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1 Clinical Pediatric Hematology-Oncology Volume 23 ㆍ Number 2 ㆍ October 2016 ORIGINAL ARTICLE 소아혈관종에서프로프라놀롤치료에대한단일기관에서의 1 년이상의추적연구 김경문 1 ㆍ민동훈 1 ㆍ정혜림 1 ㆍ심재원 1 ㆍ김덕수 1 ㆍ심정연 1 ㆍ박문수 1 ㆍ박희진 2 ㆍ이소연 2 성균관대학교의과대학강북삼성병원 1 소아과학교실, 2 영상의학교실 Propranolol as a First-line Treatment for Pediatric Hemangioma: Outcome of a Single Institution Over One Year Kyung Moon Kim, M.D. 1, Dong Hoon Min, M.D. 1, Hye Lim Jung, M.D. 1, Jae Won Shim, M.D. 1, Deok Su Kim, M.D. 1, Jung Yeon Shim, M.D. 1, Moon Soo Park, M.D. 1, Hee Jin Park, M.D. 2 and So Yeon Lee, M.D. 2 Departments of 1 Pediatrics, 2 Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Background: Propranolol, a beta-blocker and well known anti-hypertensive medication, has been used as the first-line therapy for pediatric hemangioma since The objective of this study is to analyze the efficacy and safety of propranolol when used to treat pediatric hemangioma patients for one year or longer in a single institution. Methods: A retrospective chart review analysis was done of 65 pediatric hemangioma patients treated with oral propranolol as the first-line therapy from 2010 to The patients were examined regularly at an interval of 1 to 2 months for changes in hemangioma size, growth and development, and occurrence of acute side effects of propranolol such as hypotension, hypoglycemia and bronchial constriction. Results: Twenty patients were treated with propranolol for a year or longer and their median age was 202 days (range, 36 to 4,284 days) and mean duration of treatment was 22.5 months (range, 12 to 49 months). At 12 months of treatment, the average percentage of size decrement was 40.5%. When the weight and height percentile were compared between at diagnosis and 12 months post-treatment, all 20 patients showed normal growth curve and development. Patients did not show any acute side effects of propranolol during 12 months of treatment. One patient experienced hypoglycemia induced seizure, but this event was subsequently diagnosed as ketotic hypoglycemia induced from prolonged fasting. Conclusion: Propranolol was effective and well tolerated in children with hemangioma when used for one year or longer. Key Words: Hemangioma, Propranolol pissn / eissn Clin Pediatr Hematol Oncol 2016;23: Received on September 22, 2016 Revised on October 2, 2016 Accepted on October 13, 2016 Corresponding Author: Hye Lim Jung Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: Fax: hl.jung@samsung.com ORCID ID: orcid.org/ x 서 혈관종은소아기의가장흔한양성종양으로특히영아에 론 서호발하며, 영아의약 10% 에서발생하는것으로보고되어있다 [1-3]. 혈관종은혈관의내피세포의비정상적증식에의해형성되며, 특징적으로 1-12개월에걸쳐크기가커지는증식기 (proliferative phase) 와 5-10년동안병변의크기가서서히줄 97

