This document summarizes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), including definitions, epidemiology, clinical presentation, predictors of poor outcome, mortality rates, and ventilator-based management strategies. It discusses the 1994 consensus definitions of ALI/ARDS, limitations of these definitions, updated recommendations, and stratification systems. It also describes mechanisms of ventilator-induced lung injury and the importance of limiting tidal volume and pressure to prevent further injury.

1. Acute Lung Injury and ARDS Pierre Moine, MD, PhD Associate Professor of Anesthesiology Department of Anesthesiology Edward Abraham, MD Roger Sherman Mitchell Professor of Pulmonary and Critical Care Medicine Vice Chair, Department of Medicine Head, Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Health Sciences Center

5. Stratification System of Acute Lung Injury GOCA Artigas A, et al. Am J Respir Crit Care Med. 1998. No coexisting disease that will cause death within 5 yr Coexisting disease that will cause death within 5 yr but not within 6 mo Coexisting disease that will cause death within 6 mo 0 1 2 Associated diseases A Unknown Direct lung injury Indirect lung injury 1 2 3 Cause C Lung only Lung + 1 organ Lung + 2 organs Lung +  3 organs A B C D Organ failure O Pao 2 /Fio 2  301 Pao 2 /Fio 2 200 -300 Pao 2 /Fio 2 101 – 200 Pao 2 /Fio 2  100 Spontaneous breathing, no PEEP Assisted breathing, PEEP 0-5 cmH 2 O Assisted breathing, PEEP 6-10 cmH 2 O Assisted breathing, PEEP  10 cmH 2 O 0 1 2 3 A B C D Gas exchange Gas exchange (to be combined with the numeric descriptor) G Definition Scale Meaning Letter

9. Plasma Biologic Markers Predictive of a Poor Outcome Acute inflammation Interleukin(IL)-6, IL-8 Endothelial injury von Willebrand factor antigen Epithelial type II cell molecules Surfactant protein-D Adhesion molecule Intercellular adhesion molecule-1 (ICAM-1) Neutrophil-endothelial interaction Soluble tumor necrosis factor receptors I and II (sTNFRI/II) Procoagulant activity Protein C Fibrinolytic activity Plasminogen activator inhibitor-1 Ware LB. Crit Care Med. 2005.

12. Ventilatory-based Strategies in the Management of ARDS/ALI

13. Positive-pressure Mechanical Ventilation Currently, the only therapy that has been proven to be effective at reducing mortality in ALI/ARDS in a large, randomized, multi-center, controlled trial is a protective ventilatory strategy. Tidal volume and plateau pressure

23. ARDS Network: Improved Survival with Low V T Proportion of Patients Days after Randomization Lower tidal volumes Survival Discharge Traditional tidal values Survival Discharge ARDS Network. N Engl J Med. 2000. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 180 160 140 120 100 80 60 40 20 0

24. ARDS Network: Main Outcome Variables ARDS Network. N Engl J Med. 2000. 0.007 10  11 12  11 No. of ventilator-free days, days 1 to 28 < 0.001 55.0 65.7 Breathing without assistance by day 28 (%) 0.006 12  11 15  11 No. of days without failure of nonpulmonary organs or systems, days 1 to 28 0.43 11 10 Barotrauma, days 1 to 28 (%) 0.007 39.8 31.0 Death before discharge home and breathing without assistance (%) p Value Traditional Vt Low Vt

25. Median Organ Failure Free Days * * * * = 6 ml/kg = 12 ml/kg

33. NIH-NHLBI ARDS Network FiO 2 -PEEP Step Comparison

34. NIH-NHLBI ARDS Network Cause of Lung Injury NHLBI ARDS Clinical Trials Network. N Engl J Med. 2004.

35. NIH-NHLBI ARDS Network Clinical Outcomes 0.0 0.5 1.0 Probability 0 10 20 30 40 50 60 Days after Randomization Lower PEEP, overall survival Higher PEEP, overall survival Higher PEEP, discharge Lower PEEP, discharge NHLBI ARDS Clinical Trials Network. N Engl J Med. 2004.

36. NIH-NHLBI ARDS Network Main Outcome Variables NHLBI ARDS Clinical Trials Network. N Engl J Med. 2004. 0.83 12.3  10.3 12.2  10.4 No. of days not spent in ICU from day 1 to day 28 0.51 11 10 Barotrauma (%) 0.50 13.8  10.6 14.5  10.5 No. of ventilator-free days from day 1 to day 28 0.82 16  11 16  11 No. of days without failure of circulatory, coagulation, hepatic, and renal organs from day 1 to day 28 0.89 72.3 72.8 Breathing without assistance by day 28 (%) 0.48 0.47 27.5 25.1 24.9 27.5 Death before discharge home (%) Unadjusted Adjusted for difference in baseline covariance p value Higher-PEEP group Lower-PEEP group Outcome

42. The ARDS Lungs Rouby JJ, et al. Eur Respir J. 2003. Rouby JJ, et al. Anesthesiology. 2004. Bilateral and diffuse hyperdensities “ White lungs” Bilateral and diffuse x-ray densities respecting lung apices Focal heterogeneous loss of aeration in caudal and dependent lung region Chest x-ray (zero PEEP) Massive, diffuse and bilateral non- or poorly aerated lung regions – No normally aerated lung region Lower lobes massively nonaerated – The loss of aeration involves partially the upper lobes Upper lobes normally aerated despite a regional excess of lung tissue – Lower lobes poorly or non aerated Chest CT scan (zero PEEP) Loss of aeration ++++ Lung recruitment curve Open lung concept ± PEEP <10-12 cmH 2 O Response to PEEP High potential for recruitment Low potential for recruitment Recruitment of non aerated lung unit ± ++++ Risk of overinflation of the aerated lung regions Diffuse Patchy Focal ARDS

43. The ARDS Lungs Gattinoni L, et al. Am J Respir Crit Care Med. 1998. Microvascular congestion Interstitial edema Alveolar collapse Less severe alveolar damage Lung tissue consolidation Severe intra-alveolar damage (Edema, fibrin, collagen neutrophil aggregates, red cells) Pathologic changes ++++ ± Lung recruitment   Intra-abdominal pressure Est,rs  [Est,L  Est,w] Recruitment of previously closed alveolar spaces Est,rs  [Est,L >> Est,w] Stretching phenomena Response to PEEP  /   /  Static elastance of the chest wall Est,w / Static lung elastance Est,L   Static elastance of the total respiratory system Est,rs   End-expiratory lung volume EELV “ Indirect” insult of the lung Secondary extrapulmonary ARDS Direct insult of the lung Primary pulmonary ARDS Early phases of ARDS

44. Respiratory Pressure/Volume (P/V) Curve Healthy subject In normal healthy volunteers, the P/V curve explore the mechanical properties of the respiratory system (lung + chest wall) ARDS RV, Residual volume; FRC, Functional residual capacity; TLC, Total lung capacity; UIP, Upper inflection point; LIP, Lower inflection point. The critical opening pressure above which most of the collapsed units open up and may be recruited - CLIN Compliance of the intermediate, linear segment of the P/V curve Maggiore SS, et al. Eur Respir J. 2003. Rouby JJ, et al. Eur Respir J. 2003.

59. Effect of Prone Positioning on the Survival of Patients with Acute Respiratory Failure Gattinoni L, et al. N Engl J Med. 2001. Kaplan-Meier estimates of survival at six months

64. Conclusions Positive pressure ventilation may injure the lung via several different mechanisms VILI Search for ventilatory “lung protective” strategies Alveolar distension “ VOLUTRAUMA” Repeated closing and opening of collapsed alveolar units “ ATELECTRAUMA” Oxygen toxicity Lung inflammation “ BIOTRAUMA” Multiple organ dysfunction syndrome