ORIGINAL ARTICLE J Rhinol 2016;23(1): pissn / eissn 폐쇄성수면무호흡증환자에서신

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1 ORIGINAL ARTICLE J Rhinol 2016;23(1): pissn / eissn 폐쇄성수면무호흡증환자에서신형국산지속성기도양압기치료의유효성과안전성 계명대학교의과대학이비인후과학교실, 1 성균관대학교의과대학삼성서울병원이비인후과학교실, 2 삼성생명과학연구소통계지원팀, 3 내과학교실호흡기내과 4 정종인 1 이정주 2 김선우 3 김수진 2 홍상덕 2 정승규 2 동헌종 2 김호중 4 김효열 2 Efficacy and Safety of Newly Developed Korean Continuous Positive Airway Pressure Treatment in Patients with Obstructive Sleep Apnea Syndrome Jong In Jeong, MD 1, Jung Joo Lee, MD 2, Seonwoo Kim, PhD 3, Su Jin Kim, MD 2, Sang Duk Hong, MD 2, Seung Kyu Chung, MD 2, Hun-Jong Dhong, MD 2, Hojoong Kim, MD 4 and Hyo Yeol Kim, MD 2 1 Department of Otorhinolaryngology, School of Medicine, Keimyung University, Daegu; and 2 Department of Otorhinolaryngology-Head and Neck Surgery, Seoul; and 3 Biostatistics Unit, Samsung Biomedical Reserch Institute, Seoul; and 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea Background and Objectives: Obstructive sleep apnea syndrome(osas) is characterized by repeated apnea, hypopnea, and micro-arousals during sleep. Among various treatment modalities of OSAS, continuous positive airway pressure(cpap) treatment is the most effective and successful. The aim of this study was to compare efficacy and safety of newly developed Korean CPAP with standard CPAP in OSAS patients. Materials and Method: In total, 20 of 26 recruited OSAS patients completed the study. All subjects first used the standard CPAP for 4 weeks. After an at least 2 week wash-out period, the subjects used the newly developed CPAP for 4 weeks. Polysomnography, questionnaires associated with sleep, lipid profile, pulmonary function test, cardiac marker, and physical examinations were evaluated at baseline and were followed-up after each treatment. Results: After treatment with the newly developed CPAP, the apnea-hypopnea index was decreased from 53.2/hr to 2.5/hr and was equivalent to that of the standard CPAP. Most of the changes in questionnaire scores, laboratory findings, and physical examinations after newly developed CPAP treatment were equivalent to those with standard CPAP. No serious adverse events were observed during the study. Conclusion: The efficacy and safety of a newly developed CPAP are equivalent to those of standard CPAP in OSAS patients. KEY WORDS: OSAS ㆍ AHI ㆍ Efficacy ㆍ Safety ㆍ Newly developed Korean CPAP. 서 론 수면무호흡증은수면중반복적으로호흡이감소하거나 중단되어저환기, 무호흡으로인해수면중각성이발생하고, 이로인해주간졸림증상이나타나는질환이다. 수면중상 기도구조가좁아지면서발생하는폐쇄성수면무호흡증이 논문접수일 :2015 년 8 월 24 일 / 수정완료일 :2015 년 10 월 18 일 / 심사완료일 :2016 년 1 월 4 일교신저자 : 김효열, 서울강남구일원로 81 성균관대학교의과대학삼성서울병원이비인후과학교실 Tel: , Fax: , hysiam.kim@samsung.com 이연구는산업통상자원부의신성장동력장비경쟁력강화사업 ( 과제번호 : ) 의지원에의하여이루어졌다. 6 Copyright 2016 Journal of Rhinology

