종 설 대한주산회지제 24 권제 1 호, 2013 Korean J Perinatol Vol.24, No.1, Mar., 2013 신생아폐고혈압 인제대학교의과대학일산백병원소아과학교실황종희 Neonatal Pulmonary Hypertension Jong Hee Hwang

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1 종 설 대한주산회지제 24 권제 1 호, 2013 Korean J Perinatol Vol.24, No.1, Mar., 2013 신생아폐고혈압 인제대학교의과대학일산백병원소아과학교실황종희 Neonatal Pulmonary Hypertension Jong Hee Hwang, M.D. Department of Pediatrics, Ilsan Paik Hospital, College of Medicine, Inje University, Ilsan, Korea Neonatal pulmonary hypertension is associated with meconium aspiration syndrome, sepsis, asphyxia, respiratory distress syndrome, congenital diaphragmatic hernia, congenital heart disease, or bronchopulmonary dysplasia. Newborns with pulmonary hypertension are at risk of death, chronic lung disease, neurodevelopmental disability, and other complications. Because of the diverse pathophysiology of the underlying disease, the diagnostic evaluation and therapeutic approach are important. This article will review the pathophysiologic background and the current therapeutic options for neonatal pulmonary hypertension. Key Words : Hypertension, Pulmonary, Infant, Newborn 신생아폐고혈압증 (neonatal pulmonary hypertension) 은출생후에도지속적으로폐혈관저항이감소하지않고증가되어있음으로인해폐혈류량이감소하고탈산소화혈액이전신순환으로이동하면서저산소증을나타내는질환으로주로신생아폐고혈압지속증 (persistent pulmonary hypertension of the newborn, PPHN) 으로나타난다. 이는만삭아나후기미숙아의중요한사망원인중하나로신생아생존출생아 1,000 명당 2명에서발생하며사망률은 11% (range: 4-33%) 까지보고되고있으며 1 폐포의산소분압이감소하거나산증이유발되는질환, 즉태변흡인증후군, 패혈증, 신생아가사, 신생아호흡곤란증후군이나폐나심장에선천성기형이동반되는경우에나타난다. 신생아폐고혈압증은중증의호흡부전을유발하며만성적인폐기능저하나신경학적장애등의합병증을일으키게되는데최근에는초극소미숙아생존율의증가로인해기관지폐이형성증 (bronchopulmonary dysplasia) 등의만 접수 : 2013 년 3 월 21 일, 수정 : 2013 년 3 월 22 일승인 : 2013 년 3 월 22 일주과책임자 : 황종희, 경기도고양시일산서구대화동 2240 인제대학교일산백병원소아청소년과전화 : 031) , 전송 : 031) jhhwang@paik.ac.kr 성폐질환으로인한이차적인폐고혈압증이발생하게되므로초극소저체중출생아및고위험신생아에대한예후와생존을향상시키기위해서는신생아폐고혈압증의병태생리및임상적으로사용되고있는최신치료에대한이해가필요할것이다. 본론 1. 신생아폐고혈압증의병태생리및원인태아기에는재태주령에비례하여폐혈관상 (pulmonary vascular bed) 과표면적이늘어나고폐혈관저항이점차증가하게되며임신말기에는폐혈관수축이활발하게진행된다. 이러한폐혈관수축의발생에는낮은산소분압, endothelin-1 (ET-1), leukotrienes, Ras homologus (Rho) kinase 등의폐혈관수축인자가작용하게된다. 2 이후신생아가출생하게되면호흡을시작하면서폐의물리적팽창및폐포의산소분압이증가하면서수분안에폐혈관저항이감소하게되며폐로가는혈류량이 8-10 배까지증가하게된다. 이러한폐혈관저항감소의이행에는다양한인자와전달경로가영향을주게되는데임신말기에 - 1 -

