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1 대한내과학회지 : 제 86 권제 5 호 특집 (Special Review) - 중환자의학의최신지견 기계환기로인한폐손상 고려대학교안산병원호흡기내과 김제형 Ventilator-Induced Lung Injury Je Hyeong Kim Division of Pulmonary, Sleep and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea Ventilator-induced lung injury (VILI) is the additional inflammatory damage caused by mechanical ventilation, especially in acute respiratory distress syndrome (ARDS). VILI can induce a systematic inflammatory response, resulting in multiple organ dysfunction syndrome, which is the major cause of death in ARDS patients. The two main mechanisms of VILI are physical stretch injury caused by a high tidal volume and shearing force caused by the reopening and collapse of alveoli in atelectatic lung. Protective ventilation strategies to prevent VILI include low tidal volume ventilation, high positive end-expiratory pressure, prone position ventilation, the alveolar recruitment maneuver, and extracorporeal membrane oxygenation. The clinical support is strongest for low tidal volume ventilation, which should be used in all cases of ARDS. However, its effectiveness might be limited because of the severe spatial heterogeneity of the lung involvement, which cannot completely prevent regional alveolar distension. Although there is insufficient clinical evidence supporting the other strategies, and they are controversial, various strategies other than low tidal volume ventilation should be considered in selected clinical conditions in which they might be effective. (Korean J Med 2014;86: ) Keywords: Acute respiratory distress syndrome; Mechanical ventilation; Ventilator-induced lung injury 서론급성호흡곤란증후군 (acute respiratory distress syndrome, ARDS) 은다양한직 간접적인원인으로인해서폐포- 모세혈관막 (alveolar-capillary membrane) 의투과성이증가하여폐포강내부종액이차고, 활성화된호중구및시토카인으로인 한손상, 계면활성체및응고체계의이상으로인하여산소치료에반응하지않는저산소증및비균질적인급성염증성폐손상이발생하는것이다 [1]. 지난수십년간 ARDS에대한다양한치료적접근과중환자관리에있어서괄목할만한발전이있었음에도불구하고 ARDS 환자의사망률은 40% 정도로매우높다 [2]. 국내에서최근시행된전국적인조사 Correspondence to Je Hyeong Kim, M.D., Ph.D. Division of Pulmonary, Sleep and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan , Korea Tel: , Fax: , chepraxis@korea.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

- The Korean Journal of Medicine: Vol. 86, No. 5, 2014 - 는없지만 2009년 7월한달동안전국 28개대학병원중환자실에 79명의환자들이입원을하고이중 45명이사망을해서 57% 의높은사망률을보인것으로보고되었다 [3].

