pissn: 2288 0402 eissn: 2288 0410 Allergy Asthma Respir Dis 4(4):257-263, July 2016 http://dx.doi.org/10.4168/aard.2016.4.4.257 ORIGINAL ARTICLE 소아급성호흡곤란증후군에서의 Berlin 정의 김수연, 김윤희, 설인숙, 김민정, 윤서희, 김경원, 손명현, 김규언 연세대학교의과대학세브란스병원소아과 Application of the Berlin definition in children with acute respiratory distress syndrome Soo Yeon Kim, Yoon Hee Kim, In Suk Sol, Min Jung Kim, Seo Hee Yoon, Kyung Won Kim, Myung Hyun Sohn, Kyu Earn Kim Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea Purpose: The revised Berlin definition (BD) showed better predictive validity for mortality in adults with acute respiratory distress syndrome (ARDS). We examined the validity of BD for pediatric ARDS as compared to the American European Consensus Conference definition (AECCD). Methods: This single-center, retrospective study included 127 patients aged 1 month to 19 years who were admitted to the medical intensive care unit due to acute lung injury (ALI, n = 31) or ARDS (n = 96) using the AECCD. All patient characteristics and mortality rates were compared between the individual severity groups according to the BD and AECCD. Results: Sixty-four patients (50%) died. Mortality rates increased across the severity groups according to both definitions (26% in mild, 42% in moderate, and 75% in severe by the BD [P< 0.001]; 26% in ALI non-ards and 58% in ARDS by the AECCD [P= 0.002]). The mortality risk increased only for severe ARDS (hazard radio for mortality, 2.56; 95% confidence intervals [CI], 1.14 5.78; P= 0.023) after adjusting for confounding factors. The BD better predicted mortality, with an integrated area under the receiver operating characteristic curve (iauc) of 0.651 (95% CI, 0.571 0.725), than the AECCD, with an iauc of 0.584 (95% CI, 0.523 0.637). The pediatric risk of mortality (PRISM) III and pediatric index of mortality 3 scores were significantly different across BD severity groups, whereas only PRISM III scores were different according to the AECCD. Conclusion: The BD applied to children with ARDS. It could be adopted to severity classifications and predict pediatric ARDS mortality better than the AECCD. (Allergy Asthma Respir Dis 2016:4:257-263) Keywords: Acute respiratory distress syndrome, Child, Mortality, Validity 서론 1967년 Ashbaugh 등 1 이최초로급성호흡곤란증후군 (acute respiratory distress syndrome, ARDS) 에대하여기술한이래, 많은임상연구자들에의해새로운정의들이 2-5 제안되었다. 