2 Jong Hee Hwang : - Neonatal Pulmonary Hypertension - 는혈관확장인자인 nitric oxides synthase 와 soluble guanylate cyclase 의발현이증가하게되고 NO-cyclic guanosine monophosphate (cgmp) 와 prostacyclin (PGI2) 이작용하여폐혈관을확장시키는역할을하게된다. 2 그러나출생후저산소증이나산증에의해혈관확장인자기능이방해를받게되면태아순환에서정상적인신생아심폐순환으로의이행이이루어지지못하게되면서신생아폐고혈압지속증이발생하게된다. 또한 superoxide 생성증가, phosphodiesterase (PDE)-5 의활동성증가, vascular endothelial growth factor (VEGF) 신호전달의손상이나세포내칼슘유입의증가와관련된경로가활성화되면서폐혈관저항을지속적으로증가시키는작용을하게된다. 2 이러한신생아폐고혈압지속증은병태생리에따라부적응 (maladaption), 근육의과형성 (excessive muscularization or maldevelopment), 그리고혈관구조의저형성 (hypoplastic vasculature or undervelopment) 의 3가지유형으로구분하게된다. 3 부적응 (maladaption) 유형은폐혈관은정상적인구조를가지고있으나폐실질질환으로인해비정상적인폐혈관수축이유발되는경우로태변흡인증후군, 폐렴, 신생아호흡곤란증후군이이에속하게된다. 근육의과형성 (excessive muscularization) 은폐는정상실질을가지고있으나폐혈관의평활근이과하게두꺼워지거나세엽내동맥 (intraacinar artery) 의수준까지확장되는비정상적인폐혈관의재형성 (pulmonary vascular remodeling) 으로인해발생하는데대개특발성 (idiopathic PPHN) 으로생기는경우가이에해당된다. 일부연구에서임신말기임산부에게 non-steroid antiinflammatory drugs (NASID) 를사용한경우동맥관이폐쇄되면서출생후폐고혈압지속증이발생하였다거나, 4, 5 selective- serotonin reuptake inhibitors (SSRI) 를사용한산모에게출생한신생아에서폐고혈압지속증이발생하였다는보고가 6 있으나아직까지는이에대한연구는논란의여지가있다. 7, 8 혈관구조의저형성 (hypoplastic vasculature) 유형은폐형성부전을가진경우에서폐혈관구조가충분히자라지못하면서폐혈관저항이증가하게되는데선천성횡격막탈장이나신형성부전 (renal agenesis) 의질환을가진신생아에서나타나며폐형성부전이심할 수록예후는불량하다. 이러한신생아폐고혈압지속증외에도신생아폐고혈압은선천성심기형이나이차적인원인에의해서발생하게되는데소아나성인에서사용되는 Dana point 를이용하여중요한원인에따라구분할수있다 (Table 1) 신생아폐고혈압증의진단신생아폐고혈압증은임상적으로는 10 흡입산소농도 (fraction of inspired oxygen, FiO 2 ) 를 100% 로투여하여도동맥혈산소분압 (arterial oxygen pressure, PaO 2 ) 이 55 mmhg 미만으로산소치료에불응하는경우나, 2, 11 동맥관전 (preductal) 과후 (postductal) 의산소포화도차가 20 mmhg 이상인경우로 1 진단할수있다. 그러나가장기본적이면서도유용한방법은도플러를이용한심초음파검사로대동맥축착이나전폐정맥환류이상 (total anomalous pulmonary venous return) 등의구조적인기형여부를확인하고난원공이나동맥관을통한단락의방향, 삼첨판역류정도를이용한폐동맥압측정및좌심실의기능을평가하는것이다. 신생아에서정상적인폐동맥압은평균 14±3 mmhg 이나, 10 출생직후에는정상적인환경에서도상대적으로폐혈압이높을수가있는데심도자검사에서폐동맥압이 mmhg 보다높은경우에는폐고혈압으로진단할수있다. 12 Table 1. Main Causes of Neonatal Pulmonary Hypertension Group Description A Persistent pulmonary hypertension of the newborn (PPHN) I. Pulmonary vasoconstriction -eg, meconium aspiration syndrome II. Abnormal pulmonary vascular remodelingidiopathic PPHN III. Diminished pulmonary vascular bed-pulmonary hypoplasia B Pulmonary vein stenosis C Pulmonary hypertension secondary to left heart disease D Pulmonary hypertension secondary to lung disease and/or hypoxia Quoted from Arch Dis Child Fetal Neonatal Ed. 2012;97: F

