Original Article 대한주산회지제 26 권제 4 호, 2015 Korean J Perinatol Vol.26, No.4, Dec., 2015 http://dx.doi.org/10.14734/kjp.2015.26.4.321 극소저체중출생아에서출생후덱사메타손투여시기에따른기관지폐이형성증의양상 서울대학교의과대학소아과학교실이해연 ^ 이형진 ^ 고지원 ^ 송인규 ^ 김세연 ^ 정영화신승한 ^ 최창원 ^ 김이경 ^ 김한석 ^ 김병일 ^ 최중환 Characteristics of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants according to the Timing of Dexamethasone Administration Hae Yun Lee, M.D. 1, Hyoung Jin Lee, M.D. 1, Ji Won Koh, M.D. 1, In Gu Song, M.D. 1, Sae Yun Kim, M.D. 1, Young Hwa Jung, M.D. 1, Seung Han Shin, M.D. 1,3, Chang Won Choi, MD., Ph.D. 2,3, Ee-Kyung Kim, M.D., Ph.D. 1,3, Han-Suk Kim, M.D., Ph.D. 1,3, Beyong Il Kim, M.D., Ph.D. 2,3, and Jung-Hwan Choi, M.D., Ph.D. 1,3 Department of Pediatrics, 1 Seoul National University Children s Hospital, Seoul, Department of Pediatrics 2, Seoul National University Bundang Hospital, Seongnam, Department of Pediatrics 3, Seoul National University College of Medicine, Seoul, Korea Purpose: Corticosteroids has been used for treatment and prophylaxis of bronchopulmonary dysplasia (BPD) in preterm infants. However, administration of corticosteroids could be delayed due to its potential harmful effects on neurodevelopment. The aim of this study was to evaluate the adequate dexamethasone administration timing in very low birth weight infants. Methods: Medical records of 56 VLBW infants who were admitted to neonatal intensive care unit of Seoul National University Children s Hospital and Seoul National University Bundang Hospital between January 2008 and September 2014 were collected retrospectively. Study population were divided into early administration group (dexamethasone administration before 4 weeks of postnatal days) and late administration group (after 4 weeks) and respiratory morbidities were compared between groups. Results: There were no significant differences in clinical characteristics between early administration group (n=30) and late administration group (n=26). Respiratory severity score and oxygen needs at 7 days after birth and before administering dexamethasone were comparable. Extubation was done earlier postnatal days in early administration group. Incidence of severe BPD was higher in the late administration group. There was no significant difference in diagnosed with cerebral palsy (CP) at 12 months of corrected age. When adjusting for