이후보다일관된임상적용을위해 1994년미국과유럽의연구자들에의한 American-European Consensus Conference (AECC) 정의가 6 새로이제정되었으며, 다양한원인에의한폐포 모세혈관투과도증가에따른흉부방사선상의양측성폐침윤및임상적으로급성저 산소성호흡부전 (PaO 2/FiO 2 200 mmhg) 을보이면서좌심방압증가를배제할수있는경우로 ARDS를정의하였다. 급성폐손상 (acute lung injury, ALI) 의개념또한소개되었는데, 이는산소화의지표인 PaO 2/FiO 2 ratio가 300 mmhg 이하인경증의임상스펙트럼으로정의되었다. 이러한 AECC 정의가 ARDS의표준화된정의로사용되면서이를기준으로많은임상연구와치료가진행되었으나, 약 18년의기간동안축적된임상및역학적자료들을통해 AECC 정의에대한제한점 7,8 역시보고된바있어, 2011년 European Society of Inten- Correspondence to: Myung Hyun Sohn http://orcid.org/0000-0002-2478-487x Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-2050, Fax: +82-2-393-9118, E-mail: mhsohn@yuhs.ac *This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2007-0056092 and 2011-0024036). Received: October 13, 2015 Revised: October 19, 2015 Accepted: October 29, 2015 2016 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by nc/4.0/). 257 http://www.aard.or.kr
Allergy Asthma Respir Dis Kim SY, et al. Berlin definition in pediatric ARDS sive Care Medicine 의주관하에국제적자문을통한개정작업을거쳐 ARDS의새로운정의에대한초안이발제되어이를 Berlin 정의 로명명하였다. 이러한 Berlin 정의의초안에대하여대규모성인환자코호트에대한경험적평가를통하여새로운 ARDS의진단기준을확정하였으며저산소증의정도를기준으로경증, 중등중및중증의세개의군으로 ARDS를구분하여정의하였다. 아울러 급성 의기준을 1주일이내로보다명확히하였으며, 최소호기말양압 (positive end-expiratory pressure, PEEP) 을설정함으로써 PaO 2/FiO 2 ratio의측정에있어표준화된기계환기설정을제시하였고, 침습적이고관찰자간신뢰도가낮은폐동맥쐐기압 (pulmonary artery wedge pressure) 의항목을삭제함과동시에심장초음파와같은객관적검사의활용을통한심인성폐부종의배제를권장하였다. 또한, 흉부방사선소견에대한관찰자간일치율의증가를도모하기위한명확한기준및구체적인예시를제공함으로써기존 AECC 정의의제한점을보완하였고, 이러한새로운 Berlin 정의에대하여 AECC 정의와비교하였을때사망률및 ventilatorfree days와기계환기기간에서보다높은예측타당도를확인하였으며 9 국내에도그결과가소개 10 된바있다. 그러나, 현재까지소아를대상으로한보고는미미한실정이다. 소아는성인과구별되는고유한호흡기계의특성을지니고있으며일례로유연한흉곽, 높은기저기도저항, 낮은기능잔기용량 (functional residual capacity), 높은진정요구도 (sedation requirements), 낮은적혈구용적률 (hematocrit) 을보인다. 또한, 발달중인소아의폐는성숙한성인의폐에비하여보다낮은기도압력에서도 ventilator-induced lung injury에취약한경향을보인다. 11 ARDS가복합적인임상증후군을지칭하며소아의 ARDS가역학, 치료및예후에있어성인과차이를보인다는점을고려할때, 이러한새로운 ARDS의정의를소아환자에서평가하는것은반드시필요하다. 본연구에서저자들은 Berlin 정의를소아 ARDS에적용하여, 중증도분류에따른임상적특성과생리학적변수들을비교함과동시에이러한 Berlin 정의가 AECC 정의와견주어소아중환자에서질병의중증도를보다정확하게예측할수있는지에대한예측타당도를비교하고자하였다. 대상및방법 명을통한기저질환유무, 중환자실재원기간, 기계환기일수및생체징후, 입실첫 24시간이내의혈액검사소견을조사하였다. 소아중환자사망률을예측할수있는지표인소아사망률지표 (pediatric index of mortality, PIM) 3과소아사망률위험성 (pediatric risk of mortality, PRISM) Ⅲ 값역시재확인하였다. 