3 황종희 : - 신생아폐고혈압 - 3. 신생아폐고혈압의치료신생아폐고혈압의치료는병태생리나원인에따라달라지게되는데일반적인치료방침은정상체온유지, 전해질과대사이상의교정및적절한혈압과체순환을유지하는것이다. 산소는초기단계에서부터투여하는데산소포화도를개선하기위해기계적환기요법이나계면활성제를사용하며기계적환기치료시적절한폐용적을유지하여폐부종, 폐순응도감소나염증변화등의이차적인폐손상이생기지않도록하는것이중요하다. 13 고식적기계에반응하지않은경우에는압력상해나폐손상을감소시킬수있는고빈도환기기계 (high frequency oscillatory ventilation) 를사용한다. 체외막형산소섭취 (extracorporeal membrane oxygenation) 요법은산소화지수 (oxygenation index, OI) 가 40 이상인경우에적응증이되며중증의폐고혈압지속증을가진신생아에서유용한것으로보고되 고있으며, 14 최근에는이러한치료방법과더불어흡인용산화질소 (nitric oxide) 를비롯한다양한폐혈관확장제등이사용되고있다. 1) 흡인성산화질소 (Inhaled nitric oxide, ino) 산화질소는평활근성장과혈관응집을억제하는역할을하는내재성혈관확장인자로, 15 soluble quanylate cyclase 를자극하여 cyclic guanosine 3, 5 -cyclin monophosphate (cgmp) 를생성하며이 cgmp 가 cgmp-dependant protein kinas (PKG) 를활성화시키면서 calcium-gated potassium channels 을통해혈관을이완시키는역할을하게된다 (Fig. 1). 2, 13, 16 산화질소는흡인을통해선택적으로폐혈관에작용을하여폐혈관을확장하는기능을하는데일부동물실험에서는폐의염증이나산화자극을감소시키고계면활성제기능을보존하며폐나폐혈관의성장을촉진하는것으로보고하고있다 실제임상적으로도많 Fig. 1. Mechanisms through which current drugs elicit pulmonary vasodilation to treat pulmonary hypertension. AC: Adenylate cyclase; CaM: Calmodulin; CCB: Calcium channel blocker; ET-1: Endothelin-1; MLCK: Myosin light-chain kinase: MLCP: Myosin light-chain phosphatase; NO: Nitric oxide; PDE5: Phosphodiesterase 5; PGI2: Prostcyclin; PLC: Phospholipase C; SsGC1: Soluble guanylate cyclase; SR: Sarcoplasmic reticulum. Quoted from Vasc Health Risk Manag 2009;6: and Expert Rev Cardiovasc Ther 2010;8:

4 Jong Hee Hwang : - Neonatal Pulmonary Hypertension - 이사용되고있으며산소화지수가 25 이상인저산소성호흡부전이나폐고혈압지속증에흡인성산화질소를사용하였을때임상적인호전과체외막형산소섭취치료의빈도를감소시켰다고보고하고있다. 20, 21 산화질소의농도는 5-20 ppm 을투여하는것이효과적이며갑자기중단후에폐혈압이다시증가할수있으므로 4-5 일에걸쳐서천천히이탈 (weaning) 하는것이필요하다. 산화질소가과하게투여될때에는메트헤모글로빈이증가되어독성을나타내므로적절한감시가이루어져야한다. 산화질소투여량을증가하여 40 ppm 이상사용한경우에는임상적인효과에는큰차이가없으며 80 ppm 까지투여하였을때메트헤모글로빈혈증의위험성이증가한다고보고하였다. 22 2) Phosphodiesterase 5 inhibitors (PDE-5 inhibitors) Phosphodiesterase 는 cgmp 를 GMP 로가수분해하는역할을하는데, 특히 phosphodiesterase 5 (PDE-5) 는폐나평활근에주로작용을한다. 23 Phosphodiesterase 5 Inhibitors (PDE-5 inhibitors) 는 cyclic nucleotide 의가수분해를억제하여 cyclic adenosine monophosphate (camp) 나 cgmp 를축적시킴으로써혈관확장작용을하게되는데 (Fig. 1) 2 PDE-5 inhibitor 로는 sildenafil, vardenafil, tadalafil 등이있으며그중에서 sildenafil 이가장 많이사용되고있다. Sildenafil 은경구, 주사제또는분무제등의방법으로사용할수있는데여러동물연구에서도전신혈압의감소없이폐혈관을선택적으로확장시키고흡인성산화질소와병행사용시효과를더전위시키는것으로보고하고있다 또한흡인성산화질소의중단으로인한폐혈압의재상승은 sildenafil 을사용함으로써감소시킬수있다고보고하고있다. 26 신생아나소아에서사용되어지는경구용 sildenafil 의최적용량에대해서는아직명확한기준은없으나 mg/kg/dose 로시작해서최고 2 mg/kg/dose 를사용할수있으며보통은 6-8 시간간격으로투여하나반감기가짧기때문에 4시간간격으로투여하기도한다. 