multiple risk factors, administration of dexamethasone 4 weeks after birth and severe of BPD showed a significant association (adjusted OR 17.14 [1.29-227.52], P=0.031). Conclusion: Administration of dexamethasone in order to minimize ventilator care and to reduce severe BPD might be done between 1 week and 4 weeks after birth in very low birth weight infants. Key Words: Very low birth weight, Bronchopulmonary dysplasia, Dexamethasone, Cerebral palsy Received: 23 September 2015, Revised: 17 October 2015, Accepted: 28 October 2015 Correspondence to: Seung Han Shin, M.D. Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul 110-799, Korea Tel: +82-2-2072-7230, Fax: +82-2-2072-0590, E-mail: revival421@snu.ac.kr Copyrightc 2015 by The Korean Society of Perinatology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/license/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original work is properly cited. The Korean Journal of Perinatology pissn 1229-2605 eissn 2289-0432 e-kjp.org - 321 -
Hae Yun Lee, et al. : - Characteristics of BPD in VLBWI according to the Timing of Dexamethasone Administration - 기관지폐이형성증 (bronchopulmonary dysplasia, 를목적으로부신피질스테로이드호르몬을투여하였던환 BPD) 은급성호흡부전과함께산소및인공호흡기치료가아들을대상으로부신피질스테로이드투여시기에따른임필요하였던미숙아에서발견된만성폐질환으로 1967 년상적예후를비교하여적절한부신피질스테로이드투여시 Northway 등이처음기술하였다. 1 이후산전스테로이드기를알아보고자하였다. 의사용과, 폐손상을최소화하기위한인공호흡기의적용기법, 폐표면활성제사용, 동맥관개존증에대한치료등이대상및방법도입되면서미숙아의심한폐손상이감소되고미숙아의생존율향상을가져왔지만, 여전히기관지폐이형성증은높은 1. 대상빈도로보고되고있다. 이는이전과다른병태생리기전인 2008 년 1월부터 2014 년 9월까지서울대학교병원과분폐소포의발달정지의양상을보이는기관지폐이형성증의당서울대학교병원에입원한출생체중 1,500 g 미만의미숙발생이증가하는것으로해석되고있다. 2, 3 아중, 기계환기이탈을촉진시키기위해부신피질스테로외국의경우미숙아들의약 20% 에서기관지폐이형성증이드인덱사메타손을투여했던환아들을대상으로연구를이발생한다고보고하였으며, 4 국내의전국적인발생현황진행하였다. 이중생후 7일이내에사망하거나, 선천성기형조사에따르면, 극소저체중출생아의 18% 정도에서기관지이동반된경우는제외하였다. 폐이형성증이발생하는것으로나타났다. 5 기관지폐이형성증은미숙아들의입원기간을연장시키고, 신생아기및영 2. 방법아기에사망하게되는주된요인으로작용하며, 생존한미대상환아들의의무기록을후향적으로검토하였고대숙아들에게도영구적인폐기능저하를가져올뿐만아니상군을기관지폐이형성증의첫진단이이루어지는생후 4 라, 근골격계, 소화기계및성장발달부전, 신경발달학적문주이내에덱사메타손을투여한경우와이후에투여한경제도유발하는것으로알려져있어이에대한예방및치우로나누어두군간에임상경과와입원기간동안의호흡료는미숙아진료에있어서매우중요하다. 6, 7 이러한이유기관련예후를알아보고자하였다. 대상환아들의출생체로 1990 년대기관지폐이형성증의예방및치료를위해출중, 재태주수, 성별, 다태아여부, 분만방법, 1분과 5분아생후부신피질스테로이드투여가활발히이루어졌으나, 프가점수 (Apgar score) 에대해조사하였고산모에대 2000년대에이르러부신피질스테로이드사용에의한신해서는양수과소증 (oligohydramnios), 조직학적융모양경발달장애특히, 뇌성마비발생에대한위험성이대두되면막염 (chorioamnionitis), 산전스테로이드사용력에대서부신피질스테로이드의부작용을염려하여출생후부한정보를수집하였다. 임상양상으로는호흡곤란증후군신피질스테로이드사용을제한하기시작하였다. 