또한기계환기시작첫수시간에서최대 24시간이내안정화된설정에서의 PaO 2, PaCO 2, FiO 2, PaO 2/FiO 2 ratio, 일회환기량 (tidal volume), 최고흡기압 (peak pressure) 및 PEEP과같은변수들에대한값을조사하여기본임상양상과중증도를평가하였다. 본연구의모든환자들은최소 5 cmh 2O 이상의 PEEP으로기계환기를적용하였다. 흉부방사선사진은흉수, 무기폐혹을결절등으로충분히설명되지않는양측성폐침윤이확인되는경우를기준으로 2명의저자가판독하였다. 본연구는세브란스병원임상시험윤리위원회의심의를거쳐모든환아들의의무기록을후향적으로조사하였다 ( 승인번호 : 4-2013-0207). 2. 변수와정의 AECC 정의에 6 따라 ALI non ARDS (200 mmhg< PaO 2/FiO 2 300 mmhg) 와 ARDS (PaO 2/FiO 2 200 mmhg) 를정의하였다. 비록본래의 AECC 정의에서는 ARDS를포함하는포괄적개념으로 ALI를제시하였으나, 실제임상영역에서는상대적으로경한저산소증으로지칭하여분석에사용하고있어, 12 보다정확한표현인 ALI non-ards로대신하였다. Berlin 정의에따른 ARDS의분류는다음과같다 : 경증 ARDS (200 mmhg < PaO 2/FiO 2 300 mmhg, PEEP 5 cmh 2O), 중등도 ARDS (100 mmhg < PaO 2/ FiO 2 200 mmhg, PEEP 5 cmh 2O), 중증 ARDS (PaO 2/FiO 2 100 mmhg, PEEP 5 cmh 2O). 9 일차적결과는중환자실치료중사망한경우또는사망하거나체외막산소공급장치 (extracorporeal membrane oxygenation, ECMO) 를거치한경우의합집합 (ECMO/mortality) 으로설정하였다. 실제체외막산소공급장치보조요법을예후가매우좋지않은경우에한하여구제치료로적용하고있는점을 13 반영하여사망에더하여질병의중증도를나타낼수있는결과로사용하였다. 생존자들에서의중환자실재원기간과기계환기치료일수는이차적인결과로분석에이용하였다. 1. 연구대상및자료수집 2009년 1월 1일부터 2014년 2월 28일까지연세대학교신촌세브란스병원내과계중환자실에입실한환자중생후 30일에서 19세미만의 500명의환자를대상으로분석하였다. 이중 127명 (25%) 의환자가 AECC의정의에따라 ALI 또는 ARDS로진단되어본연구에포함되었다. 신생아또는심장질환을동반한경우는제외되었다. 2명의저자가진단당시의연령, 몸무게, 성별, 입실당시의진단 3. 통계분석범주형자료는총수와빈도 (%), 연속형자료는 Kolmogorov- Smirnov test를통하여정규성검정후평균 (± 표준편차 ) 또는중앙값 (median) 과사분범위 (interquartile range) 로나타내었다. 임상자료와생리학적변수들을각각 AECC 정의및 Berlin 정의의중증도분류에따라비교하였다. 비연속변수에대한비교분석은 chisquare test 또는 Fisher exact test를사용하였고, 연속변수에대한 258 http://dx.doi.org/10.4168/aard.2016.4.4.257
김수연외 소아급성호흡곤란증후군에서의 Berlin 정의 Allergy Asthma Respir Dis 분석은 Mann-Whitney U-test와 Kruskal-Wallis H-test를이용하였다. Kaplan-Meier method를통하여생존곡선을측정하였으며, Log-rank test를통하여각생존곡선을비교하였다. 일차결과의분석에단변량 Cox 회귀분석을적용하여위험비율 (hazard ratios [HR], 95% confidence interval [CI]) 을구하였으며단변량분석에서 P<0.05를보이는변수에대하여다변량 Cox 회귀분석을적용하여분석하였다. 또한 ARDS의두정의에서의사망률에대한예측타당도를비교하기위하여시간의존성 (time-dependent) 수신자동작특성 (receiver operating characteristics, ROC) 곡선과 ROC 곡선아래면적 (area under the curve, AUC) 을활용하였다. 추적관찰의전기간동안에걸친 AUC의가중평균값인 integrated area under the curve (iauc) 는각정의의예측지표로서의분별력을반영하며그값이높을수록전반적인예측타당도가높음을의미한다. 14 이러한시간의존성수신자동작특성곡선통계는 R ver. 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria) 을, 이외의모든통계분석은 IBM SPSS Statistics ver. 20.0 (IBM Co., Armonk, NY, USA) 를이용하였으며 P 값이 0.05 미만인경우를통계적으로유의한것으로판단하였다. 