2 정종인등 : 신형한국형지속성기도양압기의효과 7 대부분이고, 1) 반복적인저산소증과수면분절을일으킴으로써주간졸림증상외에도기억력, 집중력저하로인한업무수행능력저하와심한경우우울증, 불안, 감정장애를유발하고, 심혈관계질환이나뇌혈관질환, 대사성질환등다양한전신질환의위험도를증가시킨다. 2) 우리나라의유병율은식생활의서구화와노령인구의증가로점차증가하는추세로, 3) 국민건강보험공단에따르면수면장애로치료받는환자는 2001년 5만여명에서 2008년 22만8천명으로 7년사이 4.5 배증가하였고, 이중상당수가폐쇄성수면무호흡증을가지고있을것으로생각된다. 현재폐쇄성수면무호흡증에대해서는지속성기도양압술, 구강내장치, 수술등의치료가이루어지고있는데, 그중지속성기도양압술은가장효과적인치료로여겨지고있다. 지속성기도양압술은일정압력의공기를주입하여수면호흡중에상기도가좁아지지않게유지시켜줌으로써코골이, 수면중각성, 주간기면등의임상증상을호전시키는것으로알려져있고, 4) 최근에는지속성기도양압술을시행한이후수면관련증상외에도, 폐쇄성수면무호흡증과연관되어발생하는심혈관계이상이나 5) 지질대사이상등도호전되었다는결과들이보고되고있다. 6) 현재국내에서는 Philips Respironics, ResMed, Fisher & Paykel사등, 외국산지속성기도양압기가주로사용되고있는데, 최근산업통상자원부의지원을받아국내에서도지속성기도양압기가새로개발되었으며, 이에저자들은폐쇄성수면무호흡증환자들을대상으로표준치료로사용되고있는기존의지속성기도양압기와그치료효과를비교하기위해본연구를진행하였다. 대상및방법 기사용이불가능한경우, 임신중인여성은연구대상에서 제외하였다. 또한혈중이산화탄소분압이 45 mm Hg 초과, 산소포화도 92% 이하, 폐성심, 1 초간노력호기량이예측치 의 50% 미만인심각한호흡기질환이있는경우, 조절되지 않는고혈압, 신부전, 부정맥이나인공심장박동기혹은제 세동기를가지고있거나지난 3 개월간급성심근경색증혹 은관상동맥스텐트시술이나수술의병력과같은심각한 심혈관질환이있는경우, 신부전으로투석중인경우, 간경 화로총빌리루빈수치가 3 mg/dl 를초과하거나복수가동 반된경우, 지난 3 개월간상부위장관출혈이있었던경우, 심한우울증과같은정신질환이있는경우등기저질환이 있는환자는연구대상에서제외하였다. 본임상시험은순차적비교시험 (sequential comparison trials) 으로진행하였다 (Fig. 1). 수면다원검사를통해중등도 내지중증수면무호흡증을진단받고임상시험에동의한 36 명중 10 명이중간에동의를철회하거나선정 / 제외기준에 따라탈락하였다. 26 명의대상환자들은우선 4 주간표준지 속성기도양압기 (S9 series, ResMed, Sydney, Australia) 치 료를시행하였는데, 이중 2 명이적정압력산출과정에서사 용불편감의사유로동의를철회하여 4 주치료를완료한환 ResMed CPAP visit 1: Screening n=36 ResMed CPAP visit 2: Baseline n=26 ResMed CPAP visit 3: After 4 weeks n=24 Screening failure: n=10 Withdrawal consent, n=5 Exclusion criteria, n=5 Discontinuation: n=2 Withdrawal consent, n=2 2013년 11월부터 2014년 9월까지코골이, 주간졸음증, 기억력저하, 집중력저하등의수면무호흡증상으로삼성서울병원에내원한환자중, 수면다원검사를시행하여수면무호흡의 90% 이상이폐쇄성으로나타나는중등도내지중증의수면무호흡증 ( 무호흡저호흡지수 20/hr) 이진단된 20 세이상 80세이하성인 36명을대상으로삼성서울병원임상시험윤리위원회의승인과식품의약품안전처의승인을얻어진행하였다. 연구기간이전 1년동안지속성기도양압술이나구강내장치를 1개월이상사용한경우나총수면시간이 4시간미만인경우, 이비인후과진료에서양측비폐색증상이확인된경우, 수면습관이나지적수준으로인해지속성기도양압 MEKics CPAP visit 1: Baseline n=23 MEKics CPAP visit 2: After 4 weeks n=21 Fult analysis set n=20 Fig. 1. Flow chart of study. Wash-out period Discontinuation: n=1 Withdrawal consent, n=1 Discontinuation: n=2 Withdrawal consent, n=2 Discontinuation: n=1 Refuse PSG, n=1

3 8 J Rhinol 2016;23(1):6-16 자는 24명이었고, 표준지속성기도양압기치료에대한평가를위해추적수면다원검사를시행하였다. 이후최대 6개월까지표준지속성기도양압기치료, 혹은휴식기간의연장을허용하였다. 표준지속성기도양압기치료가종료된후최소 2주간의휴식기를가지고나서, 신형국산지속성기도양압기 (M3, MEKics, Chuncheon, Korea) 치료에동의한 23명을대상으로다시 4주간지속성기도양압술을시행하였고, 이중 2명이적정압력산출과정에서사용불편감과소음의사유로동의를철회하였다. 4주치료를완료한 21명중 20명에서치료에대한평가를위해추적수면다원검사를시행하였고, 1명은수면다원검사시행을거부하여신형지속성기도양압기의치료효과분석에서제외하였다. 모든환자들은표준지속성기도양압기치료를시작하기전 1주의적응기간을두고비강마스크 (Mirage FX, ResMed, Sydney, Australia) 를사용하기편하게맞추어조절하였고, 이비강마스크를신형지속성기도양압기치료시에도계속사용하였다. 환자들은각각의 4주치료를시작하기전 1 주씩의적응기간동안한차례씩수면다원검사를실시하여적정압력을산출하는과정을거쳤다. 처음수면무호흡증을진단받은수면다원검사결과를바탕으로각양압기의초기압력을설정한후, 수면다원검사를시행하여 2회이상의무호흡, 혹은 3회이상의저호흡, 혹은 5회이상의호흡노력관련각성이나타날경우 5분이상의간격으로 1 cmh 2O씩증가시키면서 30분이상호흡장애가관찰되지않는압력으로조절하였다. 대상환자들은적정압력이결정된후각각 4주씩지속성기도양압기치료를시행하였고, 기기에서측정되는 4시간기준의사용일을바탕으로하루 4시간이상사용일과 4시간미만사용일을기록하여순응도를계산하였다. 대상환자들은각각의지속성기도양압기치료전후로, 체중, 목둘레, 허리둘레등신체계측과혈압, 맥박측정을하였고, 혈중지질검사 (Lipid profile), 심폐기능검사 (Pulmonary function test, Cardiac marker) 와수면다원검사를시행하였다. 수면다원검사는표준수면다원검사기 (Alice3, Healthdyne Technologies, Marietta, GA, USA) 를사용하여, 뇌파검사, 안구운동, 비강과구강을통한호흡기류, 흉부와복부의호흡운동, 혈중산소포화도, 턱과하지의근전도를측정하여평가하였다. 