2 - The Korean Journal of Medicine: Vol. 86, No. 5, 는없지만 2009년 7월한달동안전국 28개대학병원중환자실에 79명의환자들이입원을하고이중 45명이사망을해서 57% 의높은사망률을보인것으로보고되었다 [3]. ARDS 환자들의사망원인에대한분석들에의하면호흡부전보다는다발성장기부전증후군 (multiple organ dysfunction syndrome, MODS) 으로사망하거나 [4] 혹은호흡부전이외에다른장기부전이동반되었을경우에사망률이현저하게높은것으로보고되었다 [5]. ARDS 는다양한원인에의해서발생하고원인에따라개별환자들에게다양한치료가시행된다. 그럼에도불구하고 MODS가주요한사망원인이라는사실은모든 ARDS 환자들에서필수적이고공통적으로시행되는기계환기자체가전신적인염증반응을촉발하고심화시키는데있어서주요한역할을할수있을것이라는가설을제기하였다. 이가설이기계환기로인한폐손상 (ventilatorinduced lung injury, VILI) 으로이후 VILI 및이로인한전신적염증반응증후군 [6] 과다발성장기기능부전 [7,8] 에대한연구가진행되었다. 본론 VILI 의기전 ARDS 환자들의폐는기저부폐포들은심한염증반응으로인한울혈과무기폐가발생하고반대편의폐포들은상대적으로정상적이고비균질적인염증반응 (heterogeneous inflammation) 을특징으로한다 [1]. 이런상태에서전통적인기계환기시에설정하는 ml/kg 일호흡량 (tidal volume) 으로기계환기를시행할경우, 비교적정상적인폐포들에는과팽창으로인한물리적인신전손상 (stretch injury) 이발생한다. 그리고울혈과무기폐가발생한기저부의폐포들에서는기계환기로인한호흡주기에따라서허탈과팽창이반복되는전단력 ( 剪斷力, shearing force) 에의한손상이발생하는데, 이두가지손상이 VILI의가장주요한기전이다 [9]. 신전손상으로기흉 (pneumothorax), 종격동기종 (pneumomediastinum), 피하공기증 (subcutaneous emphysema) 등의압력상해 (barotrauma) 와투과성의증가 (permeability alteration), 폐부종 (pulmonary edema), 미만성폐포손상등의용적상해 (volutrauma) 가발생한다. 전단력으로인해서무기폐가발생한부위의폐포가허탈과팽창을반복하는허탈상해 (atelectrauma) 가발생하며이와같은상해과정에서호중구및대식세포, 림프구등의 염증성세포가침윤 활성화되고각종염증성매개물질들이증가하는생체상해 (biotrauma) 가발생한다. 그리고염증성매개물질들은폐조직에국한되지않고손상된폐포- 모세혈관막을통해서전신적으로순환하게되고감염성폐질환의경우에는폐포내의세균도역시전신순환으로이동하게됨으로써패혈증과유사한전신적인염증반응이발생한다. 이와같은전신적염증반응은기계환기로인한흉곽내압력상승으로감소된심박출량때문에저하된장기관류와함께결과적으로 MODS 발생을초래하여환자를사망에이르게한다 [7] 는것이 VILI 및이로인한 MODS의병리기전이다 (Fig. 1) [10]. 폐보호적환기전략 (lung protective ventilation strategy, LPV) LPV란일차적으로 VILI의손상기전들을근거로전통적으로적용하는일호흡량보다적은일호흡량을적용하여, 폐포에직접적으로영향을미치는고원부압력 (plateau pressure) 을제한함으로써압력상해및용적상해의발생을감소시키고, 적절한호기말양압 (positive end-expiratory pressure, PEEP) 을적용하여호기말폐용적을증가시켜허탈상해를방지함으로써 VILI의발생을최소화하고자하는기계환기전략이다 (Fig. 2) [11,12]. 넓은의미로는비균질성을감소시킴으로써 VILI 의발생을최소화하고자하는복와위환기법 (prone position Figure 1. The postulated mechanisms whereby volutrauma, atelectrauma, and biotrauma caused by mechanical ventilation contribute to multiple organ dysfunction syndrome (MODS). Biotrauma is potentially important not only because it can aggravate ongoing lung injury, but also because it can contribute to the development of MODS, possibly through the release of proinflammatory mediators from the lungs [10]

- Je Hyeong Kim. Ventilator-induced lung injury - A Figure 2. Conventional ventilation compared to protective ventilation in a 70-kg patient with ARDS.