결과 1. 대상환아의임상적특성 AECC 정의에따라 ALI/ARDS 로진단된 127명의환아를대상으로분석을진행하였다. 모든환아는 Berlin 정의에따른 ARDS의진단기준을동시에충족하였다. 대상환자의연령은중앙값 4.1 (1.7 10.5) 세였으며, 79명 (62%) 이남자였다. 64명이사망하여 50% 의사망률을보였으며 9명 (7%) 이체외막산소공급장치요법을시행받았고, 그중한명이생존하였다. 생존자들중중환자실재원일수는중앙값 11 (8 22) 일, 기계호흡치료일수는중앙값 9 (6 20) 일이었으며중환자실입실 24시간이내의 PRISM Ⅲ 값은 9 (5 15), PIM 3 값은 11.3 (5.3 28.2) 이었다. ARDS의위험인자로는폐렴이 69명 (54%) 으로가장많았고패혈증이 29명 (23%) 으로그뒤를이었다. 주요동반질병으로는신경계질환 (52명, 41%) 과혈액종양질환 (34명, 27%) 을확인하였다 (Table 1). 2. AECC 및 Berlin 정의의중증도분류에따른임상특성의비교환자의임상적인특성과생리학적변수들을 ARDS의각정의에따른중증도분류에따라비교한결과를 Table 2에나타내었다. Berlin 정의에따라 31명 (24%) 의환아가경증 ARDS로분류되었고, 이들은동시에 AECC 정의에서의 ALI non-ards에해당하였다. 나머지 96명중각각 48명 (38%) 이중등도 ARDS와중증 ARDS로분류되었다. 체외막산소공급장치요법을시행받은경우는모두 Table 1. Patient demographics (n= 127) Demographic 중증 ARDS 에해당하였다. 소아에서사용되는대표적인사망지표인 PRISM Ⅲ 와 PIM 3 값 은모두 Berlin 정의에따른중증도분류군간에유의미한차이를 나타내었으나, AECC 정의에따른군간에는 PIM 3 값만유의미한 차이를보였다. Berlin 정의에따른분류에서, PRISM Ⅲ 및 PIM 3 값은경증과중등도 ARDS 군사이에차이를보이지않았으나, 경증 과중증, 중등도와중증 ARDS 군을비교하였을때중증 ARDS 군 에서유의미하게증가하였다. 기계환기와관련된변수들중산소화 (PaO 2/FiO 2) 는 ARDS 각 정의에따른중증도가증가할수록저하되었고 FiO 2 와 PEEP 값은 유의미하게증가하였다. 인공호흡기평균일회환기량역시중증도 의증가에따라증가하였으며중증 ARDS 에서유의미한증가가확 인되었다 (Table 2). Value Age (yr) 4.1 (1.7 10.5) Male sex 79 (62) PRISM III 9 (5 15) PIM 3 11.3 (5.3 28.2) PaO2/FiO2 at the diagnosis 131.7 (82 199.5) Predisposing risk factors of ARDS Pneumonia 69 (54) Sepsis 29 (23) Aspiration 18 (14) Bronchiolitis 4 (3) Others 5 (4) Major comorbidities Neurologic disease 52 (41) Pediatric cancer 34 (27) Outcomes Mortality 64 (50) ECMO/mortality* 65 (51) In survivors (n= 63) ICU length of stay (day) 11 (8 22) Ventilator care duration (day) 9 (6 20) Values are presented as median (interquartile range) or number (%). PRISM III, pediatric risk of mortality III; PIM 3, pediatric index of mortality 3; PaO2, arterial partial pressure of oxygen; FiO2, fraction of inspired oxygen; ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit. *ECMO/mortality, composite variable including both mortality cases and ECMO insertion cases. 사망률은 AECC 정의에따른분류에서 ALI non-ards 의 26% 에비해 ARDS 에서 58% 로높았다. Berlin 정의에따른분류에서는 경증 26%, 중등도 42%, 중등 75% 로확인되었다. 이중경증과중증 ARDS, 중등도와중증 ARDS 의비교에서통계학적으로유의미한 차이가확인되었다. 그러나, 생존자들에대한분석에서는중환자 http://dx.doi.org/10.4168/aard.2016.4.4.257 259