무호흡은비강과구강을통한호흡기류가 10초이상정지한경우로정의하였고, 저호흡은호흡기류가 10초이상 50% 이하로감소하면서혈중산소포화도가 4% 이상감소한경우로정의하였다. 수면관련설문항목은피츠버그수면질지수 (Pittsburgh Sleep Quality Index, PSQI), 폐쇄성수면무호흡증관련삶의질지수 (Calgary Sleep Apnea Quality of Life Index, CSAQLI), 건강관 련삶의질척도 (Short Form-36, SF-36), 앱워스졸림증척도 (Epworth Sleepiness scale, ESS), 스탠포드졸림증척도 (Stanford Sleepiness scale, SSS), 베를린코골이설문지 (Berlin Snoring Questionnaire, BSQ) 로구성하였다. 각각의평가변수들의분포가정규성을만족하지않아, 두기기의치료효과는 bootstrap 방법을적용하여동등성검 정을수행하여분석하였다. 수면다원검사상의측정치들과 혈압은연구자의견에따라동등성한계값을정의하였고 (Table 1), 신체계측및기타검사상의측정치들은각기기 의치료전후변화량차이값으로부터 2 표준편차를구하여 동등성한계값으로정의하였다. 또한무호흡저호흡지수변 화의두기기간동등성검정에서는 97.5% 신뢰구간을추정 하여동등성한계값범위와비교평가하였고, 그외측정치 들의동등성검정에서는 95% 신뢰구간을추정하여동등성 한계값범위와비교평가하였다. 각지수에대한통계처리는 SAS(version 9.4, SAS Institute, Cary, NC, USA) 프로그램을 이용하였다. 결 과 본임상시험을완료한대상자는총 20 명이었으며, 연령은 평균 47.4±12.8 세였고, 남성의비율이 90% 였다. 신장과체 중은각각 169.2±7.7 cm, 75.6±11.5 kg 이고, 수축기 / 이완기 혈압은 124.0±9.4 mm Hg/79.7±8.3 mm Hg 이며, 허리둘레 는 93.9±7.2 cm 였고, 양와위 / 좌위목둘레는 41.3±2.9 cm/39.8±2.7 cm 였다 (Table 2). 표준지속성양압기치료의 하루평균사용시간은 251.6±99.9 분, 순응도는 63±25%, 신형지속성양압기치료의하루평균사용시간은 246.1± 분, 순응도는 51±25% 으로, 하루평균사용시간과순응 Table 1. Definitions of equivalence margin for bootstrap method Variable Equivalence margin AHI, /hr ±5 PSQI ±3 CSAQLI ±1 SF-36 ±15 ESS ±1 SSS ±3 BSQ ±2 Blood pressure, mm Hg Systolic: ±10 Diastolic: ±5 AHI: Apnea-hypopnea index, PSQI: Pittsburg sleep quality index, CSAQLI: Calgary Sleep Apnea Quality of Life Index, SF-36: Short form-36, ESS: Epworth sleepiness scale, SSS: Stanford sleepiness scale, BSQ: Berlin snoring questionnaire

4 정종인등 : 신형한국형지속성기도양압기의효과 9 도는두군간의통계적으로유의한차이는없었다 (p=0.432, 0.297). 수면다원검사상대상환자들의기저무호흡저호흡지수는 53.2±24.0/hr 였고, 표준지속성기도양압기와신형지속성기도양압기치료를 4주간시행한후수면다원검사상무호흡저호흡지수는 3.0±3.7/hr 와 2.5±2.0/hr 로, 4주치료후각각 50.2±24.7/hr, 50.7±24.2/hr 의무호흡저호흡지수의감소를보였으며, 표준지속성기도양압기에비해신형지속성기도양압기가 0.4±4.0/hr 더감소하였다. 이를바탕으로 bootstrap 방법을통해추정된신형지속성기도양압기 4주사용후무호흡저호흡지수의평균은 2.5/hr, 추정된 97.5% 신뢰구간은 1.7~3.5/hr 였고, 표준지속성기도양압기와신형지속성기도양압기사용후무호흡저호흡지수감소량간의추정된차이값은평균 0.4/hr, 추정된 97.5% 신뢰구간은 -1.1~2.5/hr 였으며, 모두동등성한계값인 -5.0~5.0/ hr를벗어나지않았으므로, 신형지속성기도양압기사용후무호흡저호흡지수의감소는표준지속성기도양압기와비교하였을때통계적으로동등하였다 (Table 3). 수면관련삶의질평가항목중, 피츠버그수면질지수는기저치 7.5±2.4 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 6.1±3.5 와 5.1±3.5 로감소하였고, 두기기간감소량의차이값추정치는 1.0, 95% 신뢰구간은 -0.1~2.1 로나타났다. 폐쇄성수면무호흡증관련삶의질지수는기저치 4.51±0.74에서표준지속성기도양압기와신형지속성기도양압기사용후각각 5.29±0.92 와 5.24± 0.79로증가하였고, 두기기간증가량의차이값추정치는 0.05, 95% 신뢰구간은 -0.35~0.44 로나타났다. 건강관련삶의질척도는기저치 48.5±15.5 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 54.8±17.2와 53.8±16.5 로증가하였고, 두기기간증가량의차이값추정치는 1.0, 95% 신뢰구간은 -5.4~7.4 로나타났다. 주간졸림증평가항목중, 앱워스졸림증척도는기저치 10.5±4.2 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 8.1±2.8과 8.1±3.9로감소하였고, 두기기간감소량의차이값추정치는 -0.06, 95% 신뢰구간은 -2.05~1.50 으로나타났다. 