2 Kyung Moon Kim, et al 어드는자연퇴화기 (involutive phase) 를거치게된다 [1-3]. 혈관종의진단은대개임상적소견과영상의학적, 조직학적검사를통해이루어진다. 영상의학적검사중도플러초음파와자기공명영상이진단및병변의크기, 위치, 악성도등을평가하는데가장좋은검사법으로알려져있다 [4]. 혈관종의치료는현재까지스테로이드, 인터페론알파등의약물치료부터레이저치료, 수술적절제, 혈관중재술등의치료법이선택적으로시행되고있으나주로영유아기환자군을대상으로약물의부작용및낮은효과때문에표준치료로정립된치료가부재한상황이었다 [5]. 2008년, 스테로이드치료를시행받던생후 1개월의혈관종영아에게발생한비후성심근염의치료목적으로프로프라놀롤을투여한후혈관종이호전되는사례가처음보고되었다 [6]. 이후영아혈관종을대상으로시행한임상연구에서프로프라놀롤을이용한혈관종의치료는적은부작용빈도와큰효과를보였다 [7]. 이에프로프라놀롤은전세계적으로혈관종치료에도입되었고, 2014년에는프로프라놀롤염산염의시럽제제가개발되어영유아의혈관종에대해미국, 유럽및국내식품의약품안전처의허가를받았으며, 현재프로프라놀롤은소아혈관종의일차치료약제로서널리사용되고있다. 프로프라놀롤은비선택적베타차단제로서전연령의고혈압및각종심장질환환자들에게사용되고있으며, 영아를대상으로투여해도안전하다고알려져있다. 혈관종에대해프로프라놀롤이치료효과를보이는기전은혈관의수축, 혈관내피세포의증식억제및세포사유도 [8], 혈관증식을유도하는여러사이토카인이나세포내전달체계의저해등으로추정된다 [9,10]. 프로프라놀롤의알려진부작용으로는저혈압, 서맥과같은심혈관계에대한영향에서부터기관지연축과같은호흡기계부작용, 저혈당과같은내분비계부작용이있고, 설사와같은소화기계부작용도보고된바있으나, 영아혈관종환자에서통상용량인 2 mg/kg/ 일이하투여시생명을위협하는치명적인부작용이보고된적은없었다 [7,11-13]. 프로프라놀롤은뇌-혈관장벽을잘통과하며동물및성인을대상으로한연구에서감정과기억에영향을미치는것으로밝혀졌다 [14,15]. 실제로소아혈관종환자의치료과정에서수면이나감정의변화를보이는사례가보고된바있다 [6,16]. 또한혈관종의호발시기가급격한성장및발달이일어나는영아기이기때문에영아혈관종환자에게프로프라놀롤치료가성장및발달에미치는영향에대한평가가필요하다. Moyakine 등은 4세이상의소아혈관종환자군을대상으로시행한환자-대조군연구에서프라프라놀롤이성장및발달에영향을미치지않는것으로보고하였다 [17]. 영아혈관종을대상으로프로프라놀롤치료의기간은아직명확하게정립되어있지않고, 혈관종의크기나반응에따라 1년이상의장기투여가필요할수있으므로프로프라놀롤의장기투여시에급성부작용의발생빈도와영아의성장및발달에미치는영향에대한연구가필요하다 [17]. 아직프로프라놀롤의장기투여시의성장및발달에미치는영향에대한연구는물론, 저혈당, 저혈압, 서맥, 기관지연축등과같은급성부작용의발현에대한연구도미진한상태이다 [18,19]. 이에저자들은영아를포함한소아를대상으로프로프라놀롤을 1년이상장기간투여시, 성장과발달에미치는영향과급성부작용의발생에대해의무기록을토대로후향적으로조사하여보고하고, 현재까지의경험을토대로치료및추적의가이드라인을제시하고자한다. 1) 연구대상 대상및방법 2010년부터 2016년 7월까지최근 6년간단일기관인성균관의대강북삼성병원의소아청소년과를방문하여혈관종으로진단받은총 65명의환자중프로프라놀롤을 1년이상투여하며정기적인경과관찰및치료를진행한 20명의환자를대상으로하였다. 2) 방법 혈관종의진단은임상적소견과영상의학적결과를토대로하였다. 전산화된의무기록을토대로한후향적연구를통해, 환자의성별, 나이, 재태연령, 출생체중, 혈관종의위치, 크기, 수, Table 1. Propranolol treatment protocol Hospital day Evaluation items Treatment dose Day 1 History taking, Weight/Height 0.5 mg/kg/day #3 PO Photography, laboratory exam ECG, echocardiography Doppler USG±MRI or CT HR, BP, BST every 8 hours Day 2 HR, BP, BST every 8 hours 1.0 mg/kg/day #3 PO Day 3 HR, BP, BST every 8 hours 2.0 mg/kg/day #3 PO Day 4 HR, BP, BST every 8 hours Discharge with 2.0 mg/kg/day #3 PO ECG, Electrocardiogram; USG, ultrasonography; MRI, magnetic resonance imaging; CT, computed tomography; PO, per oral; HR, heart rate; BP, blood pressure; BST, blood sugar test. 98 Vol. 23, No. 2, October 2016