27 Sildenafil 의용량이나투여효과에대해서는논란의여지가있지만여러임상연구나무작위대조시험 (randomized control trial) 에서유효성을보고하고있다 (Table 2) 부작용으로는시력장애, 홍조, 두통, 비출혈이나소화장애등이있다. 3) Phosphodiesterase 3 inhibitors (PDE-3 inhibitors) Phosphodiesterase 3 inhibitors (PDE-3 inhibitors) 는세포내 camp 를증가시킴으로인해근수축효과, 말초혈관확장, 좌심실후부하감소및심박출량증가의효과를나타내게되는데 (Fig. 1) 약제로는 milrinone 이있다. 2 대 Table 2. Sildenafil in Persistent Pulmonary Hypertension of the Newborn Author Patients (n) Etiololgy of PPHN Gestational age Dose/route Outcomes Steinhorn at al. (2009) Baquero et al. (2006) Herrea et al. (2006) Vargas-Origel et al. (2010) 36 MAS, HMD, Sepsis, peumonia, idiopathic Sildenafil: 7 Placebo: 6 Sildenafil: 13 Placebo: 11 Sildenafil: 31 Placebo: 20 Soliz et al. (2009) Sildenafil: 29 Placebo: 20 Baquero et al. 2008) >34 weeks and <72 h Loading followed by maintenance dose of mg/kg/hr for 2-7 days; iv. MAS, HMD > 35.5 week 1-2 mg/kg every 6h; max. 8 dose; oral Not clear Term 2 mg/kg/dose every 6h for 72h; oral Sustained improvement in oxygenation with higher doses, only one death Sildenafil: one death Placebo: five deaths Oxygenation (P<0.01) Not clear Term 3 mg/kg every 6h; oral Sildenafil: two deaths Placebo: eight deaths (P<0.01) Not clear Full term 2 mg/kg every 6h; oral Oxygenation; mortality (P<0.01) 22 Not clear Full term 2 mg/kg every 4-6h; oral 12 neurologically normal at months Noori et al. (2007) 7 CDH Full term 1-2 mg/kg every 12-24h; oral Cardiac output; pulmonary pressure; five survived Abbreviations: CDH, congenital diaphragmatic hernia; HMD, hyaline membrane disease iv.: Intravenous; MAS, meconium aspiration syndrome; PPHN, persistent pulmonary hypertension of the newborn

5 황종희 : - 신생아폐고혈압 - 개는주사제로사용하며용량은 mcg/kg 을투여하는데흡인을하였을때도효과가있다는보고가있다. 35 또한불응성의신생아폐고혈압지속증에서 milrinone 을사용한경우효과가있다는일부보고가있으나, 36 아직까지는신생아에서사용한연구가 sildenafil 에비해적은편으로부작용과관련한연구를보면성인에서 milrinone 을사용하면서전신혈압감소의위험성이있다는보고와, 37 미숙아에서무작위대조시험을하였을때 milrinone 이유의하게심박수를증가시키고평균혈압을감소시켰다는보고가있다. 38 아직까지는신생아에서임상적으로효능이나부작용에대한연구가충분하지는않다. 4) Prostaglandin 유사체 (Prostaglandin analogues) Prostaglandin 유사체로는 prostacyclin (PGI 2 ; epoprostenol), iloprost, treprostinil, betaprost 등이있다. 39 Prostacyclin 은혈관내피에서 arachidonic acid 대사로부터만들어지는데혈관평활근에있는 adenyl cyclase 을자극하여 camp 생성을증가시켜서전신및폐혈관을확장하는역할을하게된다 (Fig. 1). 2, 40 주사용제 PGI 2 인 epoprostenol 은신생아폐고혈압지속증에서폐혈관저항을감소 시켰다는보고가있으나, 41, 42 성인연구나동물연구에비해연구자료가미흡하고아직무작위대조시험에관한연구가충분하지않기때문에부작용이나안정성에대해서는더연구가필요하다. 