8, 9 미국소 (respiratory distress syndrome, RSD), 수술적치료가아과학회에서는생후 7일이전에투여하는부신피질스테필요한동맥관개존증, 기관지폐이형성증, 뇌실내출혈, 수로이드는뇌성마비등의뇌신경학적발달장애를일으킬술이필요하였던미숙아망막증, 뇌백질연화증, 괴사성장수있어사용을제한하고있으며, 기관지폐이형성증의위험염, 패혈증등의발생여부와재원기간및기계환기기간을이높고장기간의기계환기요법에서이탈이어려울것으로확인하였다. 또한, 입원중사망여부와외래에서경과관찰예상되는환자에게제한적으로사용을권고하고있다. 10 중교정연령 12 개월시점에뇌성마비 (cerebral palsy) 발생생후 7일이후의부신피질스테로이드사용은상대적으여부를조사하였다. 덱사메타손투여와관련해서는투여로신경학적발달에영향을적게미치는것으로알려져있시기및총투여용량에대해조사하였고, 투여직전의기지만, 잠재적인악영향을염려하여생후 7일이후에도부신계환기의종류, 호흡기중증도지수 (respiratory severity 피질스테로이드투여를미루게되는경우가발생하기도한 score; mean airway pressure x FiO 2 ) 와투여직후의호다. 이에본연구에서는기관지폐이형성증의예방및치료흡기중증도지수를확인하였다. - 322 -
이해연등 : - 극소저체중출생아에서출생후텍사메타손투여시기에따른기관지폐이형성증의양상 - 부당경량아는재태주령에대한출생체중이 10백분위수미만인경우로정의하였고, 기관지폐이형성증은미국 National Institute of Health 에서제시한진단기준에따라서진단과중증도를정의하였으며, 11 괴사성장염은 modified Bell s staging criteria 상 IIA 이상인경우로정의하였다. 12 호흡곤란증후군은호흡곤란증상과함께양폐에미만성의망상과립상음영이있으며, 적정한산소분압을유지하기위해인공호흡기의흡입산소농도가 40% 를초과하는경우이거나, 분만장에서호흡곤란의증상이있어폐계면활성제를조기투약한경우로정의하였다. 패혈증은미국질병관리본부 (Centers for Disease Control and Prevention) 에서제시한기준을적용하여혈액배양검사에서균이동정된경우로정의하였다. 13 뇌성마비에대해서는교정연령 12개월에소아재활의학과전문의가환아를진료한후진단한경우로정의하였다. 덱사메타손의투여시점은담당의료진의판단에의해결정되었으며 0.95 mg/kg의용량을 9일에걸쳐서서히감량하여투여하는용법을사용하였다. 14 또한, 덱사메타손은정맥으로투여되었으며투여기간중흡입용스테로이드를병용하지않았다. 본연구는서울대학교병원과분당서울대학교병원의연구윤리위원회 (institutional review board, IRB) 의승인을받았으며, 의무기록을통한후향적연구로동의서는면제되었다. 3. 통계분석통계분석은 STATA 11.0 (StataCorp, College Station, Texas, USA) 를이용하여분석하였다. 조사된자료와검사의모든값은평균 ± 표준편차또는중간값 ( 범위 ) 으로표기하였고연속범주의그룹간의비교는 independent two samples t-test 와 Mann-Whitney rank sum test 를이용하여분석하였다. 중증의기관지폐이형성증의위험인자를분석하기위해다변량로지스틱회귀분석과단변량로지스틱회귀분석을시행하였고, P값이 0.05 미만인경우통계학적으로유의성이있다고판단하였다. 1. 임상적인특징 결 연구기간동안극소저체중출생아 870 명중 56 명 (6.4%) 이기계환기이탈을위해덱사메타손을투여받았다. 덱사 메타손을투여받았던시점이기관지폐이형성증이진단되 기이전인생후 4 주였던군을조기투여군 (n=30) 으로, 그 이후에투여한군을후기투여군 (n=26) 으로나누었을때, 두군간에재태주수 (26 +6 주 vs. 26 +3 주 ) 및출생체중 (783 g vs. 750 g) 은차이를보이지않았다. 1 분과 5 분아프가점 수, 분만방법, 다태아여부, 양수과소증, 산전스테로이드사 과 용등에서도차이를보이지않았다 (Table 1). Table 1. Demographics of Study Population Median (range) or number (%) Gestational age (wks) DXM administration P- value <4 wks (n=30) 4 wks (n=26) 26 +6 (23 +2-29 +2 ) 26 +3 (23 +4-32) 0.576 Birth weight (g) 783 (530-1,260) 750 (370-1,630) 0.831 AS 1 min 3 (1-8) 2 (0-8) 0.561 5 min 5 (2-9) 5 (1-9) 0.785 Female 15 (50.0) 9 (34.6) 0.288 C/S 18 (60.0) 16 (61.5) 1.000 Multiple birth 20 (66.7) 14 (53.8) 0.414 SGA 8 (26.7) 11 (42.3) 0.265 