3 Propranolol as a First-line Treatment for Pediatric Hemangioma 발병시기, 영상의학적검사 ( 도플러초음파, 컴퓨터단층촬영, 자기공명영상 ) 상의병변크기변화, 치료기간, 결과, 치료기간중의혈당, 혈압및심박수측정내역, 치료 1년이상경과후의키와몸무게, 발달상태에대해알아보았다. 소아혈관종환자를대상으로한프로프라놀롤치료는입원후시작하였다. 치료효과와부작용을설명한후치료에대한동의서를작성하였다. 프로프라놀롤은치료첫날 0.5 mg/kg/ 일, 두번째날 1 mg/kg/ 일, 세번째날 2 mg/kg/ 일의용량을 8시간간격하루 3회분할경구투여하였으며, 매투약 1시간후혈당, 혈압및심박수를측정하였다. 세번째날, 증량된용량에대해부작용이확인되지않는다면, 이를최종치료용량으로정하고퇴원을진행하였다 (Table 1). 치료에대한효과는영상의학적검사를통해병변의장경이나두께변화를백분율화하여평가하였다. 프로프라놀롤의급성부작용여부는치료개시시점용량결정을위한입원기간중과퇴원후 1-2개월간격으로외래방문시에측정한혈당, 혈압, 심박수, 문진과진찰소견을토대로저혈당, 저혈압, 서맥, 기관지연축등의부작용이있는지평가하였다 (Table 2). 성장에대한평가는입원시와매외래방문시에키와몸 무게를측정하여백분위수를기록하였으며, 특히프로프라놀롤 12개월이상치료를진행한후의환자의키와몸무게를측정한값을토대로 2007년배포된대한민국소아및청소년표준성장도표를기준으로연령에대한백분위수를구하였다. 25 백분위수를기준으로 4개그룹으로나누어환자의성장상태를평가하였고, 10 백분위수이하의성장지연이있는경우추가적인경과관찰을시행한후지연의원인규명을위한검사를시행하였다 (Table 2, 3). 발달에대한평가는생후 4개월부터 71개월까지의영유아를대상으로시행하는한국영유아발달선별검사에서또래수준이상의경우를보이는경우를정상으로판정하기로하였으며, 이는외래방문시의문진을통해타의료기관에서시행한결과를확보하였다. 영유아건강검진대상이아닌경우, 학교생활이나일상생활상의장애정도에관한문진을시행하였다 (Table 2, 3). Table 2. Guideline of evaluation at diagnosis and during propranolol treatment At Diagnosis 1 mo Every 2 mo 12 mo History (GA, Birth weight, Onset, Family history) O Weight/Height/BP/HR/PE/Check SE O O O O Photography (Gross size measurement) O O O O Laboratory exam (CBC, PT, aptt, Glucose) O O O ECG/Echocardiogram O Doppler USG±MRI or CT O O O K-DST O O mo, month; GA, gestational age; BP, blood pressure; HR, heart rate; PE, physical examination; SE, side effect; CBC, complete blood count; PT, prothrombin time; aptt, activated partial thromboplastin time; ECG, electrocardiogram; USG, ultrasonography; MRI, magnetic resonance imaging; CT, computed tomography; K-DST, Korean Developmental Screening Test for Infants & Children. Table 3. Guideline of evaluation after off propranolol therapy At Off 1 mo 6 mo Every 12 mo Weight/Height/BP/HR/PE/Check SE O O O O Photography (Gross size measurement) O O O O Laboratory exam (CBC, PT, aptt, Glucose) O ECG O Doppler USG±MRI or CT O O K-DST O O mo, month; BP, blood pressure; HR, heart rate; PE, physical examination; SE, side effect; CBC, complete blood count; PT, prothrombin time; aptt, activated partial thromboplastin time; ECG, electrocardiogram; USG, ultrasonography; MRI, magnetic resonance imaging; CT, computed tomography; K-DST, Korean Developmental Screening Test for Infants & Children. Clin Pediatr Hematol Oncol 99

4 Kyung Moon Kim, et al 결 1) 남녀비와발생시기 (Table 4) 과 었으며 4명 (20.0%) 에서몸통에위치해있었고, 2명 (10.0%) 에서각각몸통, 사지에다발성으로위치하고있었다. 3) 진단연령및치료시작연령, 치료기간 (Table 4) 전체환자 20명중남아 5명 (25.0%) 과여아 15명 (75.0%) 으로전체대상환자중여아가차지하는비율이높았으며, 혈관종의발생시기는중앙값이생후 1일로, 13명 (65.0%) 의환자에서출생 3일이내발견되었으며, 5개월이내에발견된경우가총 5명 (25.0%) 이었다. 2명의환자에서는각각생후 10개월, 생후 62개월에발견되었는데두환자모두안면부에위치한심재성혈관종으로서초기에는외형적인이상이두드러지게관찰되지않은까닭에발견이늦어진것으로생각되었다. 2) 혈관종의크기, 개수, 위치 (Table 4) 진단당시의혈관종의크기는영상의학적검사 ( 도플러초음파, 컴퓨터단층촬영, 자기공명영상 ) 를통해최대장경을측정하였으며중앙값은 3.3 cm로서최소 1 cm에서최대 5.3 cm로측정되었다. 병변의개수는 17명 (85.0%) 의환자에서단일병변, 3명 (15.0%) 에서다수의병변이관찰되었으며, 병변의최대개수는 4개로두경부와몸통, 사지에분포해있었다. 병변의위치는총 14명 (70.0%) 의환자에서두경부에위치하고있 Table 4. Characteristics of 20 pediatric hemangioma patients treated with propranolol over one year Characteristics Value Age of onset median (range) 1 day (1 day-62 months) Age at diagnosis (days) 7 (1-1,908) median (range) Male:Female ratio 5:15 GA (weeks) median (range) 38 (32-40) Birth weight (g) median (range) 3,150 (1,940-4,100) Number of hemangioma 17 Singles and 3 Multiples Location of hemangioma Head & neck:14 Trunk:4 Head, trunk, thigh:2 Age at treatment (days) 202 (36-4,284) median (range) <12 months:14/20 (70%) 12 months:6/20 (30%) Longitudinal diameter at 3.3 ( ) diagnosis (cm) median (range) Duration of treatment (months) 22.5 (12-49) mean (range) Mean percentage of size 40.5% ( %) decrement after 12 months of treatment (N=17) GA, Gestational age. 임상적 / 영상의학적 / 조직학적소견을통해의사에게혈관종으로진단받은시기는그중앙값이생후 7일이었으며, 프로프라놀롤을이용한치료시작연령역시그중앙값이 202일이었다. 환자중최소치료시작연령은생후 36일이었다. 20명중 14명 (70.0%) 이생후 12개월미만영아기에치료를시작하였고, 6명 (30%) 이생후 12개월이후에치료를시작하였다. 치료기간은평균값이 22.5개월로최소기간 12개월에서최장 49개월까지치료를시행하였다. 4) 치료효과 (Table 4) 프로프라놀롤로 12개월이상치료를받은 20명의혈관종환자들은병변이지방조직또는섬유조직으로퇴화되면서장경과두께가감소하는소견을보였다. 총 17명 (85.0%) 의혈관종환자에서영상의학적검사를통하여치료전과치료 12개월후혈관종의크기변화를측정하였으며, 3명 (15.0%) 의환자에서는진단시에만영상의학적검사를시행하여측정후치료중과치료후에는시진시측정한수치로혈관종의크기변화를평가하였으나혈관종크기평가에는포함하지않았다. 동일한영상의학적검사를이용해병변의장경을추적측정한환자는총 11명이었고, 6명은서로다른영상의학적검사를통해장경을추적측정하였다 (Fig. 1, 2). 영상의학적검사로혈관종크기변화를추적측정한 17명 (85%) 환자에서치료전과치료 12개월후혈관종의장경이평균 40.5% 감소하였고, 이중한명의환자에서는 12개월의치료종료후병변이완전히퇴화되었다. 5) 프로프라놀롤의급성부작용 (Table 5) 프로프라놀롤치료초기의용량증량중측정한혈당은그중앙값이 96.5 mg/dl로최저 73 mg/dl부터최고 108 mg/dl 의분포를보였고, 치료초기의용량증량중의안정시심박수는중앙값이 112 회 / 분으로, 11세의환아에서최저 72 회 / 분으로측정되었으나연령에대비하여심박수의정상범위를벗어난경우는관찰되지않았다. 총 20명의환자중 1명에서저혈당이보고되었다. 해당사례의환자는프로프라놀롤치료시작후 9개월이경과한후저혈당에의한경련으로타 3차의료기관의응급실을방문하였으며, 내원당시혈당 54 mg/dl의저혈당상태가확인되었다. 환자는당시 14시간의공복상태이후 2회의연속된경련 100 Vol. 23, No. 2, October 2016

Propranolol as a First-line Treatment for Pediatric Hemangioma Fig. 1.

(B) Clinically remarkable involution of hemangioma could be observed after 1 year of propranolol treatment.

(D) Ultrasonogram taken after 1 year of propranolol treatment showing decreased depth of hemangioma from 1.0 cm to 0.5 cm. 을보였으며, 시행한뇌파및자기공명영상상특이소견을보이지않아케톤성저혈당에의한경련으로진단되어프로프라놀롤과는무관하게판단되었다.

0%) 의환자에서키의중앙값이 75 백분위수이상, 몸무게의중앙값이 50-75 백분위수의그룹에속하는결과를보여평균이상의성장양상을보였다. 4명 (20.0%) 에서키와몸무게모두가 25 백분위수이내로평가되었으나, 이들모두치료시작시기부터성장백분율의변화가없어프로프라놀롤의투여와무관한체질적성장지연의결과로추정해현재경과관찰중에있다.

5 Propranolol as a First-line Treatment for Pediatric Hemangioma Fig. 1. (A) Superficial type hemangioma covering right eye and cheek diagnosed at the age of 1 month before propranolol treatment. (B) Clinically remarkable involution of hemangioma could be observed after 1 year of propranolol treatment. (C) Pre-treatment T2 weighted image of MRI showing high signal intensity and strong homogenous enhancement of hemangioma measuring size of cm. (D) Ultrasonogram taken after 1 year of propranolol treatment showing decreased depth of hemangioma from 1.0 cm to 0.5 cm. 을보였으며, 시행한뇌파및자기공명영상상특이소견을보이지않아케톤성저혈당에의한경련으로진단되어프로프라놀롤과는무관하게판단되었다. 그러나안전성을위하여프로프라놀롤을기존용량의 80% 로감량하였으며, 그이후에는저혈당을보이지않았다. 6) 성장및발달에대한영향 (Table 5) 환자군의연령을기준으로한키와몸무게는 25 백분위수를기준으로총 4개의그룹으로나누었다. 16명 (80.0%) 의환자에서키의중앙값이 75 백분위수이상, 몸무게의중앙값이 백분위수의그룹에속하는결과를보여평균이상의성장양상을보였다. 4명 (20.0%) 에서키와몸무게모두가 25 백분위수이내로평가되었으나, 이들모두치료시작시기부터성장백분율의변화가없어프로프라놀롤의투여와무관한체질적성장지연의결과로추정해현재경과관찰중에있다. 발달의경우영유아건강검진시시행하는한국영유아발달선별검사 (Korean-developmental screening test, K-DST) 에대한문진결과를토대로하였다. 치료시작 12개월이후시점에서영유아건강검진대상자인생후 71개월이하인영유아가 18명 (90.0%) 이었다. 이중대근육운동, 소근육운동, 인지, 언어그리고사회성등의영역에서또래수준미만의발달단계를보이는경우는없었으며, 생후 72개월이상인 2명의경우에는발달수준의검사를시행하지않았으나일상생활이나학교생활상의문제는없었다. 고찰본연구에서는영아를포함한소아혈관종환자들을대상으로프로프라놀롤을 1년이상장기간투여시에프로프라놀롤의급성부작용이발생한사례가없었고, 투여받은환자군의성장과발달도정상소견을보였으며, 치료의효과역시이전에보고된바와같이유효하게확인되었다. 처음용량조절을위한입원기간중안정시와외래추적시의혈압과심박수에서저혈압과서맥은관찰되지않았고, 통상용량인 2 mg/kg/ 일투여시에심혈관계부작용은발생하지않았다. Jack 등의연구에서 43예의영아혈관종환자들에게프로프라놀롤치료중홀터모니터링을시행하였으나부정맥을보인경우는없었다고보고하였고 [20], Hengst 등의연 Clin Pediatr Hematol Oncol 101

Kyung Moon Kim, et al Fig. 2. (A) Deep type hemangioma located in right cheek of 11-year-old boy who was diagnosed at 6 years of age and treated with corticosteroid for 5 years with poor response.

(C) Pre-Treatment T2-weighted image of MRI showing a mass with highsignal intensity, measuring longitudinal length of 4.5 cm and depth of 2.4 cm.

Evaluation results of 20 pediatric hemangioma patients treated with propranolol over one year Evaluation items Value Blood glucose (mg/dl) median (range) 96.

curve Normal growth curve Development (K-DST) Normal development K-DST, Korean Developmental Screening Test for Infants & Children.

6 Kyung Moon Kim, et al Fig. 2. (A) Deep type hemangioma located in right cheek of 11-year-old boy who was diagnosed at 6 years of age and treated with corticosteroid for 5 years with poor response. (B) Clinically flattening of right cheek with disappearance of blue color could be observed after 18 months of propranolol treatment. (C) Pre-Treatment T2-weighted image of MRI showing a mass with highsignal intensity, measuring longitudinal length of 4.5 cm and depth of 2.4 cm. (D) Hemangioma size decreased to longitudinal length of 3.6 cm and depth of 0.9 cm after 13 months of propranolol treatment. Table 5. Evaluation results of 20 pediatric hemangioma patients treated with propranolol over one year Evaluation items Value Blood glucose (mg/dl) median (range) 96.5 (73-108) Hypotension (<5th percentile) No event Heart rate (/minute) median (range) 112 (72-130) Bronchial constriction No event Height percentile range Weight percentile range Growth curve Normal growth curve Development (K-DST) Normal development K-DST, Korean Developmental Screening Test for Infants & Children. 구에서는 109명의영아혈관종환자를대상으로프로프라놀롤치료중의혈압을감시하였으나저명한저혈압을보인사례는관찰되지않았다고보고하였다 [21]. 최근 1,264예의영아혈관종환자들을대상으로시행한대규모연구에서프로프라놀롤치료시심혈관계부작용발견을위하여심전도와심장 초음파시행은필요하지않을것으로결론지었다 [22]. 초기심혈관계검사상문제가없었다면주기적인혈압이나심박수의측정은수개월간격의외래기반으로시행하더라도문제가없을것으로사료되는바이다. Holland 등의연구에서는총 3명의저혈당부작용사례와더불어기타연구의 21예를종합해기술하였다. 이연구에서는창백과냉감, 축축해진피부와함께의식저하나경련이동반되는환자들에대해응급실내원후즉각적인수액치료및입원후의경과관찰을시행하였고, 이중심각한뇌손상이동반된경련은총 21명중 1명 (4.7%) 에서보고하였으나장기적인장애를남기지않고회복하였다고한다 [18]. 본연구의경우, 1년이상장기간치료를진행한총 20명의환자에게치료기간중측정한혈당검사에서저명한저혈당이확인된환자는없었으나, 치료기간중저혈당으로인한경련을보인환자가 1명보고되었다. 하지만이환자는경련발생당일 14시간의장기간공복상태가선행되었고, 증상발현전 14시간동안프로프라놀롤을복용하지않았으므로저혈당에 102 Vol. 23, No. 2, October 2016

7 Propranolol as a First-line Treatment for Pediatric Hemangioma 의한경련은프로프라놀롤과무관하다고판단되었다. 하지만이후보호자에게프로프라놀롤의저혈당유발가능성과프로프라놀롤치료중에장시간의공복을피하도록반복적으로교육을시행하게되었다. 저혈당의증상과징후에대해교육하고, 적절한섭식후에프로프라놀롤을복용하도록하며, 저혈당증상발생시응급처치후의료기관내원하도록교육해야한다. Holland 등의연구에서는식이량저하를동반하는병적상황이동반될경우프라프라놀롤치료의중단을권하고있다 [18]. 키와몸무게의백분위수의경우, 25 백분위수를기준으로한 4그룹중각각상위첫번째, 두번째그룹에해당되는, 즉 50 백분위수이상의환자가 80% 로, 대부분으로성장지연보다는오히려평균치를선회하는양상을보였다. 20% 에서성장지연이관찰되었으나치료전진단시점부터저성장양상을보였기에체질적성장지연으로추정후, 성장양상에대한경과관찰을진행중이다. 필요시에는골연령, 갑상선호르몬및성장호르몬검사등을시행할예정이다. 발달의경우영유아건강검진시의한국영유아발달선별검사를토대로평가했던영유아환자 18명모두또래수준또는그이상의정상발달상태를보였다. 실제본기관의경우, 영유아건강검진을시행하지않는바, 문진을통해타일차의료기관에서시행한검사결과를확보하여주기적으로평가하였다. 그러나발달에대해더정확한평가를도모하기위해서는발달의평가와혈관종의치료를동일기관에서시행할필요성이있을것으로보인다. 본연구에서프로프라놀롤을이용한혈관종치료개시연령은중앙값 6개월, 최소생후 36일로서혈관종호발시기인영아의치료부작용을평가하기적절한연령대집단이었다고볼수있다. 발생연령을고려할때추후신생아및생후 3개월미만의영아를대상으로한프로프라놀롤치료의안정성에대한평가역시필요할것으로보인다. 추후혈관종의치료의방식혹은치료용량이병변의중증도와연관되어조절이필요하다는최근의경향이있다 [23,24]. 이에객관적인중증도평가도구의결정이필요하며, 실제로알려져있는 Hemangioma Activity Score (HAS) 나 Hemangioma Severity Scale (HSS) 와같이치료전략수립에있어임상의로하여금객관적인결정을내릴수있는평가방식의개발내지는기존방식의개량이추후혈관종치료의과제라고할수있을것이다 [23]. 본기관에서의경험을기반으로하여소아혈관종환자를대상으로하는프로프라놀롤치료가이드라인을제시하였고 (Table 1), 치료진행시와치료종료후의효과및부작용의 감시를위한입원중과외래에서의경과관찰시수행해야할진찰및검사추적가이드라인을제시하였다 (Table 2, 3). 이와함께보호자가프로프라놀롤치료의부작용을충분히이해하고, 상황을빠르게인지하여대처할수있도록적절한교육이동반되어야할것이다. 하지만본연구는단일기관의한계와함께연구대상자의수가적기때문에추후본연구결과를토대로소아혈관종을대상으로프로프라놀롤의환자의상태에따라치료용량및기간을조절하는적절한치료프로토콜과표준화된혈관종크기측정방법, 부작용감시방법, 성장과발달의객관적평가방법등이추가된추적프로토콜이개발되어야하고, 국내의다기관에서통일된치료및추적프로토콜하에공동연구가이루어져야할것이다. 이외에도혈관종의병태생리에관한분자생물학적연구와프로프라놀롤저항성혈관종의새로운치료방법에대한다기관공동연구도필요할것이다. References 1. Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 2008;122: Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 2006;118: Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg 1983;18: Burrows PE, Laor T, Paltiel H, Robertson RL. Diagnostic imaging in the evaluation of vascular birthmarks. Dermatol Clin 1998;16: Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol 2002;138: Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358: Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 2015;372: Léauté-Labrèze C, Taïeb A. Efficacy of beta-blockers in infantile capillary haemangiomas: the physiopathological significance and therapeutic consequences. Ann Dermatol Venereol 2008;135: Annabi B, Lachambre MP, Plouffe K, Moumdjian R, Béliveau R. Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. Pharmacol Res 2009;60: Clin Pediatr Hematol Oncol 103