Allergy Asthma Respir Dis Kim SY, et al. Berlin definition in pediatric ARDS Table 2. Clinical characteristics and physiological variables of patients across severity categories using the AECC definition and the Berlin definition Variable AECC definition Berlin definition ALI non-ards (n= 31) ARDS (n= 96) Mild ARDS (n= 31) Moderate ARDS (n= 48) Severe ARDS (n= 48) Age (yr) 4.4 (1.3 9.7) 4.1 (1.8 10.8) 4.4 (1.3 9.7) 4.1 (1.6 11.8) 4.1 (2.0 10.5) Male sex 15 (48) 64 (67) 15 (48) 35 (73) 29 (60) PRISM III 8 (4 13) 10 (6 17) 8 (4 13) 7 (3 13) 12 (8 19), PIM 3 6.3 (4.5 12.7) 15.3 (6.0 30.4)* 6.3 (4.5 12.7) 7.2 (4.8 21.5) 27.5 (9.8 41.0), Ventilatory parameter PaO2/FiO2 236.7 (212.0 270.3) 100.1 (73.0 144.9)* 236.7 (212.0 270.3) 143.8 (128.3 167.1) 73.0 (58.2 86.8), FiO2 0.4 (0.4 0.5) 0.7 (0.6 1.0)* 0.4 (0.4 0.5) 0.6 (0.5 0.6) 1.0 (0.9 1.0), TV/BWt (ml/kg) 6.3 (5.3 6.9) 6.8 (6.1 7.7)* 6.3 (5.3 6.9) 6.5 (6.0 7.2) 7.2 (6.3 8.2) Ppeak 21 (15 25) 25 (20 29)* 21 (15 25) 22 (19 25) 29 (20 32), PEEP 5 (5 5) 7 (5 8)* 5 (5 5) 5 (5 7) 8 (6 10), Primary outcomes Mortality 8 (26) 56 (58)* 8 (26) 20 (42) 36 (75), ECMO/mortality 8 (26) 57 (59)* 8 (26) 20 (42) 37 (77), Secondary outcomes (in survivors) ICU length of stay (day) 11 (8 25) 12 (8 22) 11 (8 25) 10.5 (8 20.8) 20 (8.3 29.5) Ventilator care duration (day) 9 (5 24) 9.5 (6 19.8) 9 (5 24) 9 (6 17) 18 (5.3 26.3) Values are presented as median (interquartile range) or number (%). AECC, American-European Consensus Conference; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; PRISM III, pediatric risk of mortality III; PIM 3, pediatric index of mortality 3; PaO2, arterial partial pressure of oxygen; FiO2, fraction of inspired oxygen; TV, tidal volume; BWt, body weight; Ppeak, peak pressure; PEEP, positive end-expiratory pressure; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit. *ALI non-ards vs. ARDS: P< 0.01. Mild ARDS vs. moderate ARDS: P< 0.01. Mild ARDS vs. severe ARDS: P< 0.01. Moderate ARDS vs. severe ARDS: P< 0.01. Table 3. Multivariate analysis using the Cox model for mortality Variable Hazard ratio 95% Confidence interval P-value Age 0.98 0.93 1.03 0.419 Male sex 1.02 0.59 1.74 0.957 PRISM III 1.01 0.97 1.06 0.553 PIM 3 1.02 1.00 1.03 0.008 Underlying disease Pneumonia 0.91 0.49 1.68 0.753 Sepsis 2.56 1.42 4.60 0.002 Neurologic disease 1.02 