Oligohydramnios 4 (13.3) 8 (30.8) 0.175 Chorioamnionitis 16 (53.3) 9 (34.6) 0.407 Prenatal Steroid 17 (56.7) 12 (46.2) 0.593 RDS 27 (90.0) 23 (88.5) 1.000 NEC 2 (6.7) 5 (19.2) 0.231 IVH 3 2 (6.7) 2 (7.7) 1.000 PVL 3 (10.0) 4 (15.4) 0.693 Culture proven sepsis 6 (20.0) 11 (42.3) 0.087 PDA operation 13 (43.3) 14 (53.8) 0.592 ROP operation 21 (70.0) 14 (53.8) 0.273 Abbreviations: DXM, dexamethasone; AS, apgar score; C/S, cesarean section; SGA, small for gestational age; RDS, respiratory distress syndrome; NEC, necrotizing enterocolitis; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity - 323 -
Hae Yun Lee, et al. : - Characteristics of BPD in VLBWI according to the Timing of Dexamethasone Administration - 2. 임상증상조기투여군의덱사메타손투여시점은생후 3주 ( 월경후연령 29 +5 주 ) 를전후로이루어졌고, 후기투여군은생후 52 일 ( 월경후연령 34 +2 주 ) 을전후로이루어졌다 (Table 2). 덱사메타손투여직전의호흡중증도지수와산소요구량은조기투여군에서다소높은경향을보였으나통계적인유 의성은보이지않았으며, 투여전고빈도환기요법이필요했던환자들의비율도차이를보이지않았다. 덱사메타손투여후의산소요구량, 혹은투여전후의산소요구량의변화량은두군간에차이를보이지않았다. 덱사메타손투여가두회차이상반복적으로이루어졌던환아의비율은두군에서차이를보이지않았으며 (48.0% vs. 48.4%), 총누적량에서도두군간에차이를보이지않았다 (1.2 mg/kg vs. 1.1 Table 2. Clinical Settings of Study Population according to Timing of Dexamethasone Treatment Median (range) or number (%) At postnatal 7 days DXM administration <4 wks (n=30) 4 wks (n=26) P-value FiO 2 0.23 (0.21-1.00) 0.23 (0.21-0.90) 0.792 HFOV, n (%) 8 (26.7) 6 (23.1) 1.000 Before DXM started RSS 6.7 (3.5-14) 4.55 (2.5-6.6) 0.080 FiO 2 0.4 (0.21-1.0) 0.25 (0.4-1.0) 0.888 HFOV, n (%) 9 (30.0) 5 (19.2) 0.537 DXM started Postnatal day DXM started 21 (9-27) 52 (28-158) <0.001 Post conceptional age DXM started 29 +5 (26 +2-32 +1 ) 34 +2 (28 +4-49 +2 ) <0.001 First cycle DXM dose (mg/kg) 0.84 (0.35-1.25) 1.1 (0.2-3.24) 0.019 Cumulative DXM dose (mg/kg) 1.2 (0.43-25.31) 1.1 (0.45-7.41) 0.600 Multiple cycle DXM*, n (%) 12 (40.0) 15 (57.7) 1.000 DXM total cycle, median (range) 2 (1-10) 1 (1-7) 0.104 After DXM started Post FiO 2 0.3 (0.21-0.85) 0.28 (0.21-0.8) 0.133 Pre-post FiO 2 0.05 (0.45~-0.37) 0.1 (0.77~-0.5) 0.362 *Multiple cycles DXM was defined as two or more times administration. The difference before and after dexamethasone administion oxygen demand Abbreviations: DXM, dexamethasone; RSS, respiratory severity score; FiO 2, fraction of inspiration oxygen; HFOV, high frequency oscillation ventilation. Table 3. Respiratory Morbidity and Mortality during