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1 ISSN: (Print)/ (Online) Tuberc Respir Dis 2012;72:1-7 CopyrightC2012. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 성인호흡곤란증후군에있어체외막산소화장치를이용한치료 1 울산대학교의과대학서울아산병원중환자의학및호흡기내과학교실, 2 영남대학교의과대학중환자의학및호흡기내과학교실 김고운 1, 최은영 2, 홍상범 1 Review The Treatment of Adult Respiratory Distress Syndrome (ARDS) Using Extracorporeal Membrane Oxygenation (ECMO) Go Woon Kim, M.D. 1, Eun Young Choi, M.D. 2, Sang Bum Hong, M.D., Ph.D. 1 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 2 Division of Pulmonary and Critical Care Medicine, Yeungnam University College of Medicine, Daegu, Korea Extracorporeal Membrane Oxygenation (ECMO) support to tissue oxygenation has been shown to improve survival in patients with life threatening respiratory distress syndrome or cardiac failure. Extracorporeal life support such as ECMO, including extracorporeal CO 2 removal (ECCO 2 R), is used as temporary support until successful recovery of organs. A recently published multicentre randomized controlled trial, known as the CESAR (conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial, was the first trial to demonstrate the utility of ECMO in acute respiratory distress syndrome (ARDS). During the 2009 influenza A (H1N1) pandemic, there were many reports of patients with severe ARDS related to H1N1 infection treated with ECMO. These reports revealed a high survival rate and effectiveness of ECMO. In this review, we explain the indication of ECMO clinical application, the practical types of ECMO, and complications associated with ECMO. In addition, we explain recent new ECMO technology and management of patients during ECMO support. Key Words: Respiratory Distress Syndrome, Adult; Extracorporeal Membrane Oxygenation; Extracorporeal Circulation; Intensive Care Unit 서 호흡부전환자에서인공환기기의사용은많은환자의생명을구했으나, 인공환기기자체에의한기계환기유발 Address for correspondence: Sang Bum Hong, M.D., Ph.D. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul , Korea Phone: , Fax: sbhong@amc.seoul.kr Co-correspondence: Go Woon Kim, M.D. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul , Korea Phone: , Fax: taria@nate.com Received: Dec. 5, 2011 Revised: Dec. 5, 2011 Accepted: Dec. 8, 2011 론 성폐손상 (ventilator-induced lung injury, VILI) 을야기할수있음이알려졌다 1. 이에일회환기량 (tidal volume, TV) 6 ml/pbw, 고평부압 (plateau pressure) 30 cm H 2 O, 산소농도 (FiO 2 ) 60% 이하의폐보호환기법이보편화되고있다. 그러나, 일부중증호흡부전환자에서는 TV=6 ml/ PBW을사용해도 VILI가발생함이보고되어추가로다른치료가필요한실정이다 2. 이에최근체외순환을이용한 veno-venous ECMO (high flow) 및 extracorporeal CO 2 removal (ECCO 2 R, low flow) 가임상에적용되고있다. ECMO는회복가능성이있는심각한호흡부전이나심부전환자에서고식적인치료방법에실패한경우, 심폐기능이회복될때까지수일에서수주동안생명유지를도와주는체외순환의일종이다. 최근에는 ARDS 환자를대상으로 ECMO의임상적인효과및안정성그리고비용효과를전향적, 무작위, 다기관 1