스탠포드졸림증척도는기저치 Table 2. Baseline characteristics of subjects Variable Standard CPAP Newly developed CPAP Participating (n=26) Participating (n=23) Full analysis set (n=20) Age, years 47.2± ± ±12.8 Sex, n (%) Male 23 (88.5) 20 (87.0) 18 (90.0) Female 3 (11.5) 3 (13.0) 2 (10.0) Height, cm 169.0± ± ±7.7 Weight, kg 76.3± ± ±11.5 Blood pressure, mm Hg Systolic 123.7± ± ±9.4 Diastolic 80.7± ± ±8.3 Waist circumference, cm 93.9± ± ±7.2 Neck circumference, cm Supine 41.1± ± ±2.9 Sitting 39.6± ± ±2.7 CPAP: Continuous positive airway pressure Table 3. Analysis of AHI result after 4 weeks CPAP treatment using bootstrap method Variable AHI, /hr Mean (97.5% CI)* Equivalence margin Baseline 53.2±24.0 After 4 weeks standard CPAP 3.0±3.7 After 4 weeks newly developed CPAP 2.5± (1.7~3.5) Changes (After 4 weeks-baseline) Change after standard CPAP -50.2±24.7 Change after newly developed CPAP -50.7±24.2 Difference of change (standard-newly) 0.4± (-1.1~2.5) (-5~5) *: The 97.5% confidence interval was estimated from 1000 bootstrapped samples by bootstrap method. CI: confidence interval

5 10 J Rhinol 2016;23(1): ±0.8 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 2.4±1.0과 2.1±0.7로감소하였고, 두기기간감소량의차이값추정치는 0.2, 95% 신뢰구간은 -0.3~0.8 로나타났다. 베를린코콜이설문지는기저치 6.4±2.1 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 2.1± 2.3과 3.9±3.0 으로감소하였고, 두기기간감소량의차이값추정치는 -1.8, 95% 신뢰구간은 -3.5~-0.1 로나타났다. 수면관련설문항목들중베를린코골이설문지에서만두기기간차이값추정치의 95% 신뢰구간이동등성한계값으로정의한 -2.0~2.0 의하한값을벗어났으나, 그외에다른항목들은모두추정치의 95% 신뢰구간이동등성한계값을벗어나지않았으므로, 신형지속성기도양압기사용후베를린코골이설문지를제외한모든수면관련설문항목점수의변화는표준지속성기도양압기와비교하였을때통계적으로동등하였다 (Table 4). 각각의지속성양압기치료후시행한혈중지질검사결과, 총콜레스테롤수치는기저치 193.7±37.8 mg/dl에서표준지속성기도양압기와신형지속성기도양압기사용후각각 190.3±29.6 mg/dl와 ±37.3 mg/dl로감소하였고, 두기기간감소량의차이값추정치는 -2.3 mg/dl, 95% 신뢰구간은 -11.6~7.0 mg/dl로나타났다. 저밀도지단백콜레스테롤수치는기저치 124.3±35.5 mg/dl에서표준지속성기도양압기와신형지속성기도양압기사용후각각 ±30.7 mg/dl와 119.5±36 mg/dl로감소하였고, 두기기간감소량의차이값추정치는 -1.6 mg/dl, 95% 신뢰구간은 -11.5~10.6 mg/dl로나타났다. 중성지방수치는기저치 202.2±119 mg/dl에서표준지속성기도양압기와신형지속성기도양압기사용후각각 ±123.4 mg/dl와 ±118.3 bmg/dl 로오히려증가하였고, 두기기간증가량의차이값추정치는 16.2 mg/dl, 95% 신뢰구간은 -20.4~ 58.5 mg/dl로나타났다. 폐기능검사에서는노력성폐활량예측치가기저치 ±7.9% 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 88.85±6.9% 와 87.75±8.5% 로감소하였고, 두기기간감소량의차이값추정치는 1.1%, 95% 신뢰구간은 -0.6~2.8% 로나타났다. 1초간노력호기량예측치도기저치 91.45±12.2% 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 89.75±10% 와 88.1± 12.1% 로감소하였고, 두기기간감소량의차이값추정치는 1.6%, 95% 신뢰구간은 -0.8~3.7% 로나타났다. 심장표지자검사에서는 NT-proBNP 수치가기저치 20.84±19.28 ng/ml에서표준지속성기도양압기사용후에는 19.23±14.36 ng/ml로감소하였으나신형지속성기도양압기사용후에는 21.43±45.06 ng/ml로증가하였고, 두기기간변화량의차이값추정치는 -2.5 ng/ml, 95% 신뢰구간은 -22.3~10.1 ng/ml로나타났다. 폐쇄성수면무호흡증개선에따른이차적인전신반응의변화를보기위해시행한혈중지질검사및심폐기능검사에서, 중성지방수치에서만두기기간차이값추정치의 95% 신뢰구간이동등성한계값으로정의한 2 표준편차의상한값을벗어났고, 그외에검사결과들은모두추정치의 95% 신뢰구간이동등성한계값을벗어나지않았으므로, 신형지속성기도양압기사용후중성지방수치를제외한다른모든검사수치의변화는표준지속성기도양압기와비교하였을때통계적으로동등하였다 (Table 5). 각각의지속성기도양압기사용후신체변화정도를비교하기위해혈압측정및신체계측을시행한결과, 수축기혈압은기저치 124.5±11.1 mm Hg에서표준지속성기도양압기와신형지속성기도양압기사용후각각 123.8±9.3 mm Hg와 121.6±10.8 mm Hg로감소하였고, 두기기간감소량의차이값추정치는 2.2 mm Hg, 95% 신뢰구간은 -0.8~5.2 mm Hg로나타났다. 이완기혈압은기저치 83.2±11.4 mm Hg 에서표준지속성기도양압기와신형지속성기도양압기사용후각각 79.3±9.0 mm Hg와 76.3±7.2 mm Hg로감소하였고, 두기기간감소량의차이값추정치는 3.0 mm Hg, 95% 신뢰구간은 -0.2~6.2 mm Hg로나타났다. 신체계측수치중, 체중은기저치 76.5±12.3 kg에서표준지속성기도양압기와신형지속성기도양압기사용후각각 76.5±12.0 kg과 76.1±12.2 kg으로감소하였고, 두기기간감소량의차이값추정치는 0.4 kg, 95% 신뢰구간은 -0.5~1.3 kg로나타났다. 허리둘레는기저치 94.4±7.7 cm에서표준지속성기도양압기사용후에는 94.6±7.5 cm로증가하였으나신형지속성기도양압기사용후에는 94.3±7.4 cm로감소하였고, 두기기간변화량의차이값추정치는 0.3 cm, 95% 신뢰구간은 -0.7~1.6 cm로나타났다. 앙와위목둘레는기저치 41.51±3.11 cm에서표준지속성기도양압기와신형지속성기도양압기사용후각각 41.23±3.19 cm와 41.35±3.19 cm로감소하였고, 두기기간감소량의차이값추정치는 cm, 95% 신뢰구간은 -0.42~0.19 cm로나타났다. 좌위목둘레는기저치 39.99±2.8 4 cm에서표준지속성기도양압기와신형지속성기도양압기사용후각각 39.92±3.00 cm와 39.75±2.78 cm로감소하였고, 두기기간감소량의차이값추정치는 0.17 cm, 95% 신뢰구간은 -0.16~