흡인또는분무 (nebulization) 형태인 iloprost 는소실반감기가 분으로긴편이며혈관확장, 혈소판응집억제, 항염증효과를나타내며전신혈압에영향을주지않으면서선택적으로폐혈관을확장하는효능을가진다. 2 특히, iloprost 처럼흡인형태를사용하는경우에폐의비환기영역으로부터환기가잘이루어진영역으로폐혈류의재배치를촉진하고환기관류불균형 (ventilation-perfusion mismatch) 을최소화하는효과를나타내는것으로보고하였다. 41 신생아는소아의기본용량 (>20 ng/kg/min) 보다더고용량을사용하는데, 9 전신혈관확장및혈압감소가나타날수있기때문에혈압강하제를사용할수도있다. 그러나재태주령이낮은미숙아에사용한경우에도임상적인효능에있다는보고도있다 (Table 3) ) Endothelin receptor antagonists Endothelins (ET S ) 은 ET-1, ET-2, ET-3 로구분되며 Table 3. Prostacyclin/Iloprost in Persistent Pulmonary Hypertension of the Newborn Author Gestational age/ Patients (n) Etiololgy of PPHN Dose/route Outcomes Eronen at al. (1997) 34 weeks to term/8 Survived: 8 MAS, HMD, pulmonary hemorrhage, primary PPHN ng/kg/min iv. Increased to max 20 ng/kg/min Hougland et al. (2005) 38 weeks/21 Not clear 4-14 ng/kg/min iv.; 12 days Mangones et al. (2006) 25, 34, 36 and 40 weeks /4 Sepsis, ACD, Pneumonia, BPD Betremieux et al. (2005) Not clear/17 CDH, HMD, ACD, CCAM, sepsis, BA Survived: 55% 2-10 ng/kg/min iv. Oxygenation improved in all; Survived: 3 Up to 20 ng/kg/min iv. Survived: 10 Eifinger et al.(2008) weeks/4 PPROM 2μ/kg inhalation Improved oxygenation; reduced PPHN on echocardiogram Kelly et al. (2002) Term/4 Sepsis: 3 ACD 40 ng/kg/min; nebulization for 7-18 days Improved oxygenation; pulmonary pressure decreased; all survived De Jaegere et al. (1998) weeks/4 HMD/Sepsis 50 ng/kg nebulization Improved oxygenation Histol et al. (2002) weeks/3 Hypoplastic lungs Not clear; inhalation Improved oxygenation; survived: 2 Abbreviations: CDH, congenital diaphragmatic hernia; HMD, hyaline membrane disease iv.: Intravenous; MAS, meconium aspiration syndrome; PPHN, persistent pulmonary hypertension of the newborn; ACD, alveolar-capillary dysplasia; BA, birth asphyxia; BPD, bronchopulmonary dysplasia; CCAM, congenital cystic adenomatoid malformation; PPROM, preterm premature rupture of membranes

6 Jong Hee Hwang : - Neonatal Pulmonary Hypertension - 그중 ET-1 은혈관수축증진, 세포성장및혈관재형성작용을통해폐고혈압을유발하는작용을하며이러한 ET-1 의작용에는두개의 G-protein coupled receptor subtypes 인 ET A 와 ET B 가매개역할을하게된다. 50 ET A 수용체는혈관수축, 세포의증식및이동, 섬유화하는기능을하고반대로 ET B 수용체는항증식작용, 세포자멸방지및산화질소나 PGI 2 와같은혈관확장인자의분비를자극하는기능을가지게된다. 2 Endothelin receptor antago nists (ETRAs) 에는 bosentan, sitaxentan, ambisentran 이있는데 bosentan 은 ET A 와 ET B 을모두억제하는기능을가지는반면, sitaxentan, ambisentran 은 ET A 에대해서만선택적인억제기능을가진다. 