2 GW Kim et al: The treatment of ARDS using ECMO 연구인 CESAR (conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial이보고되었다 3. 이연구에서는 ECMO로배정된환자들이모두단일병원으로전원되어치료를받으며매우낮은 ECMO관련합병증및높은생존율을보여주었다. 급성호흡부전환자에서 ECMO의유용성을증명한최초의전향적무작위연구이다. 그외에전세계적으로신종플루로인한급성호흡부전으로중환자실에입원한젊은환자들의 ECMO치료를통한높은생존율이호주, 뉴질랜드, 미국, 캐나다, 이태리및영국에서보고되어중환자실호흡부전치료의중요한요소가되어가고있다 4,5. 국내에서는 1992년 Choi 등 6 의증례보고를시작으로 Capiox Emergency Bypass System R (Terumo Inc., Tokyo, Japan) 장비도입과경피적도관삽입경험이증가하면서 ECMO의사용이증가하고있다. 최근에는 ARDS 와같은호흡부전에장기간적용이가능한 Maquet PLS (prolonged life support) 회로등도사용가능하게되었다. 본종설에서는 ECMO의임상적응증과체외순환방식, 그에따른합병증을기술하고최근개발되고있는새로운기술과 ECMO 시행중환자관리에대해기술하고자한다. ECMO 역사 1976년 Bartlett 등 7 에의해신생아호흡부전증의저산소증을 VA (veno-arterial) bypass 로치료하였고이를 ECMO라기술한이후 ECMO 사용의적응증은확장되어가고있다. ECMO는혈액을대퇴정맥이나우심방에도관삽입을 통해배액된혈액을산화시키고이산화탄소를제거한후대퇴동맥이나상행대동맥을통해체내에다시공급하는장치로심폐부전이발생하였을때일시적으로심장기능및폐기능을대체하는수단이다. Morioka 8 는혈중 O 2 와 CO 2 의개선이외에폐의안정 (lung rest) 에중요성이있다고하여 ECLA (Extracorporeal lung assist) 라는명칭을사용하였고, Gattinoni 등 9 은 VV bypass 로혈중 CO 2 를제거하고저빈도양압조절호흡을병용하는 ECCO 2 R (extracorporeal membrane carbon dioxide removal) 을개발하였다. ECMO 적응증 ECMO는기저질환자체를치료하는것이아니라가스교환을보조해줌으로써회복에필요한시간동안생명유지를도와주는장치이기때문에 ECMO 를적용하기전에가장중요한점은 ECMO를통한치료와회복이가역적인지여부를고려하는것이다. 호흡부전에서가장흔한적응증은성인성호흡곤란증후군 (ARDS), 폐렴, 폐이식후원발성이식실패의경우이고, 심부전에서흔한적응증은심장수술후, 심장이식후, 심근염, 비보상성심근증, 심인성쇼크를동반한급성관상동맥증후군과같은심각한심부전의경우이다 10. ECMO 금기증은시술로인한위험이나합병증과잠재적인이득을고려하여결정하며상대적인금기증은파종성종양, 고령, 이식편대숙주반응, 기존의심각한뇌손상, 목격되지않은심정지, 장시간의심정지등이다. 대동맥박리나대동맥기능부전은기술적인측면에서금기증에해당한다. Table 1. ECMO on adult respiratory failure Indications 1. Hypoxic respiratory failure a. Mortality >50% - PaO 2/FiO 2 <150 on FiO 2 >90% and/or Murray score 2 3 b. Mortality >80% - PaO 2/FiO 2 <80 on FiO 2 >90% and/or Murray score CO 2 retention due to asthma or permissive hypercapnia (PaCO 2 >80) or inability to achieve safe inflation pressures (Pplat 30 cm H 2O) 3. Severe air leak syndromes Contraindications 1. Mechanical ventilation at high settings for 7 days or more - High setting: FiO 2 >0.9, Pplat >30 2. Major pharmacologic immunosuppression - ANC <400/mL 3 3. CNS hemorrhage that was recent or expanding ECMO: extracorporeal membrane oxygenation; ANC: absolute neutrophil count. 2

1979년 Zapol 등 12 은급성호흡부전환자에서 VA ECMO를적용한전향적, 무작위, 다기관연구를시행하였으며일반적인치료군과 ECMO 치료군에서생존율은 10% 로같았다고보고했고, 그결과로성인에서의임상연구가거의시행되지않았다.

