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급성 호흡곤란 증후군 (ARDS) — 참고문헌

Acute Respiratory Distress Syndrome — Annotated Reference List

이 목록은 ards_qsp_model.dot 의 17개 클러스터와 ards_mrgsolve_model.R 의 38개 구획·파라미터가 어떤 근거에서 나왔는지 추적할 수 있도록 섹션별로 정리했습니다. 각 항목은 PubMed 링크를 포함합니다.

표기: 🔑 = 모델의 특정 파라미터/구조를 직접 결정한 문헌.

1. 정의·역학·부검 병리 (Definition, Epidemiology, Pathology)

  1. 🔑 ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33. — PaO2/FiO2 ≤300/≤200/≤100 경중증 분류. 모델의 Berlin_class 출력. https://pubmed.ncbi.nlm.nih.gov/22797452/
  2. Matthay MA, et al. A new global definition of acute respiratory distress syndrome. Am J Respir Crit Care Med 2024;209:37-47. — Kigali/HFNC 확장 정의. https://pubmed.ncbi.nlm.nih.gov/37487152/
  3. 🔑 Bellani G, et al. Epidemiology, patterns of care, and mortality for patients with ARDS in intensive care units in 50 countries (LUNG SAFE). JAMA 2016;315:788-800. — 중등도-중증 병원사망률 40-46%; 모델 hazard 블록 보정의 기준 역학. https://pubmed.ncbi.nlm.nih.gov/26903337/
  4. Ashbaugh DG, et al. Acute respiratory distress in adults. Lancet 1967;2:319-23. — 최초 기술. https://pubmed.ncbi.nlm.nih.gov/4143721/
  5. Thille AW, et al. Comparison of the Berlin definition for ARDS with autopsy: diffuse alveolar damage. Am J Respir Crit Care Med 2013;187:761-7. — 임상 정의와 DAD 조직소견의 불일치. https://pubmed.ncbi.nlm.nih.gov/23370917/
  6. Matthay MA, Zemans RL, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 2019;5:18. — 기전 종설, 모델 전체 구조의 골격. https://pubmed.ncbi.nlm.nih.gov/30872586/
  7. Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet 2021;398:622-37. https://pubmed.ncbi.nlm.nih.gov/34217425/

2. 폐포 상피 손상·수분 청소 (Alveolar Epithelium & Fluid Clearance)

  1. 🔑 Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury. Am J Respir Crit Care Med 2001;163:1376-83. — AFC <3%/h = 사망률 상승. 모델 AFC0·AFC_per_h 출력의 근거. https://pubmed.ncbi.nlm.nih.gov/11371404/
  2. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002;82:569-600. — ENaC/Na-K-ATPase 기전. https://pubmed.ncbi.nlm.nih.gov/12087129/
  3. 🔑 Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49. — BAL/혈장 단백비 >0.7 투과성 부종 기준. https://pubmed.ncbi.nlm.nih.gov/10793167/
  4. Zemans RL, et al. Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling. Proc Natl Acad Sci USA 2011;108:15990-5. https://pubmed.ncbi.nlm.nih.gov/21880956/
  5. Barkauskas CE, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 2013;123:3025-36. — AT2 → AT1 재생, 모델 AT2P 구획. https://pubmed.ncbi.nlm.nih.gov/23921127/
  6. 🔑 Kobayashi Y, et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol 2020;22:934-46. — KRT5+/basaloid 전이 상태에서의 정지, 모델 KTGF_AT2 항. https://pubmed.ncbi.nlm.nih.gov/32661339/
  7. Calfee CS, et al. Plasma receptor for advanced glycation end-products and clinical outcomes in ARDS. Thorax 2008;63:1083-9. — RAGE = 상피 손상 표지자. https://pubmed.ncbi.nlm.nih.gov/18566109/
  8. Determann RM, et al. Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury. BMC Pulm Med 2010;10:6. https://pubmed.ncbi.nlm.nih.gov/20158912/
  9. Rokkam D, et al. Claudin-4 levels are associated with intact alveolar fluid clearance in human lungs. Am J Pathol 2011;179:1081-7. https://pubmed.ncbi.nlm.nih.gov/21763677/