3 - Je Hyeong Kim. Ventilator-induced lung injury - A Figure 2. Conventional ventilation compared to protective ventilation in a 70-kg patient with ARDS. (A) Conventional ventilation at a tidal volume of 12 ml per kilogram of body weight and an end-expiratory pressure of 0 cm of water can lead to alveolar over-distention (at peak inflation) and collapse (at the end of exhalation). (B) Protective ventilation at a tidal volume of 6 ml per kilogram limits over-inflation and end-expiratory collapse by providing a low tidal volume and adequate positive end-expiratory pressure [12]. ventilation) 및폐포모집술 (lung recruitment maneuver) 그리고기계환기및고농도의산소로인한폐손상의위험을감소시키고자하는체외막형산소섭취 (extracorporeal membrane oxygenation, ECMO) 등의경우도폐보호적전략이라고할수있다. 저일호흡량환기 (low tidal volume ventilation) 다양한실험실적연구결과들을통해서 VILI의구체적인기전이보고되고, 이를예방하기위한 LPV 전략이개념화된후, 이에대한임상연구들이시도되었다. 1998년 Amato 등 [13] 은무작위임상시험을통해 ARDS 환자에서저일호흡량환기가잠재적인임상적효과가있음을최초로보고하였다. 53 명의환자들을대상으로 12 ml/kg의일호흡량, 낮은 PEEP, mmhg 의이산화탄소분압을목표로하는전통적인환기법 (conventional ventilation) 과 6 ml/kg 이하의일호흡량, 높은 PEEP 및과이산화탄소혈증을허용 (permissive hypercapnia) 하는보호적환기법 (protective ventilation) 의효과를비교하였다. 결과에서보호적환기군에서전통적환기군에비해서 28일사망률이유의하게낮았으며 (38% vs. 71%) 임상적인압력상해의빈도는낮았고기계환기로부터의이탈률은높은것으로나타났다. 그러나거의같은시기에보고된다른임 B 상연구들에서는저일호흡량환기가 ARDS 환자들에미치는임상적영향은없는것으로나타나 [14-16] 저일호흡량환기의임상적효과에대한논란이제기되었다. 이와같은상황에서저일호흡량환기의임상적효과와관련된가장괄목할만한임상연구인 ARDS Network 연구가보고되었다 [17]. 3년간미국내 10여개의다기관에서대규모로시행된연구로 861명의환자들에서 12 혹은 6 ml/kg of predicted body weight의일호흡량을적용한기계환기양식을비교하였다. 결과에의하면저일호흡량환기군에서전통적환기군과비교하여유의하게낮은사망률을보였으며 (31% vs. 39.8%, p = 0.007), days without breathing assistance, ventilatorfree days, days without failure of nonpulmonary organs or systems 및혈중 interlinte-6의농도등의지표에있어서도저일호흡량환기군에서유의한개선이있어, 저일호흡량환기의임상적근거에있어서국면의전환이발생하였다. 기존의관련연구들에대한코크란리뷰에의하면 [18,19] 비록연구들간의비균질성이있기는하지만 28일및병원사망률이저일호흡량환기군에서현저히감소한것으로분석되었다. 이상의임상연구결과들과체계적문헌고찰결과들을근거로 2012년개정된 Surviving Sepsis Campaign Guideline에서도저일호흡량환기를높은근거수준으로권고하고있다 [20]. 또한최근보고된바에따르면 [21] 수술전호흡기합병증위험도가중등도이상이었던복부수술환자들을대상으로저일호흡량환기를포함한 LPV를시행한결과, 대조군과비교하여폐렴을비롯한급성호흡부전등의주요호흡기합병증을비롯한여러임상지표들이현저하게개선되는것으로나타났다. 따라서저일호흡량환기는 ARDS 환자뿐만이아니라다른이유로기계환기를시행받는환자들에서도기본적이고적극적으로고려해야할기계환기전략이다. 호기말양압 (positive end-expiratory pressure) ARDS에서 high PEEP 의적용은무기폐를예방하고, 허탈된폐포를모집하여산소섭취를증가시킴과동시에반복적이고주기적인폐포의허탈과팽창을감소시킴으로써전단력으로인한 VILI발생을감소시킨다 [22-24]. High PEEP에대한대규모임상시험으로 ARDS Network study (ALVEOLI study) [25], the Lung Open Ventilation trial (LOV trial) [26] 및 the Expiratory Pressure trial (Express trial) [27] 등이수행되었다. 그러나공통적으로 high PEEP 이사망률을개선시키는효과는