3 Tuberculosis and Respiratory Diseases Vol. 72. No. 1, Jan ELSO (Extracorporeal Life Support Organization) 가이드라인은급성심부전또는급성호흡부전이있는환자에서적절한치료에도불구하고사망할확률이높을때 ECMO를적용해볼수있는데 50% 의사망률이예측될때 ECMO를고려할수있고, 80% 의사망률이예측될때에는 ECMO의적응증이된다고제시하고있다 (Table 1) 년 Zapol 등 12 은급성호흡부전환자에서 VA ECMO를적용한전향적, 무작위, 다기관연구를시행하였으며일반적인치료군과 ECMO 치료군에서생존율은 10% 로같았다고보고했고, 그결과로성인에서의임상연구가거의시행되지않았다. 그러나 2004 년 Hemmila 등 13 은급성호흡부전환자에서폐보호환기법을적용한 ECMO 치료에서 67% 의이탈성공률, 52% 의생존율을보고하였다. ECMO Types 1. 정맥-정맥 ECMO (V-V ECMO) V-V ECMO (veno-venous ECMO) 는인공호흡기에반응하지않는단독호흡부전에산소를공급한다. 정맥내에위치한도관을통해배액된혈액이산화기를통과한후다시정맥으로공급되어호흡부전환자에서폐의기능을보조하게되며일반적으로양측대퇴정맥을사용한다. 배액및관류를위한 2개의정맥도관의삽입이필요한데도관간의위치가가까우면산화기를통과한산소화된혈액이체내순환을거치지않고다시배액되는재순환현상이나타나게된다 14. 최근에는한카테터에두개채널을가진상품이도입되어재순환현상을줄이기위해 사용되고있다 (Figure 1). 2. 정맥 - 동맥 ECMO (V-A ECMO) V-A ECMO (veno-arterial ECMO) 는호흡부전의유무에상관없이순환보조를치료할목적으로사용된다. 정맥내도관을통해배액된혈액을산화기를거쳐말초나중심동맥으로공급하여심장과폐기능을보조하는역할을한다. 산화기는원심력을이용하는펌프와조합하여사용되며대부분의환자에서 5 L/min 까지공급한다. 그러나패혈증과같은과역동상태에서는단일도관으로는충분한가스교환을얻을수없어 2차도관을우측내경정맥에삽관하여 7 L/min까지공급할수있다 Extracorporeal membrane carbon dioxide removal (ECCO 2 R) 호흡부전환자에서기계환기에도불구하고지속적인고탄산혈증또는중등도의저산소혈증을보이는심한급성호흡곤란증후군환자에서선택적인이산화탄소의제거를위해최근 pumpless extracorporeal interventional lung assist (ila; Novalung, Talheim, Germany) 가개발되었다 15,16. 펌프없이동정맥의압력차에의해발생하는혈류가막형산화기 (membrane oxygenator) 를통과하면서효과적인이산화탄소제거와중등도의동맥혈산소화개선에도움을주는새로운가스교환장치이다. ECMO에비해시술이쉽고도관에헤파린이도포되어있어저용량의헤파린만사용해도되고이산화탄소제거 Figure 1. (A) Recirculation phenomenon. (B) Dual-lumen cannula. This figure was reprinted from NEJM 2011:365:

4 GW Kim et al: The treatment of ARDS using ECMO 가용이하여과환기에의한기계환기유발폐손상을줄일수있다 15. 중증급성호흡곤란증후군환자 90명을대상으로 Bein 등 17 은 ila (interventional lung assist, NovaLung R GmbH, Hechingen, Germany) 에대한연구에서좋은효과를보고하였고, Zimmermann 등 18 은 ila의적용은일회환기량 (Tidal volume) 과흡기고평부압 (Inspiratory plateau pressure) 을줄여주고동맥혈이산화탄소의제거로폐보호환기법의중요한도구로사용할수있다고보고하였다. E-CPR (ECMO-Cardiopulmonary Resuscitation) 회복가능한원인을가진병원내심정지환자에서전통적인심폐소생술로자발순환의회복이어려운경우 ECMO 의시행은성인과소아모두에서생존율을향상시킨다고보고되고있다 19,20. 최근 Taiwan 의연구에서는 E-CPR 을시행한경우일반적인심폐소생술을시행한환자에비해생존퇴원율, 30일생존율, 1년생존율이유의하게높음을보고하였다 19. 