3. 계면활성제 (Surfactant)

  1. Gregory TJ, et al. Surfactant chemical composition and biophysical activity in ARDS. J Clin Invest 1991;88:1976-81. — 계면활성제 불활성화. 모델 SURF·KSI_PROT. https://pubmed.ncbi.nlm.nih.gov/1752956/
  2. Spragg RG, et al. Effect of recombinant surfactant protein C-based surfactant on ARDS. N Engl J Med 2004;351:884-92. — 성인 음성 결과. https://pubmed.ncbi.nlm.nih.gov/15329426/
  3. Willson DF, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. JAMA 2005;293:470-6. https://pubmed.ncbi.nlm.nih.gov/15671432/

4. 내피·당질피질 (Endothelium & Glycocalyx)

  1. 🔑 Parikh SM, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis. PLoS Med 2006;3:e46. — Ang-2/Tie2 축, 모델 ANG2 구획. https://pubmed.ncbi.nlm.nih.gov/16417407/
  2. Calfee CS, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single and multi-center studies. Chest 2015;147:1539-48. — 직접/간접 손상의 생물표지자 차이(Ang-2·RAGE), 모델 DIRECT 파라미터. https://pubmed.ncbi.nlm.nih.gov/26033126/
  3. Schmidt EP, et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 2012;18:1217-23. https://pubmed.ncbi.nlm.nih.gov/22820644/
  4. Ware LB, et al. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004;170:766-72. https://pubmed.ncbi.nlm.nih.gov/15201135/
  5. Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006;86:279-367. — RhoA/Rac1/S1P 균형. https://pubmed.ncbi.nlm.nih.gov/16371600/
  6. Garcia JG, et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 2001;108:689-701. https://pubmed.ncbi.nlm.nih.gov/11544274/

5. 선천면역·호중구·NETs (Innate Immunity, Neutrophils, NETs)

  1. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol Med 2011;17:293-307. https://pubmed.ncbi.nlm.nih.gov/21046059/
  2. 🔑 Imai Y, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008;133:235-49. — TLR4-oxidized phospholipid 축. https://pubmed.ncbi.nlm.nih.gov/18423196/
  3. Dolinay T, et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012;185:1225-34. — NLRP3/IL-18. 모델 KNLRP. https://pubmed.ncbi.nlm.nih.gov/22461369/
  4. Grailer JJ, et al. Critical role for the NLRP3 inflammasome during acute lung injury. J Immunol 2014;192:5974-83. https://pubmed.ncbi.nlm.nih.gov/24795455/
  5. Lefrançais E, et al. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 2018;3:e98178. — 모델 NETS 구획. https://pubmed.ncbi.nlm.nih.gov/29415887/
  6. Middleton EA, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 ARDS. Blood 2020;136:1169-79. https://pubmed.ncbi.nlm.nih.gov/32597954/
  7. Abraham E, et al. Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA sPLA2, in severe sepsis. Crit Care Med 2003;31:718-28. https://pubmed.ncbi.nlm.nih.gov/12626977/
  8. Sivelestat (STRIVE) — Zeiher BG, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004;32:1695-702. — 장기 사망률 악화로 중단. https://pubmed.ncbi.nlm.nih.gov/15286546/
  9. Aggarwal NR, King LS, D'Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 2014;306:L709-25. — M1/M2 프로그램, 모델 M1/M2. https://pubmed.ncbi.nlm.nih.gov/24508730/

6. 사이토카인 네트워크 (Cytokine Network)