4 - 대한내과학회지 : 제 86 권제 5 호통권제 645 호 없었고단지산소섭취, 불응성저산소증 (refractory hypoxemia) 및이로인한사망, rescue therapy의수행빈도, ventilator-free day 및 organ failure-free day만을유의하게감소시키는제한적인효과가있는것으로나타났다. 최근위의세가지연구들에대한메타분석및체계적문헌고찰에의하면 [28] ARDS 환자를포함한전체급성폐손상환자들에서 higher PEEP 이병원사망률을개선하지는못하지만, 심한 ARDS 환자들에서는병원및중환자실사망률을유의하게감소시키고 28일간의 days with unassisted breathing 기간을증가시키는것으로분석되었다. 따라서심한 ARDS 환자들의기계환기에있어서 high PEEP 을적용하는것은적극적으로고려되어야한다. 복와위환기법 (prone position ventilation) 앙와위 (supine position) 로치료받는 ARDS 환자들에서대부분의폐침윤, 울혈및무기폐는폐의기저부 ( 등쪽 ) 에발생한다. 이경우복와위 (prone position) 를취하게되면혈류및환기가상대적으로정상적인폐포로재분배되고분비물의배출이촉진된다. 또한, 심장을포함한종격동조직의무게에의해무기폐가발생하거나호흡운동에제한을받는폐부위가감소된다 [29]. 결과적으로환기-관류균형이개선되고폐의전반적인균질성이증가됨으로써 VILI의발생이감소된다 [30]. 그러나이와같은기전에도불구하고복와위환기의임상적효과에대해서는최근까지도많은논란이있었다. 복와위환기에대한첫번째대규모임상시험은 2001년보고된 Prone-Supine (PS) 연구로 [31] 복와위환기가환자들의사망률에미치는효과는없고, 단지산소섭취및폐역학만을개선하는것으로보고하였다. 하지만저산소증이심하고증증도지표가높은환자들에서는 10일사망률이유의하게감소하는것으로분석되어, 심한 ARDS 환자들에서복와위환기의효과에대한추가적인연구가필요함을시사하였다. 이후다양한임상연구들이시행되었고 [32-40], 이에대한메타분석결과들 [41-44] 에따르면복와위환기가산소섭취는개선하나사망률에미치는영향은없는것으로나타났다. 단지한메타분석 [42] 에서중증도가심한환자들에서사망률이개선되는것으로나타났다. 이와같은상황에서 2009년 PS II 연구 [45] 가보고된다. 기존의 PS 연구 [31] 의연구기간은 ARDS Network 의저일호흡량환기연구 [17] 의기간과거의동일하여 PS 연구에서는 ARDS 환자의사망률을개선시키는효과가있는저일호흡량환기를적용하지못하였다. 그리 고복와위의기간이 10일간하루평균 7시간으로짧았다. 따라서 PS II 연구에서는저일호흡량환기를적용하고기존의다른연구 [37] 에서효과가있을것을것으로알려진, 하루최소 20시간의복와위를 28일의연구기간혹은임상적호전이있을때까지시행하였다. 그리고 PS 연구에서저산소증이심한환자들에서사망률개선이있었다는분석결과를토대로 100 mmhg Pa O2/Fi O2 < 200 mmhg 의중등증및 Pa O2/Fi O2 < 100 mmhg 의중증 ARDS 환자들을대상으로연구를진행하였다. 그러나전체환자에서그리고중등증및중증 ARDS 환자에서복와위가사망률을비롯한임상지표들을개선시키는효과가없는것으로나타났다. 이후 PS, PS II 연구를비롯한기존의여러연구에대한메타분석 [46] 이보고되는데, 전체환자및 Pa O2/Fi O2 100 mmhg 인환자들에서는효과가없었지만 Pa O2/Fi O2 < 100 mmhg 으로저산소증이심한환자들에서는사망률을개선시키는효과가있는것으로분석되었다. 이런상황에서 2013년 PROSEVA (Prone Positioning in Severe Acute Respiratory Distress Syndrome) 연구가보고되면서복와위환기에대한임상적근거에있어서국면의전환이생긴다. 이연구에서는 12시간내지 24시간기계환기를시행했음에도불구하고 0.6 이상의 Fi O2, 5 cmh 2O 이상의 PEEP에서 Pa O2/Fi O2 가 150 mmhg 미만으로심한환자들만을대상으로하였다. 또한등록시점을 36시간이내로하여기존의연구들보다조기에복와위환기를시행하였으며 28일까지하루최소 16시간의복와위를유지하였다. 그결과복와위환기군에서 28일및 90일사망률및발관 (extubation) 성공률, 생존자들에서중환자실재원기간및 ventilator-free days가유의하게개선되는것으로나타나중증 ARDS 환자들에서지속적인복와위환기를조기에적용하는것이환자들의사망률을유의하게개선하는것으로보고하였다. 따라서기존의연구들에대한메타분석과 PROSEVA 연구의결과를미루어볼때, 복와위환기는중증 ARDS 환자의치료에있어서반드시고려되어야할치료전략이라고할수있다. 폐포모집술 (lung recruitment maneuver) 폐포모집술이란 transpulmonary pressure를일시적으로증가시킴으로써불안정적으로허탈된폐포를개방시키는역동적과정으로 ARDS에서호기말폐용적을증가시킴으로써폐포를모집할목적으로시행한다. 호기말폐용적의증가는가스교환을촉진하고불안정한폐구역의반복적인개방과