최근한메타분석은심정지후 ECMO 를시행한환자에서 ECMO이탈율은 49.6%, 생존퇴원율이 40% 에이른다고보고하고있다 년 Extracorporeal Life Support Organization (ELSO) 자료는 E-CPR생존율은성인환자에서 29%, 소아및신생아에서는 38 39% 로보고하고있다 11. E-CPR 환자에서생존율향상과관련된인자는짧은 CPR지속기간, 초기진단이심장질환인군, 병원내심정지, 회복가능한심정지원인, 관상동맥우회로조성술을받을수있는심정지원인, ECMO 시행전젖산산증이없거나신부전, 다발장기부전, 신경학적장애등과같은 ECMO 합병증이없었을때이다 22. Bridge to Lung Transplantation 1987 년성공적인폐이식보고이후, 최근에는 ECMO 가폐이식대기중호흡부전발생시이식전치료로사용되고있고 23,24, 이식전호흡부전발생환자에있어서기계환기에의한부정적인결과를피하기위한노력의하나로사용되고있다 25. 최근 Mason 등의 2010년보고와피츠버그 2011년보고에따르면수술전 ECMO를시행한군이이식후초기사망률은높으나장기생존율에있어서는시행하지않은군 과비슷한것으로보고하였다 26,27. 하지만또다른연구에서는말기호흡질환을가진선택적인환자군에서폐이식에대한교량치료로 ECMO 를이용했을때단기생존율의향상을보여줬다고보고하였다 28. V-V ECMO 환자의관리 1. Lung protective ventilation 급성호흡부전환자에서폐휴식 (lung rest) 을위해 ECMO 를시행하는경우인공호흡기설정은폐보호환기가바람직하다. 폐보호환기를위해서최고흡기압 (peak inspiratory pressure) 을 cm H 2 O, 호기말양압 (positive end-expiratory pressure, PEEP) 을 cm H 2 O, 호흡은분당 10회, 일회환기량 (tidal volume) 은 4 ml/kg 로낮게설정하면서산소농도 (FiO 2 ) 는 30% 정도까지낮추어설정한다 3. 동맥혈산소포화도 80% 가되어도, 의식상태가명료하거나혹은 lactate 등이안정적으로유지된다면 V-A ECMO로변경할필요는없다. 또한필요시혈중산도 (ph) 가유지되는범위내에서고이산화탄소혈증 (permissive hypercapnia) 은허용할수있다. 환자를되도록이면최소한의진정으로의식상태를유지하는것이추천되며, 조기기관절개술을통한호흡치료가도움이될것이다. 2. Anticoagulation 헤파린사용은도관, 튜브, 산화기등의혈전형성과말초기관손상을예방하기위해필요하나적정용량은확립되어있지않다. ACT secs 혹은 aptt secs, 혈소판 8만이상, 그리고 Hemoglobin 10 g 정도가적정하다 10. 최근에는이전의단점을극복한미세섬유폴리메틸펜틴막 (microfiber, microporous polymethylpentene membrane) 을이용한산화기들이개발되어효과적인가스교환능을가지면서 4주이상의장기간사용이가능하게되었고 Quadrox, MEDOS, Novalung, Dideco 등의산화기들이사용중이다 29,30. 또한산화기내부에헤파린코팅을시행하여생체적합성을향상시키고, 혈류에대한저항이낮아혈구파괴를최소화함으로써출혈및혈전형성에대한합병증을줄일수있을것으로기대한다. 3. Complication 출혈은 ECMO시술중에발생하는중요한합병증중의하나로환자의응고장애나혈소판수에비례하여나타나며다량의수혈을필요로하는경우가많고생명을위협하 4

5 Tuberculosis and Respiratory Diseases Vol. 72. No. 1, Jan 는경우도있다. 도관삽입부출혈이흔히발생하며, 보다심각한위궤양출혈, 뇌출혈등으로인해환자가사망하는경우도있으며, 출혈이발생하는경우이를해결하기가어려운경우도많다 13,31. 또한, ECMO 자체도응고장애를초래한다. 응고인자의소모와희석뿐만아니라회로와의접촉으로인해섬유소용해계가활성화되고 32, 혈소판이섬유소원표면에부착, 활성화되어결과적으로혈소판응집을초래하고혈소판수를감소시킨다 33. 최근에는헤파린코팅된회로를사용하여적혈구파괴 34, 보체계 35 와과립구활성화 36 를감소시키려는노력과함께 Dipyridamole이나저용량아스피린을사용하는혈소판보호기법과 aprotinin 주입을통해과도한섬유소분해를막으려는시도들이되고있어출혈합병증을 81% 에서 9% 까지낮췄다는보고가있다 37. 