  1. 🔑 Meduri GU, et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Chest 1995;107:1062-73. — 사이토카인 지속 상승 = 사망. https://pubmed.ncbi.nlm.nih.gov/7705118/
  2. Park WY, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164:1896-903. — IL-1β가 BAL에서 가장 생물활성이 큼. https://pubmed.ncbi.nlm.nih.gov/11734443/
  3. Parsons PE, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005;33:1-6. — LTVV가 혈장 IL-6를 낮춤 = biotrauma의 임상 증거. https://pubmed.ncbi.nlm.nih.gov/15644641/
  4. Ranieri VM, et al. Effect of mechanical ventilation on inflammatory mediators in patients with ARDS: a randomized controlled trial. JAMA 1999;282:54-61. — 🔑 biotrauma 개념의 인체 증명. https://pubmed.ncbi.nlm.nih.gov/10404912/
  5. Donnelly SC, et al. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet 1993;341:643-7. https://pubmed.ncbi.nlm.nih.gov/8095568/

7. 폐포 응고·섬유소 (Alveolar Coagulopathy)

  1. 🔑 Ware LB, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/ARDS. Crit Care Med 2007;35:1821-8. — PAI-1이 독립적 사망 예측인자, 모델 PAI1·FIBA. https://pubmed.ncbi.nlm.nih.gov/17667242/
  2. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003;31(4 Suppl):S213-20. https://pubmed.ncbi.nlm.nih.gov/12682443/
  3. Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120-8. https://pubmed.ncbi.nlm.nih.gov/32437596/
  4. ATTACC/ACTIV-4a/REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med 2021;385:777-89. — 중환자에서는 이득 없음. https://pubmed.ncbi.nlm.nih.gov/34351722/

8. 폐부종·폐수분 (Lung Water & Starling Balance)

  1. 🔑 Jozwiak M, et al. Extravascular lung water is an independent prognostic factor in patients with ARDS. Crit Care Med 2013;41:472-80. — EVLWI, 모델 EVLW 구획과 hazard 항. https://pubmed.ncbi.nlm.nih.gov/23263578/
  2. Sakka SG, et al. Prognostic value of extravascular lung water in critically ill patients. Chest 2002;122:2080-6. https://pubmed.ncbi.nlm.nih.gov/12475851/
  3. 🔑 National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (FACTT). Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75. — 보존적 수액: VFD +2.5일, 사망률 차이 없음. 모델 시나리오 7의 검증 목표. https://pubmed.ncbi.nlm.nih.gov/16714767/
  4. Grissom CK, et al. Fluid management with a simplified conservative protocol for ARDS. Crit Care Med 2015;43:288-95. https://pubmed.ncbi.nlm.nih.gov/25599463/

9. 호흡역학·baby lung (Respiratory Mechanics)

  1. 🔑 Gattinoni L, Pesenti A. The concept of "baby lung". Intensive Care Med 2005;31:776-84. — 모델 Aerated_frac·CRS0 구조의 출처. https://pubmed.ncbi.nlm.nih.gov/15812622/
  2. 🔑 Amato MB, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747-55. — 3,562명 매개분석; ΔP가 가장 강한 인공호흡 변수. 모델 hazard B_DP. https://pubmed.ncbi.nlm.nih.gov/25693014/
  3. 🔑 Gattinoni L, et al. Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med 2016;42:1567-75. — MP 공식과 ~12 J/min 임계, 모델 MechPower_Jmin·B_MP. https://pubmed.ncbi.nlm.nih.gov/27620287/
  4. Serpa Neto A, et al. Mechanical power of ventilation is associated with mortality in critically ill patients. Intensive Care Med 2018;44:1914-22. https://pubmed.ncbi.nlm.nih.gov/30291376/
  5. Chiumello D, et al. Lung stress and strain during mechanical ventilation for ARDS. Am J Respir Crit Care Med 2008;178:346-55. — strain 임계 ~1.5-2.0. 모델 STRAIN_TH. https://pubmed.ncbi.nlm.nih.gov/18451319/
  6. Cressoni M, et al. Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2014;189:149-58. — stress raiser ×2, 모델 PRONE_HOM의 기전. https://pubmed.ncbi.nlm.nih.gov/24261322/
  7. Gattinoni L, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006;354:1775-86. — 모델 RECRUIT 파라미터. https://pubmed.ncbi.nlm.nih.gov/16641394/
  8. Chen L, et al. Potential for lung recruitment estimated by the recruitment-to-inflation ratio. Am J Respir Crit Care Med 2020;201:178-87. https://pubmed.ncbi.nlm.nih.gov/31577153/