5 - 김제형. 기계환기로인한폐손상 - 허탈을예방함으로 VILI를감소시킨다 [47,48]. 그리고통기된 (aerated) 폐구역을증가시켜상대적으로건강한폐포의선택적인과팽창을감소시킴으로써 VILI를예방한다 [49,50]. 그러나이미통기된폐포의직접적인과팽창을유도하여역설적으로 VILI를증가시킬수도있다 [47-50]. ARDS 에서폐포모집술에대한임상연구들은다양한결과들을보이는데 [51-53], 시행시기 ( 초기혹은후기 ), ARDS의원인 [ 폐 (pulmonary) 혹은폐외 (extrapulmonary)] 등이폐포모집의정도및반응을결정하는주요한결정인자인것으로보고되었다 [54,55]. 또한폐포모집술의방법도효과에영향을미칠수있으며 [56] 가장적정한압력, 기간및빈도에대해서는대규모연구를통해서결정되거나시험된바가없다. 일시적인저혈압과저산소증이가장흔한부작용이며기흉등의압력상해나부정맥및세균의전위 (bacterial translocation) 등이발생할수있다 [51,57]. 폐포모집술과관련된 7개의임상연구들에대한코크란리뷰에의하면 [58] 폐포모집술이사망률, 기계환기의기간및재원기간에미치는영향은명확하지않으며, 동맥혈산소분압을일시적으로상승시키기는하나폐포모집술단독으로산소분압을장기간동안상승시키는지그리고이효과가장기예후에어떤영향을미치는지에대해서는추가적인연구가필요한것으로분석하고있다. 이와같은결과는각환자들에서폐의모집정도 (recruitability) 가다르기때문인것으로추정되는데, ARDS 환자들을대상으로 5 cmh 2O 및 45 cmh 2O의기도압에서전산화단층촬영을시행하여폐의모집정도를측정한결과 [54] 각환자들에서심한편차를보였다. 따라서일률적인폐포모집술을통해서전체 ARDS 환자들에서임상적효과를기대하기는어려울것으로판단된다. 체외막형산소섭취 (extracorporeal membrane oxygenation, ECMO) VILI를예방하는다른방법중의하나는기계환기를피하고대신 ECMO 시행하는것이다 [59]. 적극적인치료에도불구하고 alveolar-arterial oxygen delivery (A-aDO 2) > 600 mmhg 그리고 / 혹은 Pa O2/Fi O2 100 on 100% oxygen을특징으로하는중증 ARDS 환자들은사망의가능성이높고, 기계환기및고농도의산소로인한추가적인폐손상의위험이높아서 ECMO 의고려대상이될수있다. 하지만산소섭취를개선시키고이산화탄소를제거하기는하나생존율이나기계환기의기간은개선시키지못하는것으로보고되었고감염, 출혈 등의위험성이높아일반적인치료로권고되지않는다 [60]. The Extracorporeal Life Support Organization (ELSO) 이보고한바에따르면 [61] 1986년부터 2006년까지호흡부전으로 ECMO 를시행한것으로등록된 1,473명의환자들을분석한결과, 치료를시행한환자들의생존율은 50% 이고환자의나이가많을수록 ECMO 시작전기계환기의기간이길수록급성호흡부전중 ARDS의상병을가진경우및합병증이발생한경우에사망가능성이높은것으로보고하였다. 따라서적절한환자의선택및적절한시기에 ECMO 를시행하는것이환자의예후를결정하는데있어서중요하다. 결 ARDS 환자들의치료에있어서가장중요한발전이라고할수있는것은생명유지에필수적인기계환기자체가환자들의이환과사망률을증가시킬수있다는사실, 즉 VILI 를인지하고이를예방하기위한 LPV를모색하고도입한것이다. 임상적으로 LPV의여러전략중가장근거수준이높은것은저일호흡량환기로모든 ARDS 환자들에서반드시시행되어야한다. 하지만 ARDS 폐의심한비균질성으로인해서저일호흡량환기만으로 VILI의발생을충분히예방하기에는많은제한이있다 [62]. 따라서저일호흡량환기이외에도 high PEEP, 복와위환기, 폐포모집술및 ECMO 등의치료전략들을임상적으로효과가있을수있는환자들에서선택적으로그리고적극적으로적용하려는노력이필요하다. 저일호흡량환기를기본으로하고여러치료전략들을임상상황에맞게적용한다면 VILI의발생을예방하고최소화함으로써 ARDS 환자들의예후를개선할수있을것으로판단된다. 중심단어 : 급성호흡곤란증후군 ; 기계환기 ; 기계환기로인한폐손상 론 REFERENCES 1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342: Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:

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untitled REVIEW ARTICLE 외과중환자에서급성호흡부전증후군 연세대학교의과대학외과학교실, 중환자관리및외상외과 이재길 Acute Respiratory Distress Syndrome in Critically Ill Surgical Patients Jae Gil Lee, M.D., Ph.D. Division of Surgical Critical Care & Trauma,