Hospital Stay and Cerebral Palsy at 12 Months of Corrected Age Median (range) or number (%) DXM administration <4 wks (n=30) 4 wks (n=26) P-value From DXM started until extubation (days) 8 (1-721) 9 (1-41) 0.786 From Birth until extubation (days) 32 (16-732) 63.5 (27-170) 0.001 Length of stay (days) 101 (30-562) 115 (81-435) 0.158 Death before discharge 3 (10.0) 1 (3.8) 0.615 Severe BPD 13 (43.3) 22 (84.6) 0.040 Death or severe BPD 14 (46.7) 22 (84.6) 0.005 CP 2 (6.7) 3 (11.5) 0.652 Death or CP 5 (16.7) 4 (15.4) 1.000 Tracheostomy 3 (10.0) 5 (19.2) 0.455 Abbreviations: DXM, dexamethasone; BPD, bronchopulmonary dysplasia; CP, cerebral palsy. - 324 -
이해연등 : - 극소저체중출생아에서출생후텍사메타손투여시기에따른기관지폐이형성증의양상 - mg/kg). 하지만, 첫번째투여의투여량은조기투여군에서오히려낮은것으로나타났다 (0.84 mg/kg vs. 1.1 mg/ kg, P=0.019). 덱사메타손투여후기관지튜브의발관이이루어지기까지의기간은차이를보이지않았으나 (8 일 vs. 9일 ), 출생후기관지튜브의발관이이루어지기까지의기간은두군간에차이를보였다 (32.0 일 vs. 63.5 일, P=0.001)(Table 3). 중증의기관지폐이형성증은후기투여군에서많은것으로나타났으며 (44.8% vs. 84.6%, P=0.04), 사망혹은중증의기관지폐이형성증을조합하였을때에도후기투여군에서많이발생하는것으로나타났다 (46.7% vs. 84.6%, P=0.005). 두군간에재원기간은차이를보이지않았으며, 교정연령 12 개월에뇌성마비가진단된경우도두군간에차이를보이지않았다. 다변량분석을통해출생주수, 부당경량아여부, 양수과소증여부, 조직학적융모양막염과산전스테로이드사용여부및동맥관개존증수술, 부신피질스테로이드투여전고빈도환기사용여부등을보정하였을때, 중증의기관지폐이형성증과관련된인자는출생 4주이후에덱사메타손을투여하는것이유일하였다 (adjusted OR 17.14 [1.29-227.52], P=0.031). 고찰본연구에서기관지폐이형성증과관련하여출생 4주이내에덱사메타손을사용하였을때중증의기관지폐이형성증의발생빈도와침습적인기계환기의적용기간이감소하는것을보여주었다. 기관지폐이형성증을가진환자들은잦 은호흡기감염으로인한재입원이흔하고, 영유아기및소아기를거치는동안지속적인폐기능저하를보이며기관지천식같은반응성기도질환의이환율이높다. 7, 15-20 또한이러한폐기능저하와반응성기도질환은성인기까지지속되어일반적으로는만성폐쇄성호흡기질환발병과연관성이있다고알려져있다. 21 이러한장기간의호흡기계문제는성장부진, 신경발달학적장애를초래하며, 사망률역시증가시킨다. 따라서미숙아의기관지폐이형성증을예방하고적극적인치료를하는것은장기적예후에매우중요하다. 6, 7 부신피질스테로이드는기관지폐이형성증환자에게단기간사용시항염증작용을통해서가스교환과폐기능을개선시키고특히인공호흡기를적용하고있는환아에서폐기능호전에빠른효과를보이는것으로알려져있다. 22, 23 또한조기에발관을가능하게하고기관지폐이형성증의발생률과퇴원후산소투여율을의미있게감소시키는효과를보인다는보고도있다. 이에 1990 년대에기관지폐이형성증을예방하고치료하기위해서부신피질스테로이드투여가활발하게이루어졌다. 하지만, 부신피질스테로이드의사용은단기적으로고혈당, 당뇨, 고혈압과심근비대등의부작용을보일수있을뿐만아니라장기적으로는심한미숙아망막증이나뇌성마비를포함한신경발달학적문제를일으킬수있다는보고들이나오기시작하였다. 24 이를바탕으로 2010 년미국소아과학회에서는아직까지기관지폐이형성증을치료하거나예방하기위한부신피질스테로이드의사용은안전성에대한데이터가불충분하며, 장기적인신경학적예후를고려하여제한적으로사용할것을권고하였다. 