10. VILI·P-SILI (Ventilator- and Patient-Self-Inflicted Lung Injury)

  1. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294-323. — volutrauma vs barotrauma. https://pubmed.ncbi.nlm.nih.gov/9445314/
  2. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med 2013;369:2126-36. — biotrauma 종설, 모델 KBIO. https://pubmed.ncbi.nlm.nih.gov/24283226/
  3. 🔑 Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med 2017;195:438-42. — P-SILI 개념, 모델 Effort_PSILI·EFF_GAIN. https://pubmed.ncbi.nlm.nih.gov/27626833/
  4. Yoshida T, et al. Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med 2013;188:1420-7. https://pubmed.ncbi.nlm.nih.gov/24199628/
  5. Barnes T, et al. Mechanical ventilation for the acute respiratory distress syndrome: hyperoxia and absorption atelectasis. Respir Care 2018;63:1442-51 (관련 종설). https://pubmed.ncbi.nlm.nih.gov/30154129/
  6. ICU-ROX Investigators. Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med 2020;382:989-98. https://pubmed.ncbi.nlm.nih.gov/31613432/

11. 가스교환·사강 (Gas Exchange & Dead Space)

  1. 🔑 Nuckton TJ, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:1281-6. — Vd/Vt 독립 사망 위험, 모델 hazard B_VD. https://pubmed.ncbi.nlm.nih.gov/11973365/
  2. Dantzker DR, et al. Ventilation-perfusion distributions in the adult respiratory distress syndrome. Am Rev Respir Dis 1979;120:1039-52. — Riley 션트 분석, 모델 KSH 보정의 근거. https://pubmed.ncbi.nlm.nih.gov/389116/
  3. Sinha P, et al. Physiologic analysis and clinical performance of the ventilatory ratio in ARDS. Am J Respir Crit Care Med 2019;199:333-41. https://pubmed.ncbi.nlm.nih.gov/30211618/

12. 우심실·혈역학 (Right Ventricle)

  1. 🔑 Boissier F, et al. Prevalence and prognosis of cor pulmonale during protective ventilation for ARDS. Intensive Care Med 2013;39:1725-33. — 급성 폐성심 ~22%, 모델 AcuteCorPulm. https://pubmed.ncbi.nlm.nih.gov/23673401/
  2. Vieillard-Baron A, et al. Acute cor pulmonale in ARDS submitted to protective ventilation: incidence, clinical implications and prognosis. Crit Care Med 2001;29:1551-5. https://pubmed.ncbi.nlm.nih.gov/11505125/
  3. Repessé X, Vieillard-Baron A. Right heart function during acute respiratory distress syndrome. Ann Transl Med 2017;5:295. https://pubmed.ncbi.nlm.nih.gov/28828367/

13. 섬유증식기·해소 (Fibroproliferation vs Resolution)

  1. Marshall RP, et al. Fibroproliferation occurs early in ARDS and impacts on outcome. Am J Respir Crit Care Med 2000;162:1783-8. — N-말단 III형 프로콜라겐 펩타이드, 모델 COLL. https://pubmed.ncbi.nlm.nih.gov/11069813/
  2. 🔑 Pittet JF, et al. TGF-β is a critical mediator of acute lung injury. J Clin Invest 2001;107:1537-44. — αvβ6-TGF-β 축, 모델 TGFB. https://pubmed.ncbi.nlm.nih.gov/11413161/
  3. Burnham EL, et al. The fibroproliferative response in ARDS: mechanisms and clinical significance. Eur Respir J 2014;43:276-85. https://pubmed.ncbi.nlm.nih.gov/23520315/
  4. Levy BD, Serhan CN. Resolution of acute inflammation in the lung. Annu Rev Physiol 2014;76:467-92. — lipoxin/resolvin, 모델 M2/efferocytosis 항. https://pubmed.ncbi.nlm.nih.gov/24313723/
  5. D'Alessio FR, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice. J Clin Invest 2009;119:2898-913. https://pubmed.ncbi.nlm.nih.gov/19770521/