0.53 1.97 0.954 Pediatric cancer 2.43 1.16 5.08 0.018 AECC definition ALI non-ards (reference) ARDS 1.73 0.80 3.76 0.166 Berlin definition Mild ARDS (reference) Moderate ARDS 1.17 0.50 2.72 0.725 Severe ARDS 2.56 1.14 5.78 0.023 PRISM III, pediatric risk of mortality III; PIM 3, pediatric index of mortality 3; AECC, American-European Consensus Conference; ALI, acute lung injury; ARDS, acute respiratory distress syndrome. 실재원기간이나기계환기치료기간에있어두정의모두에서중 증도에따른군간유의미한차이를확인할수없었다 (Table 2). 3. 결과분석단변량 Cox 회귀분석결과사망위험도는 Berlin 정의에따른중증도분류중중증 ARDS에서통계학적으로유의미한증가 ( 중등도 ARDS: HR, 1.7; 95% CI, 0.75 3.86; P = 0.205; 중증 ARDS: HR, 4.31; 95% CI, 2.0 9.31; P<0.001) 를나타내었다. 단변량분석에서 P 값이 0.05 미만으로결과와의유의미한연관성이확인된 PRISM Ⅲ 와 PIM 3, 동반기저질환과연령, 성별의임상변수들을보정한다변량분석에서도사망위험도는오직중증 ARDS에서유의미하게증가 (HR, 2.56; 95% CI, 1.14 5.78; P = 0.023) 하였다. 반면, AECC 정의에따른 ARDS군간비교에서는유의미한차이를나타내지않았다 (HR, 1.73; 95% CI, 0.8 3.76; P = 0.166) (Table 3). 체외막산소공급장치를거치한경우를포함한복합변수 (ECMO/mortality) 에대한분석에서도유사한결과를확인할수있었다 (Berlin 정의에따른중증 ARDS: HR, 2.74; 95% CI, 1.22 6.16; P = 0.015; AECC 정의에따른 ARDS: HR, 1.8; 95% CI, 0.83 3.91; P = 0.137). Fig. 1은 AECC 및 Berlin 정의에따른각중증도별분류에서의 Kaplan-Meier 생존곡선을나타낸것이다. AECC 정의에따른분류에서, ALI non-ards 에비하여 ARDS 군에서누적생존율이유의미하게낮은것이확인되었다 (P = 0.004). Berlin 정의에서는경증및중등도 ARDS군사이에서는유의미한차이가없었으나, 중증 ARDS군에서누적생존율의유의미한감소가확인되었다 ( 경증 vs. 중증 ARDS, P<0.001; 중등도 vs. 중증 ARDS, P<0.001) (Fig. 1). 260 http://dx.doi.org/10.4168/aard.2016.4.4.257
김수연외 소아급성호흡곤란증후군에서의 Berlin 정의 Allergy Asthma Respir Dis Cummulative survival 1.00 0.75 0.50 0.25 0 The AECC definition ALI non ARDS vs. ARDS: P=0.004 ALI non ARDS ARDS 0 50 100 150 Follow up time (day) A Cummulative survival 1.00 0.75 0.50 0.25 0 The Berlin definition Mild Moderate Severe Mild vs. moderate: P=0.576 Mild vs. severe: P<0.001 Moderate vs. severe: P<0.001 0 50 100 150 Follow up time (day) B Fig. 1. Kaplan-Meier curves for mortality according American-European Consensus Conference (AECC) and Berlin definition severity classes. Survival according to the AECC (A) and Berlin (B) definition. (A) Solid and dashed lines represent acute lung injury (ALI) non-ards and acute respiratory distress syndrome (ARDS) classes, respectively. (B) Solid, dashed, and dotted lines represent mild, moderate, and severe ARDS, respectively. Significant differences are shown in both definitions (P= 0.004 and P< 0.001, respectively by Log-rank test). 