10 특히생후 7일이후에인공호흡기를적용하고있는환 Table 4. Association of Severe BPD with Clinical Findings Variables Univariable OR (95%CI) P-value Mutivariable OR (95%CI) P-value GA 26 wks 0.57 (0.18-1.84) 0.347 0.94 (0.12-7.43) 0.954 SGA 4.25 (1.05-17.20) 0.043 9.47 (0.33-273.49) 0.19 Oligohydramnios 7.77 (0.88-68.44) 0.065 4.24 (0.16-111.38) 0.386 hcam 1.92 (0.63-5.88) 0.285 1.73 (0.18-16.73) 0.637 Prenatal DXM 2.06 (0.66-6.41) 0.211 3.68 (0.40-34.22) 0.253 PDA operation 3.11 (0.97-10.00) 0.057 5.12 (0.57-45.67) 0.144 Before DXM start HFOV apply 4.13 (0.82-20.97) 0.088 8.55 (0.57-129.32) 0.121 DXM 4 wks 6.77 (1.86-24.65) 0.004 17.14 (1.29-227.52) 0.031 Abbreviations: BPD, bronchopulmonary dysplasia; GA, gestational age; SGA, small for gestational age; hcam, histological chorioamnionitis; DXM, dexamethasone; PDA, patent ductus arteriosus; HFOV, high frequency oscillation ventilation. - 325 -
Hae Yun Lee, et al. : - Characteristics of BPD in VLBWI according to the Timing of Dexamethasone Administration - 자에서중증의기관지폐이형성증이발병하였거나발병할위험성이있는경우에만제한하여부신피질스테로이드투여를하도록권고하고있다. 2014 년 Cochrane review 에서는미숙아의만성폐질환을위한출생후부신피질스테로이드사용에대한연구들을바탕으로메타분석을발표하였다. 24, 25 부신피질스테로이드투여시기를생후 7일이내와이후로나누어그예후를비교하였으며, 7일이내투여하는부신피질스테로이드는뇌성마비등의신경학적발달에나쁜예후를보였으나, 7일이후에투여하는부신피질스테로이드가뇌성마비나, 중증의신경계이상의증가없이사망률을낮췄다는보고를하였다. 생후 7일이후에부신피질스테로이드를사용하는것이비교적안전한것으로알려져있지만잠재적인신경학적발달장애에대한우려로인공호흡기이탈과기관지폐이형성증의예방과치료를위해부신피질스테로이드를사용하는것에소극적일수도있게되는데, 이로인해적절한치료시기를놓치는경우가있다. 본연구에서는기관지폐이형성증의첫진단이이루어지는생후 4주를기준으로 4주이내덱사메타손치료를시작했던환아군과 4주이후에덱사메타손치료를시작하였던환아군을비교하여호흡기계예후에차이가있는지알아보고자하였다. 두군에서재태주수및출생체중의차이가없었고생후 7일째의산소요구량및고빈도환기요법이필요했던환아비율에도차이가없었다. 통계적으로유의하지않았지만, 호흡기중증도지수가조기투여군에서오히려높았던것으로보아호흡기예후가좋지않았던후기투여군이조기투여군에비해특별히중증기관지폐이형성증에대한고위험군은아니였던것으로생각된다. 교정연령 12개월에뇌성마비가진단된경우는두군에서차이가없었고여러관련된인자들을보정하였을때중증의기관지폐이형성증은출생 4주이후에덱사메타손을투여하는것에서만의미있는연관성을보였다. 결국미숙아의기관지폐이형성증예방및치료적목적으로사용하는덱사메타손은생후 4주이후에투여할경우가생후 4주이내투여하였던군에비해사망률과중증도가높아, 덱사메타손사용은생후 4주이내투여를고려할필요가있겠다. 이와더불어기존연구들에서보고하고있는생후 7일이내부신피질스테로이드의투여가뇌성마비 발생과신경학적발달예후에악영향을미친다는것을고려한다면, 고위험환아군에서생후 1주에서 4주사이에부신피질스테로이드를투여하는것을고려해볼수있을것이다. 이번연구는두기관의의무기록리뷰를통한후향적연구로대상환아수가 56명으로비교적적었다. 또한두집단에서생후 1주경의호흡보조정도에차이를보이지않았지만, 이것이이들이스테로이드를투여받지않았을경우유사한기관지폐이형성증의중증도를가질집단임을보장하지않는다는제한점이있다. 또한, 신경학적평가를비교적이른시기인교정연령 12 개월에뇌성마비진단여부로확인한것은비교적이른시점에이루어졌기때문에신경학적예후에대한평가를일반화하기어렵다는제한점이있다. 이에적절한부신피질스테로이드사용시기및용량에대한추가적대규모연구가필요하며, 장기적효과및부작용에대한추적관찰연구가필요하겠다. 24, 26 이와더불어부신피질스테로이드사용이필요한고위험군환아를선별하기위한평가기준의확립이필요하겠다. 결론적으로, 고위험군환아에서신경발달학적부작용없이기계환기를최소화하고중증의기관지폐이형성증발생을막기위한부신피질스테로이드사용은그안전성과이득을고려하여생후 1주에서 4주사이에신중하게투여하는것이필요하다. References 1) Northway WH Jr, Rosan RC, Porter D. Pulmonary disease following respiratory therapy of hyaline membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967;276:357-68. 