51 신생아폐고혈압지속증을가진신생아는 endothelin 농도가증가되어있는데, 52 폐고혈압을가진환아에서 bosentan 1 mg/kg 을하루에 2회사용한경우임상적인증상이호전되었다고보고하고있다. 53, 54 부작용으로는간기능장애, 구토, 폐출혈이나타날수있으며현재까지임상적인사용에대해서는더연구가필요한상태이다. 6) Scavengers of reactive oxygen species (ROS) 최근연구에서는과도한산소자극 (oxygen stress) 으로인해나타나는기전들, 즉폐동맥외막및평활근에있는 superoxide, hydrogen peroxide 와같은 reactive oxygen species (ROS) 증가, 55 폐동맥내피에있는 NADPH oxidase 로부터의활성산소 (oxygen free radicals) 생성등이신생아폐고혈압지속증의발생과연관이있다고보고하고있다. 56 또한산소에의한손상을최소화함으로써활성산소 (free radical) 의제거제 (scavenger) 인 superoxide dismutase (SOD) 가고혈압지속증을호전시킬수있다고하였는데신생아폐고혈압지속증을가진동물모델에서 recombinant human SOD (rhsod) 를투여하였을때폐동맥수축력이감소하고산소포화도가호전되었으며, 57 rhsod 가 endothelin nitric oxide synthase (enos) 의기능을향상시켰다고보고하였다 미숙아및기관지폐이형성증과폐고혈압증에서의사용미숙아에서기관지폐이형성증의빈도는 30% 까지보고 되고있으며출생체중 1,000 그람미만의초극소저체중출생아에서발생빈도가증가하며특히중증의기관지폐이형성증을가진미숙아는폐고혈압증, 우심실부전, 폐성심 (cor pulmonale) 이동반될위험성이증가하게된다. 13 최근증중의기관지폐이형성증을가진미숙아에서도흡인성산화질소, PDE-5 억제제 (sildenafil), endothelin receptor antagonist (bosentan) 의단독사용이나이들의병합요법이임상적으로사용되면서폐고혈압증이개선되었다고보고하고있다 일부연구를보면출생초기에중증의호흡곤란증후군 (OI 25) 을가진재태주령 31주미만의미숙아에서흡인성산화질소를사용하였을때산소포화도는호전되었으나뇌실내출혈, 기관지폐이형성증의빈도나사망률은감소시키지못하였고기관지폐이형성증에의한폐고혈압증에도큰효능은없다는보고등, 62 논쟁의차이는있으나폐혈관확장제의임상적사용은점차증가하고있는추세이다. 최근에는기관지폐이형성증의병태생리에 phosphodiesterase 4 (PDE-4) 가영향을준다고보고하고있으며동물연구에서 PDE-4 inhibitor 인 rolipram, piclamilast 을사용하였을때폐의염증반응, 혈관누출 (vascular leakage), 폐중격근육이감소하고폐포형성이증가하는등폐고혈압증에대해개선효과가있다고하였다 결론신생아폐고혈압증은만삭아의사망률과연관된중요한질환의하나이며초극소저체중출생아에서는기관지폐이형성증에의한합병증과신경학적인장애를감소시키기위해서적절한진단과치료가이루어져야하는질환이다. 특히후기미숙아나만삭아에서영상의학적검사상명확한폐실질병변이없음에도불구하고중증의호흡부전이생기는경우에는출생전기의폐혈관발육불량에의한특발성폐고혈압증을의심하여적절한시기에치료가이루어지도록하는것이필요하다. 최근국내에서도고빈도환기기계와흡인성산화질소의사용이확대되면서폐고혈압증의치료에도움을주고있으나이러한치료에도불응성폐고혈압증을나타내는경우에는폐혈관확장제를병용하 - 6 -

7 황종희 : - 신생아폐고혈압 - 여사용할수밖에없게된다. 그러나폐혈관확장제로사용되고있는약물들은아직까지는성인에비해신생아에서는임상적인효과나부작용에대해서는연구가미비한편이며, 특히치료후장기적인영향에대해서는연구가거의없는실정이다. Sildenafil 의사용에대해서도미국식품의약기구 (U.S. Food and Drug Administration) 에서도 1-17 세소아청소년에서장기간 sildenafil 을사용하였을때에사망률이증가한다고보고하였고, 66 이러한위험성을줄이기위해사용후에 sildenafil 을갑자기중단하지말도록하며체중이 8 kg 미만인신생아나영유아에서는하루에 mg/kg 를하루에 3번이상사용하지않도록권장하고있기도하다. 67 따라서임상적으로사용이증가하고있는폐혈관확장제에대해서적절한감시와용량조절이필요하며특히 milrinone, iloprost, bosentan 등은신생아폐고혈압증에사용하는것이나폐혈관확장제의병합요법에 68 대해서는아직까지일부보고로국한되어있기때문에신생아를대상으로는한동물연구나무작위대조시험들과같은유효성과안정성에대한연구가충분히이루어져야할것이다. References 1) Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcome. Pediatrics 2000;105: ) Rao S, Bartle D, Patole S. Current and future therapeutic options for persistent pulmonary