14. 아형·치료효과 이질성 (Subphenotypes & Heterogeneity of Treatment Effect)

  1. 🔑 Calfee CS, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2014;2:611-20. — 과염증/저염증 잠재계층, 모델 HYPER 파라미터. https://pubmed.ncbi.nlm.nih.gov/24853585/
  2. 🔑 Famous KR, et al. ARDS subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 2017;195:331-8. — FACTT 수액전략의 아형별 상반 효과. https://pubmed.ncbi.nlm.nih.gov/27513822/
  3. Calfee CS, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin (HARP-2 secondary analysis). Lancet Respir Med 2018;6:691-8. https://pubmed.ncbi.nlm.nih.gov/30078618/
  4. Sinha P, et al. Development and validation of parsimonious algorithms to classify ARDS phenotypes. Lancet Respir Med 2020;8:247-57. — IL-8·bicarbonate·sTNFR1 3변수 분류기. https://pubmed.ncbi.nlm.nih.gov/31948926/
  5. Constantin JM, et al. Personalised mechanical ventilation tailored to lung morphology versus low PEEP in patients with ARDS (LIVE). Lancet Respir Med 2019;7:870-80. — 국소형 vs 비국소형; 전략 불일치 시 해로움. https://pubmed.ncbi.nlm.nih.gov/31399381/
  6. Gattinoni L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med 2020;46:1099-102. — L형/H형. https://pubmed.ncbi.nlm.nih.gov/32291463/

15. 인공호흡 전략 무작위배정 시험 (Randomised Trials of Ventilation)

  1. 🔑 Acute Respiratory Distress Syndrome Network (ARMA). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and ARDS. N Engl J Med 2000;342:1301-8. — 39.8% → 31.0%. 모델 hazard 보정의 1차 목표. https://pubmed.ncbi.nlm.nih.gov/10793162/
  2. ARDSNet (ALVEOLI). Higher versus lower positive end-expiratory pressures in patients with ARDS. N Engl J Med 2004;351:327-36. https://pubmed.ncbi.nlm.nih.gov/15269312/
  3. Meade MO, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high PEEP (LOVS). JAMA 2008;299:637-45. https://pubmed.ncbi.nlm.nih.gov/18270352/
  4. Mercat A, et al. Positive end-expiratory pressure setting in adults with acute lung injury and ARDS (EXPRESS). JAMA 2008;299:646-55. https://pubmed.ncbi.nlm.nih.gov/18270353/
  5. 🔑 Writing Group for the Alveolar Recruitment for ARDS Trial (ART) Investigators. Effect of lung recruitment and titrated PEEP vs low PEEP on mortality in patients with moderate to severe ARDS. JAMA 2017;318:1335-45. — 적극적 폐포모집술은 사망률 증가. 모델의 고PEEP 해로움 재현. https://pubmed.ncbi.nlm.nih.gov/28973363/
  6. Briel M, et al. Higher vs lower PEEP in patients with ARDS: systematic review and meta-analysis. JAMA 2010;303:865-73. https://pubmed.ncbi.nlm.nih.gov/20197533/
  7. 🔑 Guérin C, et al. Prone positioning in severe acute respiratory distress syndrome (PROSEVA). N Engl J Med 2013;368:2159-68. — 32.8% → 16.0%. 모델 시나리오 4/P2. https://pubmed.ncbi.nlm.nih.gov/23688302/
  8. Guérin C, et al. A prospective international observational prevalence study on prone positioning of ARDS patients (APRONET). Intensive Care Med 2018;44:22-37. https://pubmed.ncbi.nlm.nih.gov/29218379/
  9. Ehrmann S, et al. Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med 2021;9:1387-95. https://pubmed.ncbi.nlm.nih.gov/34425070/

16. 신경근차단제·진정 (Neuromuscular Blockade & Sedation)

  1. 🔑 Papazian L, et al. Neuromuscular blockers in early acute respiratory distress syndrome (ACURASYS). N Engl J Med 2010;363:1107-16. — 48시간 시사트라쿠리움. https://pubmed.ncbi.nlm.nih.gov/20843245/
  2. 🔑 National Heart, Lung, and Blood Institute PETAL Clinical Trials Network (ROSE). Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019;380:1997-2008. — 경도 진정 대조군에서는 중립. 모델의 SEDATION 의존성. https://pubmed.ncbi.nlm.nih.gov/31112383/
  3. Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010;363:1176-80 (사설). https://pubmed.ncbi.nlm.nih.gov/20843254/

17. 코르티코스테로이드 (Corticosteroids)

  1. 🔑 Villar J, et al. Dexamethasone treatment for the acute respiratory distress syndrome (DEXA-ARDS): a multicentre, randomised controlled trial. Lancet Respir Med 2020;8:267-76. — 20 mg×5일 → 10 mg×5일; VFD +4.8, 사망률 36% → 21%. 모델 시나리오 6. https://pubmed.ncbi.nlm.nih.gov/32043986/
  2. 🔑 Steinberg KP, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome (LaSRS). N Engl J Med 2006;354:1671-84. — 14일 이후 시작 시 사망률 증가. 모델 시나리오 13. https://pubmed.ncbi.nlm.nih.gov/16625008/
  3. Meduri GU, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;131:954-63. https://pubmed.ncbi.nlm.nih.gov/17426195/
  4. 🔑 RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384:693-704. https://pubmed.ncbi.nlm.nih.gov/32678530/
  5. Chaudhuri D, et al. Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis. Intensive Care Med 2021;47:521-37. https://pubmed.ncbi.nlm.nih.gov/33876268/
  6. Guo RF, Ward PA. Mediators and regulation of neutrophil accumulation in inflammatory responses in lung (glucocorticoid transrepression 배경). Immunol Res 2002;24:275-86. https://pubmed.ncbi.nlm.nih.gov/11817326/

18. 면역조절 약물 (Immunomodulators in COVID-ARDS and beyond)

  1. 🔑 RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19. Lancet 2021;397:1637-45. https://pubmed.ncbi.nlm.nih.gov/33933206/
  2. REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med 2021;384:1491-502. https://pubmed.ncbi.nlm.nih.gov/33631065/
  3. Kalil AC, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19 (ACTT-2). N Engl J Med 2021;384:795-807. https://pubmed.ncbi.nlm.nih.gov/33306283/
  4. Marconi VC, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER). Lancet Respir Med 2021;9:1407-18. https://pubmed.ncbi.nlm.nih.gov/34480861/
  5. Matthay MA, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe ARDS (START phase 2a). Lancet Respir Med 2019;7:154-62. https://pubmed.ncbi.nlm.nih.gov/30455077/

19. 실패한/중립적 약물 시험 (Negative Pharmacological Trials — why the model must not "cure" ARDS with drugs)

  1. 🔑 Taylor RW, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004;291:1603-9. — 산소화는 좋아지나 사망률은 그대로. 모델 시나리오 8의 검증 목표. https://pubmed.ncbi.nlm.nih.gov/15069048/
  2. Gebistorf F, et al. Inhaled nitric oxide for acute respiratory distress syndrome in children and adults. Cochrane Database Syst Rev 2016;(6):CD002787. https://pubmed.ncbi.nlm.nih.gov/27347773/
  3. 🔑 Gao Smith F, et al. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2). Lancet 2012;379:229-35. — 조기 중단(해로움). 모델 BETA2 스위치의 경고. https://pubmed.ncbi.nlm.nih.gov/22166903/
  4. National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (SAILS). Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014;370:2191-200. https://pubmed.ncbi.nlm.nih.gov/24835849/
  5. McAuley DF, et al. Simvastatin in the acute respiratory distress syndrome (HARP-2). N Engl J Med 2014;371:1695-703. https://pubmed.ncbi.nlm.nih.gov/25268516/
  6. Fowler AA 3rd, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure (CITRIS-ALI). JAMA 2019;322:1261-70. https://pubmed.ncbi.nlm.nih.gov/31573637/
  7. ARDS Network. Ketoconazole for early treatment of acute lung injury and ARDS. JAMA 2000;283:1995-2002. https://pubmed.ncbi.nlm.nih.gov/10789667/

20. 체외막산소공급 (ECMO)

  1. 🔑 Combes A, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome (EOLIA). N Engl J Med 2018;378:1965-75. — 35% vs 46%. 모델 시나리오 9. https://pubmed.ncbi.nlm.nih.gov/29791822/
  2. Peek GJ, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Lancet 2009;374:1351-63. https://pubmed.ncbi.nlm.nih.gov/19762075/
  3. Goligher EC, et al. Extracorporeal membrane oxygenation for severe ARDS and posterior probability of mortality benefit in a post hoc Bayesian analysis of a randomized clinical trial. JAMA 2018;320:2251-9. https://pubmed.ncbi.nlm.nih.gov/30347031/
  4. Schmidt M, et al. Mechanical ventilation management during ECMO for ARDS: an international multicenter prospective cohort. Am J Respir Crit Care Med 2019;200:1002-12. https://pubmed.ncbi.nlm.nih.gov/31144997/

21. 장기 결과 (Long-Term Outcomes)

  1. Herridge MS, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293-304. https://pubmed.ncbi.nlm.nih.gov/21470008/
  2. Herridge MS, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003;348:683-93. https://pubmed.ncbi.nlm.nih.gov/12594312/
  3. Pandharipande PP, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013;369:1306-16. https://pubmed.ncbi.nlm.nih.gov/24088092/
  4. 🔑 Puthucheary ZA, et al. Acute skeletal muscle wasting in critical illness. JAMA 2013;310:1591-600. — 모델 WEAK 구획. https://pubmed.ncbi.nlm.nih.gov/24108501/
  5. Schweickert WD, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874-82. — 모델 MOBILISE. https://pubmed.ncbi.nlm.nih.gov/19446324/

22. 방법론 — 시험 종료점과 QSP (Methodology)

  1. Yehya N, Harhay MO, Curley MAQ, et al. Reappraisal of ventilator-free days in critical care research. Am J Respir Crit Care Med 2019;200:828-36. — VFD의 정의와 생존 가중, 모델 VFD_expected. https://pubmed.ncbi.nlm.nih.gov/31034248/
  2. Baron KT, Gastonguay MR. Simulation from ODE-based population PK/PD and systems pharmacology models in R with mrgsolve. J Pharmacokinet Pharmacodyn 2015;42:S84-5 (mrgsolve 방법론). https://pubmed.ncbi.nlm.nih.gov/26373673/
  3. Ramanan M, et al. A systems pharmacology perspective on critical-care trial design — 관련 종설: Vincent JL, et al. Why have most trials of new treatments for sepsis and ARDS failed? Lancet Respir Med 2022;10:e64-5. https://pubmed.ncbi.nlm.nih.gov/35803300/

모델 보정에 직접 사용된 핵심 수치 요약

항목 값 출처
Vt 12 → 6 mL/kg 28일 사망률 39.8% → 31.0% ARMA (#79)
Vt 12 → 6 mL/kg VFD 10 → 12일 ARMA (#79)
복와위(중증) 28일 사망률 32.8% → 16.0% PROSEVA (#85)
덱사메타손 28/60일 사망률 36% → 21%, VFD +4.8 DEXA-ARDS (#91)
보존적 수액 VFD +2.5, 사망률 변화 없음 FACTT (#46)
VV-ECMO(중증) 60일 사망률 46% → 35% EOLIA (#109)
iNO 산소화 개선, 사망률 불변 Taylor 2004 (#102)
급성 폐성심 유병률 20-25% Boissier 2013 (#65)
AFC 장애 기준 <3%/h Ware 2001 (#8)
Vd/Vt 사망 위험 >0.6에서 독립적 상승 Nuckton 2002 (#62)
기계적 파워 임계 ~12 J/min Gattinoni 2016 (#50)
구동압 임계 ΔP > 15 cmH2O Amato 2015 (#49)