2) Jobe AH. The new BPD: an arrest of lung development. Pediatr Res 1999;66:641-3. 3) Hodgman JE. Relationship between Wilson-Mikity syndrome and the new bronchopulmonary dysplasia. Pediatrics 2003;112:1414-5. 4) Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birth weight infants. Am J Obstet Gynecol 2007;196:147.e1-8. 5) Choi CW, Kim BI, Kim EK, Song ES, Lee JJ. Incidence of - 326 -
이해연등 : - 극소저체중출생아에서출생후텍사메타손투여시기에따른기관지폐이형성증의양상 - bronchopulmonary dysplasia in Korea. J Korean Med Sci 2012;27: 914-21. 6) Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60. 7) Kim BI. Recent progress in the understanding of clinical characteristics, epidemiology, and pathogenesis of new bronchopulmonary dysplasia. Korean J Pediatr 2009;52:6-13. 8) Finer NN, Powers RJ, Ou CH, Durand D, Wirtschafter D, Gould JB, et al. Prospective evaluation of postnatal steroid administration: a 1-year experience from the California Perinatal Quality Care Collaborative. Pediatrics 2006;117: 704-13. 9) Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;(1):CD001146. 10) American Academy of Pediatris. Policy Statement-postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010;126;800-13. 11) Jobe AH, Bancalari E. NICHD/NHLBI/ORD workshop summary-bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 12) Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of surgery 1978;187:1-7. 13) Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am. J. Infect. Control 1988;16:128-40. 14) John PC, Eric CE, Anne RH, Ann RS. Manual of Neonatal Care. 6th ed. North American:Lippincott Williams & Wilkins, 2007:379. 15) Kitchen WH, Olinsky A, Doyle LW, Ford GW, Murton LJ, Slonim L, et al. Respiratory health and lung function in 8-year-old children of very low birth weight: a cohort study. Pediatrics 1992;89:1151-8. 16) Greenough A, Giffin FJ, Yüksel B. Respiratory morbidity in preschool children born prematurely. Relationship to adverse neonatal events. Acta Paediatr 1996;85:772-7. 17) Giacoia GP, Venkataraman PS, West-Wilson KI, Faulkner MJ. Follow-up of school-age children with bronchopulmonary dysplasia. J Pediatr 1997;130:400-8. 18) Korhonen P, Koivisto AM, Ikonen S, Laippala P, Tammela O. Very low birthweight, bronchopulmonary dysplasia and health in early childhood. Acta Paediatr 1999;88:1385-91. 