6 정종인등 : 신형한국형지속성기도양압기의효과 11 Table 4. Analysis of questionnaires associated with sleep after 4 weeks CPAP treatment using bootstrap method Quality of life PSQI Variable Result Mean (95% CI)* Equivalence margin Baseline 7.5±2.4 After 4 weeks standard CPAP 6.1±3.5 After 4 weeks newly developed CPAP 5.1±3.0 Change after standard CPAP -1.4±2.3 Change after newly developed CPAP -2.4±2.2 Difference of change (standard-newly) 1.0± (-0.1~2.1) (-3~3) CSAQLI Baseline 4.51±0.74 After 4 weeks standard CPAP 5.29±0.92 After 4 weeks newly developed CPAP 5.24±0.79 Changes (after 4 weeks-baseline) Change after Standard CPAP 0.78±0.76 Change after newly developed CPAP 0.74±0.63 Difference of change (standard-newly) 0.05± (-0.35~0.44) (-1~1) SF-36 Baseline 48.5±15.5 After 4 weeks standard CPAP 54.8±17.2 After 4 weeks newly developed CPAP 53.8±16.5 Change after standard CPAP 6.3±10.0 Change after newly developed CPAP 5.3±11.1 Difference of change (standard-newly) 1.0± (-5.4~7.4) (-15~15) Daytime sleepiness ESS Baseline 10.5±4.2 After 4 weeks standard CPAP 8.1±2.8 After 4 weeks newly developed CPAP 8.1±3.9 Change after standard CPAP -2.4±4.8 Change after newly developed CPAP -2.4±4.4 Difference of change (standard-newly) -0.1± (-2.05~1.50) (-3~3) SSS 2.7±0.8 Baseline 2.4±1.0 After 4 weeks standard CPAP 2.1±0.7 After 4 weeks newly developed CPAP -0.4±1.3 Change after standard CPAP -0.6±1.1 Change after newly developed CPAP 0.3±1.3 Difference of change (standard-newly) 0.2 (-0.3~0.8) (-1~1) Snoring index BSQ Baseline 6.4±2.1 After 4 weeks standard CPAP 2.1±2.3 After 4 weeks newly developed CPAP 3.9±3.0 Change after standard CPAP -4.3±3.0 Change after newly developed CPAP -2.5±2.9 Difference of change (standard-newly) -1.8± (-3.5 ~-0.1) (-2~2) * : The 95% confidence interval was estimated from 1000 bootstrapped samples by bootstrap method, : Out of lowest equivalence margin. PSQI: Pittsburg sleep quality index, CSAQLI: Calgary sleep apnea quality of life index, SF-36: Short form-36, ESS: Epworth sleepiness scale, SSS: Stanford sleepiness scale, BSQ: Berlin Snoring Questionnaire

7 12 J Rhinol 2016;23(1):6-16 Table 5. Analysis of laboratory results associated with obstructive sleep apnea syndrome after 4 weeks CPAP treatment using bootstrap method Lipid profile, mg/dl T-chol Variable Result Mean (95% CI)* Equivalence margin Baseline 193.7±37.8 After 4 weeks standard CPAP 190.3±29.6 After 4 weeks newly developed CPAP ±37.3 Change after standard CPAP -3.4±20.9 Change after newly developed CPAP -1.1±20.5 Difference of change (standard-newly) -2.3± (-11.6~7.0) (-38~38) LDL-C