1.0 0.9 0.8 iauc (95% CI) AECC definition: 0.584 (0.523 to 0.637) Berlin definition: 0.651 (0.571 to 0.725) Estimated difference: 0.067 (0.125 to 0.008) AECC definition Berlin definition 도에있어통계학적으로유의미한차이가존재함을나타낸다. 복합변수 (ECMO/mortality) 에대한분석에서도동일하게 Berlin 정의가 iauc 0.659 (95% CI, 0.579 0.737) 로 AECC 정의 (iauc, 0.587 [95% CI, 0.534 0.640]) 에비하여사망률에있어더나은예측타당도를보였다. AUC 0.7 고찰 0.6 0.5 0.4 0 20 40 60 80 Follow up time (day) Fig. 2. Predictive accuracy for mortality: integrated area under the curve (iauc) by follow-up time. Solid and dotted lines represent the American-European Consensus Conference (AECC) definition and Berlin definition, respectively. The Berlin definition had better mortality predictions, with an iauc of 0.651 (95% confidence interval [CI], 0.571 0.725), than the AECC definition, which had an iauc of 0.584 (95% CI, 0.523 0.637). 복합변수 (ECMO/mortality) 에대한분석에서도유사한결과를 확인하였다 (AECC 정의, P = 0.003; Berlin 정의, P<0.001). 추적관찰기간에걸친시간의존성수신자동작특성곡선분석 의결과는 Fig. 2 에나타내었다. iauc 값은 Berlin 정의에서 0.651 (95% CI, 0.571 0.725) 로 AECC 정의에서의 0.584 (95% CI, 0.523 0.637) 보다높았다. 이러한 iauc 값의차이는 0.067 (95% CI, 0.125 to 0.008) 로이는두정의사이에사망률에대한예측타당 본연구에따르면 ARDS에대한 Berlin 정의는사망률에대한높은예측타당도를나타냄과동시에, 여러예후관련지표들과보다높은상관관계를보임으로서소아 ARDS 환아들의임상양상을잘반영하는도구라고할수있다. 특히, 이러한높은예측타당도는중증 ARDS군의도입으로인한것으로생각한다. ARDS는양측폐의급성염증반응으로인하여폐포모세혈관의투과도가증가, 미만성폐포부종과염증성손상에따른저산소성호흡부전을특징으로하는질환으로, 2012년에 Berlin 정의가새로운진단기준으로제안되었다. Berlin 정의는기존 AECC 정의의제한점을보완하여심인성폐부종의감별에있어실제적이고명확한기준을제시하였고, 최소 PEEP값을통한기계환기설정을제안하였으며, 독립된세군으로 ARDS를세분함으로써, 대규모성인코호트를통한임상적분석결과사망률과기계환기요구도에대한기존정의에비해통계학적으로높은예측타당도를확보하였다. 9 그러나기존 AECC 정의에견주었을때통계학적수치의차이가크지않아, 임상적예측도구로서의가치가크지않다는한계점이대두되었으며, 이는실제 AECC 정의에비하였을때진단기준에있어새로운변수의도입이미미하였다는점과도연관된다. 또한, 기존 AECC 정의를적용하였을때, 급성호흡곤란증후군의임 http://dx.doi.org/10.4168/aard.2016.4.4.257 261
Allergy Asthma Respir Dis Kim SY, et al. Berlin definition in pediatric ARDS 상상과해부병리학적소견의일치여부가충분히증명되지못하였던한계점에대하여추가적인연구를통한평가가이루어지지않았다는점도 15,16 한계점으로지적된다. 더욱이, 최근다기관에서진행된, 전향적연구에서 Berlin 정의가사망률에대한예측타당도에있어기존 AECC 정의에비하여유의미한차이를나타내지못한다는보고도 17 발표된바있어, 보다많은환자를대상으로하는추가적인연구에대한필요성역시대두되고있다. 소아환자를대상으로한평가는매우부족한실정이다. 18 ARDS 가복잡한병태생리를아우르는임상적으로다양한경과를보이는증후군임을고려할때, 실제질병상태에대한평가와치료과정에서연령에따른해부학적, 생리학적차이에대한고려가반드시필요하다. 발달과정에있는소아호흡기계의고유한특성에더하여, 소아의 ARDS는역학, 병태생리, 예후및치료에있어성인의 ARDS와분명한차이를나타낸다. 