19) Evans M1, Palta M, Sadek M, Weinstein MR, Peters ME. Associations between family history of asthma, bronchopulmonary dysplasia, and childhood asthma in very low birth weight children. Am J Epidemiol 1998;148:460-6. 20) Schaubel D, Johansen H, Dutta M, Desmeules M, Becker A, Mao Y. Neonatal characteristics as risk factors for preschool asthma. J Asthma 1996;33:255-64. 21) Brostrom EB, Thunqvist P, Adenfelt G, Borling E, Katz- Salamon M. Obstructive lung disease in children with mild to severe BPD. Respir Med 2010;104:362-70. 22) Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1983;1:1356-58. 23) Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Collaborative Dexamethasone Trial Group. Pediatrics 1991;88:421-27. 24) Doyle LW, Ehrenkranz RA, Halliday HL. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2014;5: CD001146 25) Halliday HL, Ehrenkranz RA, Doyle LW. Late (>7 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2009;(1): CD001145 26) Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 2010;98:217-24. 27) Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee SK, Ohlsson A. Changes in the use of postnatal steroids for bronchopulmonary dysplasia in 3 large neonatal networks. Pediatrics 2006;118:e1328-35. 28) Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330-8. 29) Jefferies AL. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Paediatr Child Health 2012;17:573-4. - 327 -
Hae Yun Lee, et al. : - Characteristics of BPD in VLBWI according to the Timing of Dexamethasone Administration - = 국문초록 = 목적 : 기관지폐이형성증의예방과치료를위해서사용하는부신피질스테로이드의효과에대해서는잘알려져있지만부작용에대한우려로부신피질스테로이드투여가지연되어충분한효과를얻지못하는경우가많다. 본연구에서는극소저체중출생아에서기관지폐이형성증예방및치료목적으로부신피질스테로이드를투여한경우, 투여시기에따른임상적예후를비교하여적절한투여시기를알아보고자하였다. 방법 : 2008 년 1월부터 2014 년 9월까지서울대학교병원과분당서울대병원에입원한극소저체중출생아중부신피질스테로이드를투여받은미숙아 56 명을후향적으로분석하였다. 대상환아들을출생후 4주이전과 4주이후에부신피질스테로이드를투여한경우로나누어서두군간에호흡기계예후에대해서조사하였다. 결과 : 부신피질스테로이드를생후 4주이전에투여한조기투여군은 30 명, 생후 4주이후에투여한후기투여군은 26 명이였다. 두군간재태주수, 출생체중등임상적인특성에는차이가없었다. 조기투여군에서는후기투여군과비교하여스테로이드투여직전의호흡중증도지수와산소요구량이높았으나, 출생에서부터발관이이루어지는기간은짧았다 (32.0 일 vs 63.5 일, P=0.001). 또한후기투여군에서는중증의기관지폐이형성증이발생빈도가높았으며, 교정연령 12 개월에뇌성마비가진단된경우는두군에서차이가없었다. 여러관련된인자들을보정하였을때중증의기관지폐이형성증은출생 4주이후에부신피질스테로이드를투여하는것과의미있는연관성을보였다 (adjusted OR 17.14 [1.29-227.52], P=0.031). 결론 : 고위험군환아에서신경발달학적부작용없이기계환기를최소화하고, 중증의기관지폐이형성증발생을막기위한부신피질스테로이드사용은그안전성과이득을고려하여생후 1주에서 4주사이에신중하게투여하는것이필요하다. 중심단어 : 극소저체중출생아, 기관지폐이형성증, 부신피질스테로이드, 덱사메타손, 뇌성마비 - 328 -