이외에도출혈합병증을줄이기위해항섬유소용해제인 aminocaproic acid (Amicar; Xanodyne Pharmaceuticals, Newport, KY, USA) 와 tranexamic acid (Cyklokapron; Pharmacia & UpJohn Inc., Somerset Count, NJ, USA) 등도사용되고있으나 38, BART (Blood conservation using antifibrinolytics: A randomized trial) study 39 나다기관전향적임상시험 40 등에서는출혈을줄인다는명확한결론은얻지못했다. 최근사용되고있는 Nafamostat mesilate 은합성단백분해효소억제제로출혈위험이있는혈액투석환자에서널리사용되는항응고제로매우짧은반감기 (8분) 를가지고있어최근에는 ECMO 영역에서도많이활용되고있다. 용혈은잘알려진합병증중의하나로 5 8% 에서발생하며혈장유리혈색소 (plasma free hemoglobin) 를주기적으로확인해야하며 0.1 g/l 이상시용혈을의심해야한다. 이외에도도관삽입한하지의허혈, 공기색전증, 혈전색전증과기계적인합병증인교환이필요한산화기장애, 튜브파열, 펌프기능부전, 도관관련문제등이발생할수있다. 4. ECMO Weaning ECMO 이탈에대한표준화된방법과기술은없다. V-V ECMO의경우 ECMO회로를통한가스순환을변경하여산화기의 FIO 2 <30% 나회로의순환율이 2 L/min 이하에서가스교환이원활하다면이탈이가능하다. V-A ECMO 의경우심장기능의회복을나타내는요인에는혈압상승, 동맥압파형박동성의회복이나증가, 심장기능회복에따라불충분하게산화된혈액의증가로인한 우측요골동맥의 PO 2 감소, 중심정맥압과폐정맥압의감소등이다. 이때는 ECMO 의순환을감소시켜본래의심장기능을확인하면서낮은 ECMO순환량에따른울혈과혈전형성예방을위해헤파린용량을증가시켜야한다 10. 향후방향 최근기술적인측면의향상과다양한산화기, 펌프등의개발로인해 ECMO 시술이활발해졌고적용범위도다양해졌지만출혈, 감염및혈관손상을비롯한많은중요합병증이여전히높은것이현실이다. 의사및간호사모두 ECMO 기계에대한지식뿐만아니라 ECMO에대한생리학적인이해및이에대한철저한교육없이는환자의성공적인치료가어려운실정이다. 호흡부전에대한이해와 ECMO 에대한경험과지식이점차확장되고, 기계의기술적발전이동반되면서치료결과가점진적으로향상되고적응증도점점넓어지고있다. 잘훈련된인적구성요소로전담중환자실의사, 외과의사및전문간호사로구성된팀이성공의중요요소로생각되며현재많은전향적연구가진행되고있어서그결과가기대된다. 참고문헌 1. de Prost N, Ricard JD, Saumon G, Dreyfuss D. Ventilatorinduced lung injury: historical perspectives and clinical implications. Ann Intensive Care 2011;1: Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175: Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374: Higgins AM, Pettilä V, Harris AH, Bailey M, Lipman J, Seppelt IM, et al. The critical care costs of the influenza A/H1N pandemic in Australia and New Zealand. Anaesth Intensive Care 2011;39: Patroniti N, Zangrillo A, Pappalardo F, Peris A, Cianchi G, Braschi A, et al. The Italian ECMO network experience during the 2009 influenza A(H1N1) pandemic: preparation for severe respiratory emergency out- 5

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untitled 대한중환자의학회지 : 제 25 권제 1 호 Vol. 25, No. 1, March, 2010 / DOI: 10.4266/kjccm.2010.25.1.37 증 례 장기간체외막형산소섭취사용후호전된중증급성호흡곤란증후군 1 예 증례보고 연세대학교의과대학 * 내과학교실호흡기내과, 흉부외과학교실, 폐질환연구소 박병훈 * ㆍ장준 * ㆍ김세규 * ㆍ강영애 * ㆍ손지영 *