hypertension in the newborn. Expert Rev Cardiovasc Ther 2010;8: ) Rudolph AM. High pulmonary vacular resistance after birth: I. Pathophysiologic considerations and etiologic classification. Clin Pediatr (Phila) 1980;19: ) Levin DL, Mills LJ, Parkey M, Garriott K, Campbell W. Con striction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe. J Pediatr 1979;94: ) Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammtory drug consumption during pregnancy. Pediatrics 1996;97: ) Chambers CD, Hermandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354: ) Van Marter LJ, Hermandez-Diaz S, Werler MM, Louik C, Mitchell AA. Nonsteroidal anti-inflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborm. Pediatrics 2013;131: ) Galbally M, Gentile S, Lewis AJ. Further findings linking SSRIs during pregnancy and persistent pulmonary hyperten sion of the newborn: clinical implications. CNS Drugs 2012; 26: ) Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed. 2012;97:F ) Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J 2009;34: ) Shah PS, Ohlsson A. Sildenafil of pulmonary hypertension in neonates. Cochrane Database Syst Rev 2011;10:CD ) Adatia I. Recent advances in pulmonary vascular disease. Curr Opin Pediatr 2002;14: ) Barman SA, Zhu S, White RE. RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension. Vasc Health Risk Manag 2009;5: ) Mugford M, Elbourne D, Field D. Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev 2008;16:CD ) Moore C, Tymvios C, Emerson M. Functional regurgitation of vascular and platelet activity during thrombosis by nitric oxide and endothelial nitric oxide synthase. Thromb Haemost 2010;104: ) Bin-Nun A, Schreiber M. Role of ino in the modulation of pulmonary vascular resistence. J Perinatol 2008;28:S ) Issa A, Lappalainen U, Kleinmam M, Bry K, Hallman M. Inhaled nitric oxide decrease hyperoxia induced surfactant abnormality in preterm rabbits. Pediatr Res 1999;45: ) Cotton RB, Sundell HW, Zeldin DC, Morrow JD, Roberts LJ, Hazinski TA, et al. Inhaled nitric oxide attenuated hyperoxic lung injury in lambs. Pediatr Res 2006;59: ) McCurnine DC, Pierce RA, Chang LY, Gibson LL, Osborne-Lawrence S, Yoder BA, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 2005; 288: ) Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term - 7 -

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