마취의가마취전환자의신체적인상태의평가를통하여 ASA 단계를분류하였으며, ASA 3-4 단계가 63.3% 를차지하였다. 현재 ASA 3-5 단계의환자에서사용할수있는소수의마취유도제가있으며, Psatha 등 (19) 은 ASA 3-5 단계의환자에서심혈관계에안전한 fentanyl-diazepampropofol 합제와 alfaxalone 의비교연구를실시하였으며, 두마취제는부드러운마취유도와심혈관계안전성을보였다. 다 % Tracheal washing 1/ Endoscope 1/ Sedation 3/ Pyometra 3/ Castration 1/ Cataract 7/ Corneal disease 8/ Etc 16/ CT 11/ MRI 22/ Urinary 4/ Tumor 8/ Etc 15/ Orthopedic surgery 20/ Neurosurgery 11/ Dentistry 19/ CT: computed tomography, MRI: magnetic resonance imaging

4 138 장민 손원균 조상민 이인형 Table 6. Premedication drugs in dogs and cats treated with alfaxalone for induction of anesthesia Acepromazine (0.01) Diazepam (0.2) Premedication drugs (mg/kg) Alfaxalone 2 mg/kg Num/tot Hydromorphone ( ) 22/ Fentanyl (0.1 µg/kg/min) 1/ Hydromorphone ( ) 10/ Fentanyl (0.1 µg/kg/min) 3/ Tramadol (2-4) 3/ Hydromorphone ( ) 59/ Midazolam (0.2) Butorphanol (0.2) 9/ Fentanyl (0.1 µg/kg/min) 14/ Tramadol (2-4) 10/ Diazepam (0.2) 6/ Midazolam (0.2) 10/ Butorphanol (0.2) 1/ Tramadol (2-4) 2/ % 른연구에서는심혈관계의안정성이뛰어난 etomidate 와 alfaxalone 의비교시유사한심혈관계안전성을보였으나, alfaxalone 에서심박수의증가가관찰됨으로빈맥이있는환자에서는더느린주입이필요하다 (20). 마취시환자의나이는마취의관리에중요한영향을미치며, 신생견및자견에서는심폐기능의미성숙이문제가되며, 노령견의경우신경전달물질및심폐기능의감소로마취시위험성이증가한다 (6). Alfaxalone 은 12 주미만의어린개 (16) 와고양이 (17) 의유도제로의적합성이보고가되어있으며, 노령동물의마취에적합한심혈관계안전성을가지고있다 (9,19,20). 본연구에서도안검무형성증으로내원한 3 개월령의어린고양이와 16 년 9 개월의각막천공으로내원한노령견에서 alfaxalone 의사용시부드러운유도와회복을보였다. 본연구에서는환자의신체상태와수술시예상되는통증에따라다양한진정제와진통제를병용투여하였다. 전마취제는환자의스트레스및호흡마취제의심혈관계억압을줄임으로마취의유지시필수적이며 (12), 중증도에서고도의전신질환을가진환자의전신마취에서는전마취제로 opioid/benzodiazepine 또는 opioid/acepromazine 의조합이추천된다 (15). 본연구에서는마취를실시한환자의 ASA 3-4 단계의비율이 63.3% 로높았으며, 이에따라 midazolam 과 hydromorphone 의조합이 40% 로가장높은빈도를차지하였고, acepromazine 과 hydromorphone 의조합이 15% 를차지하였다. Alfaxalone 은진정되지않은환자에서는개에서 2-3 mg/kg, 고양이에서 5 mg/kg 를 60 초동안천천히정맥주사하는것이추천되며, 진정한개에서는 1-2 mg/kg, 고양이에서 mg/kg 로고양이에서는전마취제의투여시에도개보다더높은용량이요구된다 (5). 본연구에서도개에서 2-3 mg/kg, 고양이에서 3-5 mg/kg 의용량에서부드러운마취유도를보였다. Alfaxalone 은다른마취유도제에비하여정맥주사시통증반응이없다는장점이있다 (11). 마취유도제로널리사용되는 propofol 의경우정맥주사시통증반응을느끼는경우가사람에서 28-90% 로보고되고있으며 (18), 개에서는 1-7.5% 로보고가되고있다 (11). 위연구에서는 30 마리의개에서 alfaxalone 의투여시통증반응이관찰되지않았으며근육단일수축, 사지강직등의흥분증상은 10% 로관찰되었다. 본연구에서도 150 마리의증례에서 alfaxalone 의주입시통증반응은관찰되지않았으며, 마취유도중발생한흥분증상및기침은 alfaxalone 의추가적인투여후사라졌다. 본연구를통한실제임상에서사용시추가주의점은 alfaxalone 액체의무색투명한성상이다. 미국의대학동물병원에서마취시환자의안전성을개선하기위한연구에따르면, 흔히일어날수있는사람에의한오류로마취회로의오작동, 기관내튜브의삽관실수, 약물주입시다른약물혹은용량의오류, 약물표시의오류등을보고하고있다 (8). 위의연구와같이실제무색투명한 alfaxalone 의경우흔히사용되고있는생리식염수와혼동이되어마취시사람에의한실수를증가시킬수있으므로, 약물주사기에표시기록을통하여오류를줄일수있는노력이필요하다. 결론 질환이있는환자의전신마취시호흡마취의유도제로서 alfaxalone 은대부분의증례에서통증반응이없이부드러운유도를보였다. 몇몇증례에서마취유도시발생하는일시적흥분증상은 alfaxalone 의추가적인투여로조절이가능하며, 이때보일수있는일시적인무호흡은주의가필요하다. Alfaxalone 은질환이있는 ASA 2-4 단계의환자에서적절한마취유도제로판단되며, 마취시무색투명한성상으로인해발생할수있는사람에의한오류를줄이기위하여약물주사기에표시가필요하다. 감사의글 본연구는 BK21 과수의과학연구소및 2014 년정부 ( 교육부 ) 의재원으로한국연구재단의지원을받아수행된기초연구사업임 (NRF ).