19 현재까지보고된소아 ARDS 의연간유병률은성인에비해낮으나, 20 여전히높은사망률및이환율을보인다. 20 22 연구에따라차이는있으나, 소아 ARDS 환자에서의사망률은 20% 63% 로보고되고있으며, 23,24 최근성인 ARDS 환자에서꾸준한생존율의향상을보이는것과 25,26 대비하여소아를대상으로한문헌에서는이러한경향의보고가드물다. 20,23,24 이러한차이점을반영하여최근소아만을대상으로한 ARDS의새로운정의가 Pediatric Acute Lung Injury Consensus Conference 를통해제시되었다. 27 그러나이역시추가적인연구와공론을통한평가가필요하다. 이번연구에서 ARDS 환자는동일기간내중환자실입실환자들의 25.4% 를차지하였다. 이러한유병률은다른소아 ARDS에대한보고에서확인되는유병률 (0.6% 7.7%) 에비해현저히높은데, 이는외과계중환자실, 심장혈관센터및신생아집중치료실로분산된환자군이제외된것이원인일것으로생각한다. 사망률은 50% 였으며 7% 의환자가체외막산소공급장치요법을시행받았다. 본코호트에서의사망률은최근미국 28 과유럽 20,29 등에서발표된사망률에비하여 2 3배높은수치이다. 실제, 본연구대상환자들중많은수가신경계질환또는혈액종양질환을동반하였으며, 이러한대상환아들의역학적특성이높은사망률과연관되었을것으로추측한다. 동일기간내본내과계중환자실에입실하였던소아환자들의사망률은평균 26% 였으며, 따라서이번연구결과를통해 ARDS가현재까지도중환자실에입실하는소아환자들에있어사망과연관된주요한원인임을확인할수있다. 이번연구에서저자들은사망률과 ECMO/ 사망률의복합변수에대한위험도에대하여 Berlin 정의에따른 ARDS의중증도분류를적용하여 Cox 회귀분석과생존곡선을통해 ARDS군간유의미한차이를확인하였다. 이중오직중증 ARDS군에서통계학적으로유의미한차이가확인되었으며, 경증 ARDS와비교하였을때보정위험도 (adjusted risk) 는사망률및 ECMO/ 사망률에있어각각 2.6, 2.7배로나타났다. 이러한결과는 European Society for Pediatric and Neonatal Intensive Care에서영, 유아를대상으로 Berlin 정의를평가하였던기존의보고 30 와도유사하다. 이에반해, 연관된변수들은보정하여다변량 Cox 분석을통해 AECC 정의에따른 ARDS군을비교했을때에는군간유의미한차이가나타나지않았다. 또한, 두정의의예측타당도를비교하기위하여 iauc 분석을진행한결과, AECC 정의에견주어 Berlin 정의에서통계학적으로유의미한높은예측타당도가확인되었다. PRISM Ⅲ와 PIM 3 값은소아중환자에있어복합적사망예측지표로서널리사용되고있는수치로서, 중환자실입실시의질병의중증도를반영하는생리현상과검사소견을점수화하여반영한값이다. 31,32 Berlin 정의에따른중증도분류에서중증 ARDS 군과비교할때이러한 PRISM Ⅲ와 PIM 3 값이모두유의미한증가를보임을확인할수있었으며, AECC 정의에따른분류에서는오직 PIM 3 값만이유의미한차이를보였다. 이러한결과는 Berlin 정의가임상적인중증도를반영하는예후예측지표와보다강한연관성을보인다는것을의미함과동시에, Berlin 정의가실제중증질환의임상상을보다잘반영할수있는정의임을가리킨다. 또한, 위의통계결과분석에서도중증 ARDS군이이러한예측타당도의차이에기여함을다시확인할수있다. 생존자들에대한분석에서, 중환자실재원기간이나기계환기치료기간에있어서는두정의모두에서중증도에따른 ARDS군간유의미한차이를확인할수없었다. 이러한결과는본연구가후향적으로진행됨으로써, 명확하고구체적이며표준화된기계환기이탈지침이나, 중환자실퇴실기준을확보하지못했다는한계점과도연관되었을것으로생각한다. 이외에도이번연구는몇가지한계점을내포하고있다. 첫째, 본연구는단일기관에서제한된수의환아를대상으로진행되었다. 둘째, 단일기관에서비교적짧은기간동안의환자를대상으로분석을진행하였으나, 기계환기및체외막산소공급장치거치와같은치료에있어표준화된치료지침이결여됨으로써시기에따라치료방법의차이를보일수있으며따라서주요변수들이불완전할수있다는한계를지니고있다. 또한, 이번연구에서는오직단기예후에대한분석만이이루어졌다. 새로운 Berlin 정의가단순예후예측을위한도구가아니며, 호흡부전증후군을보다정확하게정의하기위한진단기준임을상기할때, 폐기능의해부학적, 기능적변화, 동반질환, 또는삶의질과같이 ARDS 환자의장기적치료결과와관련한항목들에대한평가도추가적으로행하여져야할것이다. 마지막으로이번연구가후향적으로진행되었기때문에환자군표본선택에있어편향이있을수있다. 따라서향후에더많은기관의환자를대상으로하여상기의한계점들을보완할수있는전향적인연구가이루어져야할것이다. 262 http://dx.doi.org/10.4168/aard.2016.4.4.257
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