TG Baseline 124.3±35.5 After 4 weeks standard CPAP ±30.7 After 4 weeks newly developed CPAP 119.5±36 Change after standard CPAP -6.35±18.2 Change after newly developed CPAP -4.8±20.5 Difference of change (standard-newly) -1.55± (-11.5~10.6) (-52~52) Baseline 202.2±119 After 4 weeks standard CPAP ±123.4 After 4 weeks newly developed CPAP ±118.3 Change after standard CPAP 18.25±62.5 Change after newly developed CPAP 1.85±105.9 Difference of change (standard-newly) 16.4± (-20.4~58.5 ) (-52~52) Pulmonary function test, % of estimated volume FVC Baseline 90.05±7.9 After 4 weeks standard CPAP 88.85±6.9 After 4 weeks newly developed CPAP 87.75±8.5 Change after standard CPAP -1.2±4.3 Change after newly developed CPAP -2.3±6 Difference of change (standard-newly) 1.1± (-0.6~2.8) (-8~8) FEV1 Baseline 91.45±12.2 After 4 weeks standard CPAP 89.75±10 After 4 weeks newly developed CPAP 88.1±12.1 Change after standard CPAP -1.7±6.3 Change after newly developed CPAP -3.35±9.9 Difference of change (standard-newly) 1.65± (-0.8~3.7) (-10~10) Cardiac marker, ng/ml NT-proBNP Baseline 20.84±19.28 After 4 weeks standard CPAP 19.23±14.36 After 4 weeks newly developed CPAP 21.43±45.06 Change after standard CPAP -1.61±14.91 Change after newly developed CPAP 0.59±40.22 Difference of change (standard-newly) -2.21± (-22.3~10.1) (-78~78) * : The 95% confidence interval was estimated from 1000 bootstrapped samples by bootstrap method, : Out of highest equivalence margin. T-chol: Total cholesterol, LDL-C: Low density lipoprotein cholesterol, TG: Triglyceride, FVC: Forced vital capacity, FEV1: Forced expiratory volume in 1 second, NT-proBNP: N-terminal prohormone of brain natriuretic peptide

8 정종인등 : 신형한국형지속성기도양압기의효과 13 Table 6. Analysis of physical examinations associated with obstructive sleep apnea syndrome after 4 weeks CPAP treatment using bootstrap method Blood pressure, mm Hg Systolic Variable Result Mean (95% CI)* Equivalence margin Baseline 124.5±11.1 After 4 weeks standard CPAP 123.8±9.3 After 4 weeks newly developed CPAP 121.6±10.8 Change after standard CPAP -0.8±8.0 Change after newly developed CPAP -3.0±10.1 Difference of change (standard-newly) 2.2± (-0.8~5.2) (-10.0~10.0) Diastolic Baseline 83.2±11.4 After 4 weeks standard CPAP 79.3±9.0 After 4 weeks newly developed CPAP 76.3±7.2 Change after standard CPAP -3.9±8.5 Change after newly developed CPAP -6.9±9.4 Difference of change (standard-newly) 3.0± (-0.2~6.2 ) (-5.0~5.0) Body measurement Weight, Kg Baseline 76.5±12.3 After 4 weeks standard CPAP 76.5±12.0 After 4 weeks newly developed CPAP 76.1±12.2 Change after standard CPAP 0.005±1.1 Change after newly developed CPAP -0.4±2.1 Difference of change (standard-newly) 0.4± (-0.5~1.3) (-4.0~4.0) Waist, cm Baseline 94.4±7.7 After 4 weeks standard CPAP 94.6±7.5 After 4 weeks newly developed CPAP 94.3±7.4 Change after standard CPAP 0.2±2.6 Change after newly developed CPAP -0.04±1.2 Difference of change (standard-newly) 0.2± (-0.7~1.6) (-6.0~6.0) Neck-supine, cm Baseline 41.51±3.11 After 4 weeks standard CPAP 41.23±3.19 After 4 weeks newly developed CPAP 41.35±3.04 Change after standard CPAP -0.28±0.75 Change after newly developed CPAP -0.16±0.89 Difference of change (standard-newly) -0.13± (-0.42~0.19) (-1.38~1.38) Neck-sitting, cm Baseline 39.99±2.84 After 4 weeks standard CPAP 39.92±3.00 After 4 weeks newly developed CPAP 39.75±2.78 Change after standard CPAP -0.07±0.69 Change after newly developed CPAP -0.24±0.45 Difference of change (standard-newly) 0.17± (-0.16~0.48) (-1.48~1.48) * : The 95% confidence interval was estimated from 1,000 bootstrapped samples by bootstrap method, : Out of highest equivalence margin

9 14 J Rhinol 2016;23(1):6-16 Table 7. Adverse events during study Adverse events ResMed CPAP MEKics CPAP Total Severity Mild Moderate Severe Related with CPAP No Yes Serious adverse event No Yes cm로나타났다. 지속성기도양압기사용후신체변화정도를비교하기위해시행한혈압측정및신체계측에서, 이완기혈압에서만두기기간차이값추정치의 95% 신뢰구간이동등성한계값으로정의한 -5~5 mm Hg의상한값을벗어났고, 그외에검사결과들은모두추정치의 95% 신뢰구간이동등성한계값을벗어나지않았으므로, 신형지속성기도양압기사용후이완기혈압을제외한다른모든신체계측수치와수축기혈압의변화는표준지속성기도양압기와비교하였을때통계적으로동등하였다 (Table 6). 본임상시험기간동안보고된모든이상반응은총 8건으로발현대상자수는 6명이었고, 8건의이상반응중 6건은경증, 2건은중등도로나타났고, 중대한이상반응은없었다. 지속성기도양압기사용과의관련성이없는것으로판단되었던이상반응은 4건으로그중 3건은경증의비인두염을호소하였고, 1건은경증의소화불량을호소하였다. 지속성기도양압기사용과의관련성이의심되었던이상반응은 4 건이었고, 표준지속성기도양압기에서 2건, 신형지속성기도양압기에서 2건이었으며, 그중중등도이상반응이각각 1건씩총 2건이었다 (Table 7). 표준지속성기도양압기사용과관련하여중등도의수포가 1건, 경증의피부미란이 1건발생하여치료후모두회복되었다. 신형지속성기도양압기사용과관련하여중등도의복부팽만이 1건, 경증의두통이 1건발생하였으나모두특별한치료없이저절로회복되었다. 고찰 지속성기도양압술은중등도및중증수면무호흡증의기본치료이며가장효과적인치료이다. 하지만환자가치료에적응하고안정화되기까지는시간이필요하며, 최근의보고 에서는착용후시간이지남에따라 1/3~1/2 정도의환자에서 3주 ~3개월후압력조절이필요하다는점이지적되었다. 4)7) 또한지속성기도양압술을통해무호흡저호흡지수가개선되는치료효과를얻기위해서는 1개월이상의치료기간과하루평균사용시간 4시간이상의순응도가필요한것으로알려져있다. 8)9) 특히 Faccenda 등은 78명의중증도내지중증폐쇄성수면무호흡증환자를대상으로시행한지속성기도양압술의무작위, 위약군대조임상시험에서 1개월사용후무호흡저호흡지수가유의하게감소하였다고보고하였다. 10) 이러한기존연구결과를바탕으로, 본임상시험에서는폐쇄성수면무호흡증환자에서새로개발된국산지속성기도양압기를 4주간적용하였을때, 기존의표준지속성기도양압기와비교하여수면무호흡증개선및숙면을통한삶의질향상의효과가동등한지를평가하였다. 우선, 폐쇄성수면무호흡증의직접적인개선에대한유효성통계분석결과, 신형지속성기도양압기사용 4주후무호흡저호흡지수의추정된평균은 2.5/hr(97.5% 신뢰구간, 1.7~3.5/hr) 로나타났으며, 이는처음진단당시중등도내지중증수면무호흡증에서치료후에는단순코골이수준으로호전된것이기때문에, 임상적으로직접적인개선이있음을의미한다. 또한대조기기인표준지속성기도양압기와치료효과를비교하였을때, 무호흡저호흡지수감소량차이의 97.5% 신뢰구간이동등성한계값내에있으므로두기기의치료효과는통계적으로동등함이증명되었다. 지속성기도양압술은무호흡저호흡지수의직접적인개선효과외에도, 주간졸림증이나기억력, 집중력저하로인한업무수행능력저하등폐쇄성수면무호흡증에서나타나는삶의질저하에도효과가있는것으로알려져있다. 11)12) 본연구에서수면과관련된여러설문항목을통해폐쇄성수면무호흡증개선으로인한삶의질향상에대하여신형지속성기도양압기와표준지속성기도양압기를비교평가한결과, 두기기모두사용후삶의질향상이개선되는효과가나타났으며, 베를린설문지항목을제외한모든항목에서추정치가통계적동등성한계내에있었다. 따라서폐쇄성수면무호흡증개선에의한삶의질향상에있어서도두기기간에임상적으로유의한차이는없는것으로판단되었다. 또한, 폐쇄성수면무호흡증에따른이차적전신반응으로지질대사이상이나 6)13) 심혈관계질환혹은고혈압이유발될수있고 14)15) 호흡기질환에도악영향이나타날수있는데, 16)17) 여러연구에서지속성양압술은이러한이차적전신반응을개선시키는것으로나타났다. 본연구에서는이차적

10 정종인등 : 신형한국형지속성기도양압기의효과 15 전신반응의변화를반영하는혈중지질검사, 심폐기능검사를비롯하여혈압, 신체계측수치들을측정하여비교평가하였는데, 중성지방과이완기혈압수치를제외한모든검사에서두기기간에통계적, 임상적으로유의한차이를보이는항목은없었다. 각각의지속성기도양압기사용후나타난중성지방과이완기혈압수치의변화는통계적으로서로동등하지는않았으나, 중성지방의경우표지속성기도양압기사용후중성지방수치보다신형지속성기도양압기사용후중성지방수치가더낮았고, 이완기혈압도표준지속성기도양압기사용후에비하여신형지속성기도양압기사용후이완기혈압이더낮았으므로, 신형지속성기도양압기의유효성은그대로유지될수있다. 안전성측면을고려해보면, 본임상시험에서발생한 8건의이상반응중 6건이경증이었으며, 2건은중등도로나타났고, 그중 4건에서지속성기도양압기와의관련성이의심되었으며, 표준지속성기도양압기사용중 2명에서각 1건씩, 신형지속성기도양압기사용중 1명에서총 2건이발생하였으나, 대조기기와시험기기간이상반응발현건수는같았고중대한이상반응도관찰되지않았다. 또한이학적검사결과, 임상시험종료후모두에서신체검진결과가정상이었고, 실험실적검사항목, 기타안전성관련하여시행된검사항목들과연관된이상반응의보고는없었으며, 임상적으로유의미한결과도보고되지않았다. 따라서, 시험기기인신형지속성기도양압기는대조기기인표준지속성기도양압기와비교하여안전성측면에서동등하고평가할수있다. 그러나본연구는적은대상환자내에서각각 4주간의단기간지속성기도양압기치료의효과와안전성을평가한것으로, 장기치료시의효과와안전성을예측하기어려운제한점이있다. 또한, 통계적으로유의한차이는없었으나동일한대상환자에서신형지속성기도양압기의치료순응도가표준지속성기도양압기의치료순응도보다낮은경향을보였는데, 임상시험자체에서두기기에대한눈가림이이루어지지못했고, 신형지속성기도양압기로바뀌면서기계소음이나습도유지등에있어미리사용하던기기와차이를보이면서좀더낮은순응도를보였을가능성을배제할수없다. 치료순응도는지속성기도양압술의성공적인치료에있어중요한인자이므로, 치료순응도에대한추가적인평가가필요할것으로생각된다. 마지막으로본연구는순차적비교시험으로연구설계가되었기때문에, 비록중간에치료기간휴식기를두었다고하더라도, 무작위비교시험과비교했을때표준지속성기도양압기치료의효과가이후에시행된신형지속성기도양압기치료효과에영향을미쳤을가 능성을완전히배제하기어려운한계가있다. 따라서좀더 장기적인치료효과및안전성, 치료의순응도등을평가하 기위해서는, 추가적인대규모장기간무작위비교연구가 필요할것으로생각된다. 결 론 폐쇄성수면무호흡증환자에서신형국산지속성기도양 압기는표준지속성기도양압기와비교하여동등한유효성 과안전성을보인다. 중심단어 : 폐쇄성수면무호흡증 무호흡저호흡지수 유효성 안전성 신형국산지속성기도양압기. REFERENCES 1) Chung YS. Pathogenesis of Obstructive Sleep Apnea. J Rhinol 2009;16: ) Mo JH. Obstructive Sleep Apnea and Systemic Diseases. J Rhinol 2013;20: ) Kim J, In K, Kim J, You S, Kang K, Shim J, et al. Prevalence of sleep-disordered breathing in middle-aged Korean men and women. Am J Respir Crit Care Med 2004;170: ) Gordon P, Sanders MH. Sleep.7: positive airway pressure therapy for obstructive sleep apnoea/hypopnoea syndrome. Thorax 2005; 60: ) Varounis C, Katsi V, Kallikazaros IE, Tousoulis D, Stefanadis C, Parissis J, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: a systematic review and meta-analysis. Int J Cardiol 2014;175: ) Lin MT, Lin HH, Lee PL, Weng PH, Lee CC, Lai TC, et al. Beneficial effect of continuous positive airway pressure on lipid profiles in obstructive sleep apnea: a meta-analysis. Sleep Breath. In press. 7) Kakkar RK, Berry RB. Positive airway pressure treatment for obstructive sleep apnea. Chest 2007;132: ) Jokic R, Klimaszewski A, Sridhar G, Fitzpatrick MF. Continuous positive airway pressure requirement during the first month of treatment in patients with severe obstructive sleep apnea. Chest 1998;114: ) Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized Placebo-controlled Trial of Continuous Positive Airway Pressure on Blood Pressure in the Sleep Apnea-Hypopnea Syndrome. Am J Respir Crit Care Med 2001;163: ) Weaver TE, Maislin G, Dinges DF, Bloxham T, George CF, Greenberg H, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007; 30: ) Cheshire K, Engleman H, Deary I, Shapiro C, Douglas NJ. Factors impairing daytime performance in patients with sleep apnea/hypopnea syndrome. Arch Intern Med 1992;152: ) Hack M, Davies RJ, Mullins R, Choi SJ, Ramdassingh-Dow S, Jenkinson C, et al. Randomised prospective parallel trial of therapeutic versus subtherapeutic nasal continuous positive airway pressure on simulated steering performance in patients with obstructive sleep apnoea. Thorax 2000;55: ) Phillips CL, Yee BJ, Marshall NS, Liu PY, Sullivan DR, Grunstein

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