5 호흡마취유도제로서 alfaxalone 의후향적평가 : 150 례 139 참고문헌 1. Ambros B, Duke-Novakovski T, Pasloske KS. Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-βcyclodextrin and propofol in dogs. Am J Vet Res 2008; 69: Amengual M, Flaherty D, Auckburally A, Bell AM, Scott EM, Pawson P. An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone. Vet Anaesth Analg 2013; 40: Brodbelt DC, Hammond R, Tuminaro D, Pfeiffer DU, Wood JL. Risk factors for anaesthetic-related death in referred dogs. Vet Rec 2006; 158: Clarke KW, Trim CM, Hall LW. An introduction to anaesthesia and general considerations. In: Veterinary anaesthesia, 11th ed. Edinburgh: Elsevier Saunders. 2014: Clarke KW, Trim CM, Hall LW. General pharmacology of the injectable agents used in anaesthesia. In: Veterinary anaesthesia, 11th ed. Edinburgh: Elsevier Saunders. 2014: Clarke KW, Trim CM, Hall LW. Anaesthesia of the dog. In: Veterinary anaesthesia, 11th ed. Edinburgh: Elsevier Saunders. 2014: Ferré PJ, Pasloske K, Whittem T, Ranasinghe MG, Li Q, Lefebvre HP. Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU. Vet Anaesth Analg 2006; 33: Hofmeister EH, Quandt J, Braun C, Shepard M. Development, implementation and impact of simple patient safety interventions in a university teaching hospital. Vet Anaesth Analg 2014; 41: Maney JK, Shepard MK, Braun C, Cremer J, Hofmeister EH. A comparison of cardiopulmonary and anesthetic effects of an induction dose of alfaxalone or propofol in dogs. Vet Anaesth Analg 2013; 40: Mathis A1, Pinelas R, Brodbelt DC, Alibhai HI. Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone. Vet Anaesth Analg 2012; 39: Michou JN, Leece EA, Brearley JC. Comparison of pain on injection during induction of anaesthesia with alfaxalone and two formulations of propofol in dogs. Vet Anaesth Analg 2012; 39: Muir W, Hubbell JA, Bednarski RM, Lerche P. Preanesthetic and perioperative medication. In: Handbook of veterinary anesthesia, 5th ed. St. Louis: Elsevier. 2013: Muir W, Lerche P, Wiese A, Nelson L, Pasloske K, Whittem T. Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs. Vet Anaesth Analg 2008; 35: Muir W, Lerche P, Wiese A, Nelson L, Pasloske K, Whittem T. The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats. Vet Anaesth Analg 2009; 36: Murrell JC. Premedication and sedation. In: BSAVA manual of canine and feline anaesthesia and analgesia, 2nd ed. Gloucester: British Sm Anim Vet Assoc. 2007: O'Hagan B, Pasloske K, McKinnon C, Perkins NR, Whittem T. Clinical evaluation of alfaxalone as an anaesthetic induction agent in dogs less than 12 weeks of age. Aust Vet J 2012; 90: O'Hagan B, Pasloske K, McKinnon C, Perkins NR, Whittem T. Clinical evaluation of alfaxalone as an anaesthetic induction agent in cats less than 12 weeks of age. Aust Vet J 2012; 90: Picard P, Tramer MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000; 90: Psatha E, Alibhai HI, Jimenez-Lozano A, Armitage-chan E, Brodbelt DC. Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk. Vet Anaesth Analg 2011; 38: Rodríguez JM, Muñoz-Rascón P, Navarrete-Calvo R, Gómez- Villamandos RJ, Domínguez Pérez JM, Fernández Sarmiento JA, Quirós Carmona S, Granados Machuca MM. Comparison of the cardiopulmonary parameters after induction of anaesthesia with alphaxalone or etomidate in dogs. Vet Anaesth Analg 2012; 39: Szebeni J, Alving CR, Rosivall L, Bünger R, Baranyi L, Bedöcs P, Tóth M, Barenholz. Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J Liposome Res 2007; 17:

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical