1. Acute Respiratory Distress Syndrome Jason D. Sciarretta, M.D. Critical Care Conference October 13, 2010

2. History ARDS The syndrome of acute pulmonary failure was recognized during World War I “The acute onset of severe respiratory distress and cyanosis that was refractory to oxygen therapy and associated with diffuse CXR abnormality and decreased lung compliance” “The acute onset of severe respiratory distress and cyanosis that was refractory to oxygen therapy and associated with diffuse CXR abnormality and decreased lung compliance” –Ashbaugh DG. Acute Respiratory distress in Adults. Lancet 1967

3. 3 History ARDS In 1988, Murray: In 1988, Murray: –4 point scoring system: Lung Injury Score (LIS)  PEEP, compliance, CXR, PaO2/FiO2 ratio North American-European Consensus Committee North American-European Consensus Committee –devised of multiple subcommitees: –1994: “Adult” RDS now referred back to “acute” –Study the pathophysiologic mechanisms, prevention & treatment –further defined diagnostic criteria, future studies –1998: severity ARDS should be assessed by the Lung Injury Score or by APACHE Bernard GR et al., Am J Respir Crit Care Med. 1994 Bernard GR et al., Am J Respir Crit Care Med. 1994 Murray JF, et al. Am Rev Respir Dis. 1988;138:720 Artigas A, et al., Am J Respir Crit Care Med 1998

4. 4 Epidemiology 1972 - Incidence US: ~ 150,000 cases/yr 1972 - Incidence US: ~ 150,000 cases/yr “true” incidence defined by LIS lower—1.5 to 8 cases per 100,000 people ARDS Network Study (NAECC definitions), 2003 ARDS Network Study (NAECC definitions), 2003 –Incidence United States: 32 cases per 100,000/y Goss CH et al., ARDS Network, Crit Care Med 2003 10 % ICU admission in US related ARDS

5. ALI v.s. ARDS

6. 6 Lung Injury Score Chest radiographic score 0 No alveolar consolidation 1 Alveolar consolidation in one quadrant 2 Alveolar consolidation in two quadrants 3 three quadrants 4 four quadrants Hypoxemia score 0 PaO 2 /FiO 2 ≥300 1 PaO 2 /FiO 2 225–299 2 PaO 2 /FiO 2 175–224 3 PaO 2 /FiO 2 100–174 4 PaO 2 /FiO 2 <100 Respiratory system compliance score (mL/cm H 2 O) 0 ≥80 1 60–79 2 40–59 3 20–39 4 ≤19 PEEP score (cm H 2 O) 0 ≤5 1 6–8 2 9–11 3 12–14 4 ≥15 Final value 0 No lung injury 1–2.5 Acute lung injury (ALI) 2- >2.5 Severe lung injury (ARDS) Murray JF, et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720

7. 8 ARDS Risk DIRECT - Common: Pneumonia Pneumonia Aspiration Aspiration –Less common Pulmonary contusion Pulmonary contusion Fat emboli Fat emboli Near-drowning Near-drowning Inhalational injury Inhalational injury Reperfusion after lung transplant or pulmonary embolectomy Reperfusion after lung transplant or pulmonary embolectomy INDIRECT Common: Sepsis (40%) Sepsis (40%) Severe trauma Severe trauma Shock Shock - Less Common: - Less Common: Multiple transfusions Multiple transfusions Cardiopulmonary bypass Cardiopulmonary bypass Drug overdose Drug overdose Burns Burns Acute pancreatitis Acute pancreatitis Multiple transfusions Multiple transfusions The American-European Consensus Conference on ARDS. Am J Respir Crit Care Med. 1994;149:818. Atabai K, Matthay MA. Thorax. 2000. Estenssoro E et al Crit Care Med 2002 Frutos-Vivar F, et al. Curr Opin Crit Care. 2004.

8. 9 Associated Conditions Shock –Hemorrhagic, Cardiogenic, Septic, Anaphylactic Trauma –Burns, Nonthoracic trauma (especially head trauma), Fat emboli, Lung contusion, Near-drowning Infection –Viral/bacterial/fungal pneumonia, Gram- negative sepsis, TB Inhalation of toxic Gas –Oxygen, smoke, Cadmium, Phosgene NO 2, NH 3, Cl 2 Drug ingestion – Cocaine, Heroin, Methadone, Barbiturates, Ethchlorvynol, Thiazides, Fluorescein, Propoxyphene, Salicylates, Chlordiazepoxide,Colchicine, Dextran 40 Aspiration of Gastric contents and Metabolic Miscellaneous –Pancreatitis, Postcardiopulmonary bypass, Postcardioversion, Multiple transfusions, DIC, Leukoagglutinin reaction, Eclampsia, Air or amniotic fluid emboli, Bowel infarction, Carcinomatosis The American-European Consensus Conference on ARDS. 1994

9. 9 Pathophysiology Neutrophils release inflammatory mediators -->degrading integrity of capillary endothelial cells--->capillary permeability, interstitial edema. Influx of proteinaceous plasma fluid, erythrocytes, and inflammatory cells into the interstitium – destroyed surfactant and type 1 and 2 pneumocyte  Increases alveolar surface tension, thus producing alveolar collapse Asensio J, Trunkey D: Current Therapy Trauma & Surgical Critical Care Civetta: Critical Care,4th edition Chapter 136: Acute Lung Injury & Acute Respiratory Distress Syndrome

10. 10 Stages of ARDS 1. Exudative (acute): 0-4 d 1. Exudative (acute): 0-4 d 2. Proliferative:4-8 d 2. Proliferative:4-8 d 3. Fibrotic:>8 d 3. Fibrotic:>8 d 4. Recovery 4. Recovery

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12. Histologic finding Exudative phase Exudative phase

13. Histologic findings early proliferative stage: type 2 pneumocytic proliferation, widening septa & interstitial fibroblast proliferation. early proliferative stage: type 2 pneumocytic proliferation, widening septa & interstitial fibroblast proliferation. late proliferative stage: extensive fibroblast proliferation: incorporation of the hyaline membranes late proliferative stage: extensive fibroblast proliferation: incorporation of the hyaline membranes

14. Plasma Biologic Markers Predictive of a Poor Outcome Acute inflammation Endothelial injury Epithelial type II cell Adhesion molecule Neutrophil-endothelial interation Procoagulant activity Fibrinolytic activity Ware LB, Crit Care Med. 2005 Ware LB, Crit Care Med. 2005 IL-6, IL-8 vWF antigen Surfactant protein-D Intercellular adhesion molecule (ICAM-1) Soluble TNF receptors I & II (sTNFRI/II) Protein C Plasminogen activator inhibitor-1 5

15. 15 Clinical Progression Phase 1: Acute Injury Normal physical examination and chest radiograph Tachycardia, tachypnea, and respiratory alkalosis develop Phase 2: Latent Period Lasts ~ 6–48 h after injury: remains clinical stable Hyperventilation & hypocapnia persist; mild increase work breathing Minor abnormalities on physical examination and chest radiograph Phase 3: Acute Respiratory Failure Decreased lung compliance: marked tachypnea & dyspnea Diffuse infiltrates on chest radiograph High-pitched crackles heard throughout all lung fields Phase 4: Severe Abnormalities Severe hypoxemia unresponsive to therapy Metabolic and respiratory acidosis lethargy, obtunded Gomez AC: Pulmonary insufficiency in non-thoracic trauma [discussion]. J Trauma. 1968;8:666

16. Radiography

17. Radiography CT scan findings: 74 patient review CT scan findings: 74 patient review –Bilateral abnormalities in almost all the patients, predominantly dependent abnormalities (86%) –Patchy abnormalities (42%) –Homogeneous abnormalities (23%) –Ground-glass attenuation (8%) –Mixed ground-glass appearance and consolidation (27%) –Basilar predominant abnormalities (68%) –Areas of consolidation with air bronchograms (89%) –Tagliabue M, Casella TC, Zincone GE, Fumagalli R, Salvini E. CT and chest radiography in the evaluation of adult respiratory distress syndrome. Acta Radiol. May 1994;35(3):230-4

18. 18 Clinical Risk Factors Predictive of Poor Outcomes Independent predictors repeatedly: higher mortality rates – Severity of the illness –Non-pulmonary organ dysfunction –Comorbid diseases, Sepsis, Liver dysfunction/cirrhosis –Advanced age Other independent risk factors: –Organ transplantation –HIV infection and Immunosuppression –Active malignancy –Mechanisms of lung injury –Barotrauma –Fio2 (High) – Atabai K, Matthay MA. Thorax. 2000. Ware LB. Crit Care Med. 2005. Ferguson ND, et al. Crit Care Med. 2005. 18

19. 19 Management In 1990, Hickling et al.: improved mortality w/ lower than “traditional” Vt ARMA (Acute Respiratory Distress Syndrome Network Low Tidal Volume) trial: – limited Vt & plateau pressures compared to higher values  result: reduction in mortality from 40% to 31% Considered Standard: V t = 6–8 mL/kg ideal body wt & plateau pressure <30 cm H 2 O – Strategy associated with:  PaO2/FiO2 lower  High RR prevented hypercapnia  less organ failures  reduction in IL-6 and IL-8 levels  ~ 10% mortality reduction Hickling KG, et al., Intensive Care Med. 1990;16(6):372–377. ARDS Network. N Engl J Med. 2000. Hough CL, et al., Critical Care Med 2005.

20. 20 Non-Ventilatory Base Strategies Inhaled Nitric Oxide –selectively vasodilates pulmonary capillaries –anti-inflammatory properties Prone Positioning Steroids: ? controversial Further Investigations: –Liquid Ventilation –Surfactant Davis JWDavis JW. et al, J Trauma. 2007 May;62(5):1201-6.

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22. Mortality ARDS mortality rates - 31% to 74% --> 30-58% 1990s ARDS mortality rates - 31% to 74% --> 30-58% 1990s –Variability: difference populations studied & definitions used. –age & etiology of lung injury Main causes of death: nonrespiratory (i.e., die w/, rather than of ARDS). Main causes of death: nonrespiratory (i.e., die w/, rather than of ARDS). Respiratory failure cause of death: 9% to 16% of patients with ARDS. Respiratory failure cause of death: 9% to 16% of patients with ARDS. Early deaths (within 72 hours): underlying illness or injury; Early deaths (within 72 hours): underlying illness or injury; late deaths sepsis or multi-organ dysfunction. late deaths sepsis or multi-organ dysfunction. Frutos-Vivar F, et al. Curr Opin Crit Care. 2004. Vincent JL, et al. Crit Care Med. 2003. Ware LB. Crit Care Med. 2005. 6

23. One-year Outcomes in Survivors of ARDS Persistent functional limitation Extrapulmonary diseases (primarily): Extrapulmonary diseases (primarily): Muscle wasting and weakness Muscle wasting and weakness (corticosteroid-induced & critical-illness-associated myopathy), (corticosteroid-induced & critical-illness-associated myopathy), Intrinsic pulmonary morbidity (5%): Intrinsic pulmonary morbidity (5%): Bronchiolitis obliterans organizing pneumonia Herridge MS, et al. N Engl J Med. 2003. Herridge MS, et al. N Engl J Med. 2003.. 18

24. 24 Long term outcomes Outcomes variable Lung mechanics may return to normal 1 year –gas exchange abnormalities may persist Spirometry normal at 6 months Mild to moderate: Quality of Life 78% patients return to work McHugh LG, et al. Recovery of function in survivors of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1994;150:90. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003;348:683