8 Kyung Moon Kim, et al 10. Munabi NC, England RW, Edwards AK, et al. Propranolol targets hemangioma stem cells via camp and mitogen-activated protein kinase regulation. Stem Cells Transl Med 2016;5: Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 2013;131: Couto RA, Maclellan RA, Zurakowski D, Greene AK. Infantile hemangioma: clinical assessment of the involuting phase and implications for management. Plast Reconstr Surg 2012;130: Luo Y, Zeng Y, Zhou B, Tang J. A retrospective study of propranolol therapy in 635 infants with infantile hemangioma. Pediatr Dermatol 2015;32: Bryan BA. Reconsidering the use of propranolol in the treatment of cosmetic infantile hemangiomas. Angiol 2013;1: 1000e Langley A, Pope E. Propranolol and central nervous system function: potential implications for paediatric patients with infantile haemangiomas. Br J Dermatol 2015;172: Hermans DJ, Bauland CG, Zweegers J, van Beynum IM, van der Vleuten CJ. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol 2013;168: Moyakine AV, Kerstjens JM, Spillekom-van Koulil S, van der Vleuten CJ. Propranolol treatment of infantile hemangioma (IH) is not associated with developmental risk or growth impairment at age 4 years. J Am Acad Dermatol 2016;75: Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol 2010; 146: Aletaha M, Salour H, Bagheri A, Raffati N, Amouhashemi N. Oral propranolol for treatment of pediatric capillary hemangiomas. J Ophthalmic Vis Res 2012;7: Jacks SK, Kertesz NJ, Witman PM, Fernandez Faith E. Experience with Holter monitoring during propranolol therapy for infantile hemangiomas. J Am Acad Dermatol 2015;73: Hengst M, Oelert M, Hoeger PH. Blood pressure monitoring during the induction and maintenance period of propranolol therapy for complicated infantile hemangiomas: A prospective study of 109 infants. Pediatr Dermatol 2015;32: Wedgeworth E, Glover M, Irvine AD, et al. Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey. Br J Dermatol 2016;174: Janmohamed SR, van Oosterhout M, de Laat PC, van Rosmalen J, Madern GC, Oranje AP. Scoring the therapeutic effects of oral propranolol for infantile hemangioma: A prospective study comparing the Hemangioma Activity Score (HAS) with the Hemangioma Severity Scale (HSS). J Am Acad Dermatol 2015;73: Mancini AJ. Hemangiomas and -blockers: On the rebound. Pediatrics 2016;137:e Vol. 23, No. 2, October 2016

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar