1. ARDS The Fundamentals

2. Objectives Know the epidemiologic risk factors for ARDS Understand the pathogenesis of lung dysfunction in ARDS Know how to diagnose ARDS Understand the pathophysiology of ARDS Know the principles of management in ARDS Plan mechanical ventilation in ARDS

3. Features of ARDS Definition: clinically defined hypoxemic respiratory failure Causes: multiple Pathophysiology: heterogeneous process mediated by inflammatory pathways Treatment: identify and treat underlying cause and provide supportive care

4. Definition American-European Consensus Conference (1994) Require: –1)Acute onset and persistence of respiratory symptoms –2) Frontal chest radiograph w/bilateral infiltrates –3) No clinical evidence of left atrial hypertension (pulmonary capillary wedge <18 mm Hg) Define: –ALI: P/F ratio <300 mm Hg –ARDS: P/F ratio <200 mm Hg Bernard GR et al., Am J Respir Crit Care Med 1994

5. Problems with the Definition Broad definition that does not address cause What is acute?? Radiology criteria unspecific P/F ratio does not account for PEEP or MAP P/F ratio has not been shown to correlate with the severity of the lung injury, the clinical course, or mortality

6. Epidemiology Mortality decreasing –> 50% in mid 80’s –36% in mid 90’s UpToDate Mortality is still significant

7. Causes Multifactorial Direct Lung Injury –Aspiration / chemical pneumonitis –Infectious PNA –Trauma – contusions, penetrating injury, inhalation injury –Near drowning –Fat embolism Indirect Injury –Inflammation, sepsis –Multiple trauma, burns –Shock, hypoperfusion –Acute pancreatitis –Bypass –Transfusion related

8. Causes: Children Shock, sepsis, drowning seem to be top three In single institution: –Highest incidence (12%) for ARDS was for those with sepsis/viral pneumonia/smoke inhalation/drowning –2.7% of all admissions developed ARDS.

9. Risk Factors of Poor Outcome Clinical –Severity of illness (APACHE) –Other organ involvement, comorbid conditions Specifically liver dysfunction –Sepsis Plasma Markers –Acute inflammation (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 TNF receptors I and II) –Procoagulant activity (Protein C) –Fibrinolytic activity (Plasminogen activator inhibitor-1) Ware LB. Crit Care Med. 2005

10. Early deaths (within 72 hours) are caused by the underlying illness or injury, whereas late deaths are caused by sepsis or multiorgan dysfunction

11. Pathophysiology of ARDS Insult ↓ Activation of inflammatory mediators and cellular components ↓ cytokines (TNF, IL-1, IL-6, IL-8) neutrophil infiltration ↓ damage to capillary endothelial and alveolar epithelial cells

12. Pathophysiology of ARDS Starling forces fall out of balance –Increased in capillary hydrostatic pressure –Diminished oncotic pressure gradient Exudative fluid in both the interstitium and alveoli –impaired gas exchange –decreased compliance –increased pulmonary arterial pressure –Type II pneumocyte damage  decreased surfactant –Loss of aeration (mainly in caudal and dependent lung regions in patients lying supine)

13. A Picture is Worth a Thousand Words?

14. The 3 Pathologic Phases of ARDS Exudative Phase –diffuse alveolar damage Proliferative Phase –pulm edema resolves –myofibroblasts infiltrate the –interstitium –collagen begins to deposit Fibrotic Phase –obliteration of normal lung architecture –diffuse fibrosis and cyst formation

15. Principles of Management Identify and treat underlying process Offer supportive care Improve gas exchange Trial unproven last ditch therapies No effective modalities to intervene the only therapy that has been proven to be effective at reducing mortality in ARDS in a large, randomized, multi-center, controlled trial is a protective ventilatory strategy

16. Supportive Care Sedatives and neuromuscular blockade Hemodynamic management Nutritional support Control of blood glucose levels VAP and other nosocomial infection prevention Prophylaxis against DVT and GI bleeding

17. Sedatives and NMBs improve tolerance of mechanical ventilation decrease oxygen consumption BUT routinely wake patients each day use intermittent doses when possible follow a sedation and analgesia protocol

18. Paralysis: improved oxygenation vs. prolonged neuromuscular weakness multicenter RCT of ARDS patients - N=340 cisatracurium vs. placebo drip x 48 hrs statistically significant decrease in 90-day mortality for subset of patients with P/F < 120 there was no difference in the frequency of ICU-acquired neuromuscular weakness Papazian L, et al. Neuromuscular blockers in early acute respiratory distress syndrome. NEJM. 2010 Sep;363(12):1107-16

19. Hemodynamic Management Decrease oxygen consumption –Because of pulmonary shunting, increasing SvO2 may increase SaO2 –Avoid fever –Avoid anxiety and pain –Avoid excessive use of respiratory muscles Improve oxygen delivery –CO x (SaO2 x Hgb x 1.34)

20. Nutrition ARDS is a catabolic state Use gut when able Avoid overfeeding Keep HOB 30 degrees upright for reflux precautions in intubated patients Arginine: inhibit platelet aggregation, improve wound healing, changes into NO Glutamine: fuel for mucosa, lymphocytes, macrophages PolyUnsaturated Fatty Acids: affect immune balance

21. VAP Pulmonary edema is an excellent growth medium for bacteria Pneumonia is difficult to diagnose Proven strategies –keep HOB elevated –avoid unnecessary antibiotics –good mouth care –wean vent timely –avoid excessive sedation –vent circuit change per protocol –routine vent tubing care

22. Improve Gas Exchange Mechanical ventilator strategies Use of high fractions of inspired oxygen Prone positioning

23. There’s no free lunch!

24. VILI Pulmonary edema –Mechanical ventilation alters the alveolar-capillary barrier permeability Increased transmural vascular pressure Surfactant inactivation Mechanical distortion and disruption of endothelial cells Regional activation of inflammatory cells Lung inflammation –Repetitive opening /collapse of atelectatic lung units –Surfactant alterations –Loss of alveoli-capillary barrier function –Bacterial translocation –Overinflation of healthy lung regions

25. Normal – 5 min – 20 min of 45 cmH 2 O Dreyfuss, Am J Respir Crit Care Med 1998;157:294-323

26. ARDS Network Study

28. ARDS Network Study – Other Findings No difference in their supportive care requirements (vasopressors-IV fluids-fluid balance-diuretics-sedation) ~10% mortality reduction Less organ failures Lower IL-6 and IL-8 levels

29. Physiologic Effects of Hypercapnia Resp –Benefits: Improves oxygenation by Enhancing hypoxic pulmonary vasoconstriction and decreasing intrapulmonary shunting right-shift of oxygen-hemoglobin dissociation curve –Dangers: Low PaO2. For a constant FIO 2, as the PaCO 2 ↑, PAO 2 ↓ (alveolar gas equation). Low pH. (Henderson­Hasselbalch equation) Decreased ventilatory reserve. Small changes in alveolar ventilation  big change in CO2 when unhealthy

30. Physiologic Effects of Hypercapnia Renal: Worsens perfusion by –direct renal vasoconstriction from acidosis and sympathetic-meditated release of NE –But, maintains pH with compensatory bicarb reabsorption CV: Compromises hemodynamics –Sympathetic stimulation with increased CO Increased HR and SV, decreased SVR –Intracellular acidosis of cardiomyocytes –When combined with high PEEP strategy, can lead to severely decreased preload and cardiovascular compromise

31. Permissive Hypercapnia Is it worth it? Early adult ARDS trial showed a reduction in expected mortality of 56% to an actual mortality of 26% Included in adult trauma patients protocol for mechanical ventilation Several pediatric studies showing benefit when used in conjunction with low TV and high PEEP Hickling, CCM, 1994 Nathens, J Trauma, 2005 Sheridan, J Trauma, 1995 Paulson, J Pediatr, 1996

32. PEEP Improves oxygenation by –Increasing end-expiratory lung volume –Recruiting unventilated alveoli –Decreasing perfusion to unventilated alveoli –Improving V/Q matching –Decreasing intrapulmonary shunt

33. PVR Increases at Lung Volumes Below and Above FRC Lung Volume

34. What is adequate PEEP? Measuring P/V curve is not practical clinically. A single inflation P/V curve doesn’t represent whole lung. The P/V curve for the whole lung = sum of multiple regional P/V curves A lot of variation btwn dependent and nondependent lung

35. Recruitment Maneuvers inflating to 40 cm H2O for 15 - 26 seconds Intermittent increase of PEEP Sigh breaths When alveolar recruitment is optimized by increasing PEEP, recruitment maneuvers are either poorly effective or deleterious

36. Proning Proning 7 hrs/day x 10 days Gattinoni, et al AJRCCM 164(9), 1701-11 (2001)

37. Effects from changes in position End expiratory views, PEEP 10 supine  prone  supine Relatively quick change in alveolar gas distribution Gattinoni, et al AJRCCM 164(9), 1701-11 (2001)

38. Proning How does it work? Increases FRC Improves ventilation of previously dependent regions Redistribute tidal volume to atelectatic dorsal region Difference in diaphragm movement: when supine, dorsal and ventral move symmetrically, when prone, dorsal > ventral

39. Mechanical Ventilation Summary Avoid overdistension (limit tidal volume and plateau pressure) Avoid derecruitment (adequate PEEP)

40. Unproven Therapies for Times of Desperation Inhaled vasodilators: iNO Steroids Beta Agonists Surfactant Liquid Ventilation ECMO

41. Role of Nitric Oxide in Lung Injury Optimizes V/Q matching Inhibits neutrophil adhesion Effects on long term lung disease unclear

42. Role of Nitric Oxide in Lung Injury

43. Steroids in ARDS Theoretical anti-inflammatory, anti-fibrotic benefit –Inhibit transcriptional activation of various cytokines –Inhibit synthesis of phospholipase A 2 : cycloxygenase –Reduced prod. of prostanoids, PAF –  fibrinogenesis 2 meta-analyses –High dose methylpred for < 48 hrs (30 mg/kg/d) –In early ARDS  no benefit LEFERING et al CCM 1995 CRONIN et al., CCM 1995

44. Steroids in ARDS Randomized, double-blind, placebo-controlled trial Adult ARDS ventilated for > 7 days without improvement No evidence of untreated infection Randomized: –Placebo –Methylprednisolone 2 mg/kg/day x 14 days, tapered over 1 month Meduri et al, JAMA, 1998

45. Steroids in ARDS By day 10, steroids improved: –PaO 2 /FiO 2 ratios –Lung injury scores –Static lung compliance 24 patients enrolled; study stopped due to survival difference Meduri et al, JAMA, 1998 P< 0.01

46. Steroids in ARDS ARDSNET 2006:354(16) 1671-83 N = 180 Methylpred vs. placebo > 14 days into course Steroids showed no benefit and some potential adverse effects NOT recommended

47. Exogenous Surfactant Multicenter trial-uncontrolled, observational Calf lung surfactant (Infasurf) - intratracheal Immediate improvement and weaning in 24/29 children with ARDS and 14% mortality In several other studies, there is no evidence for sustained benefit from Surfactant administration Wilson et al, CCM, 24:1996 Wilson et al, JAMA, 2005 P = 2T/r

48. Liquid Ventilation Fill the lungs with liquid – Perfluorocarbon: colorless, odorless, inert, high vapor pressure, oxygen rich liquid Anti-inflammatory properties (↓ TNF, IL-1 and IL-8, inhibits neutrophil activation and chemotaxis) Reduces surface tension ↑ surfactant phospholipid synthesis and secretion 2 published adult trials of PLV in ARDS have confirmed its safety but not efficacy over HFOV Hirschl et al JAMA 1996, 275; 383-389 Gauger et al, CCM 1996, 24; 16-24

49. ECMO for Severe Lung Injury Alternative means for gas exchange Allows lung rest May be beneficial in fluid removal High risk/ high cost venture

50. Issues with use of ECMO Is the disease process potentially reversible? –Is there a diagnosis? Are the pre-ECMO therapies harmful? –Can we prevent iatrogenic complications? –Have we created hemodynamic instability? Are there other complicating comorbidities? –Will these increase the risk of ECMO? Requires balancing the risks and benefits

51. Combination Therapies Now to look at RCTs of combination therapies …. Just kidding

52. Summary Clinically defined Multiple causes Mediated by inflammatory pathways Heterogeneous process Identify and treat underlying cause Do no harm Supportive interventions Decrease in ARDS mortality in recent years largely due to improved CCM capabilities rather than ARDS-specific therapies

53. References ARDS Clinical Trial Network. 2006. Comparison of Two Fluid-Management Strategies in Acute Lung Injury. N Engl J Med. 354 (24). pp 2564-75. ARDS Clinical Trial Network. 2006. Pulmonary-Artery versus Central Venous Catheter to Guide Treatment of Acute Lung Injury. N Engl J Med. 354 (21). pp 2213-24. Fan, E., Needham, D.M., Stewart, T.E. Ventilatory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome. 2005. JAMA. 294 (22). pp. 2889-96. Hansen-Flaschen, J., Siegel, M.D. Acute Respiratory Distress Syndrome: Definition; Epidemiology; Diagnosis; and Etiology. 2006. www.utdol.com. Heresi, G.A., Arroligo, A.C., Weidemann, H.P., Matthay, M.A. 2006. Pulmonary Artery Catheter and Fluid Management in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Clin Chest Med. 27. pp 627-628. Marino, P.L. The ICU Book. 3 rd Ed. Lippincott Williams & Wilkins. Philadelphia. pp. 419- 35. Petty, T.L. Acute Respiratory Distress Syndrome: Consensus, Definitions, and Future Directions. 1996. Crit Care Med. 24(4). pp 555-556. Rouby, J-J., Puybasset, L., Nieszkowska, A., Lu, Q. Acute Respiratory Distress Syndrome: Lessons form Computed Tomography of the Whole Lung. 2003. Crit Care Med. 31(4S). pp. S285-95. Weinhouse, G.L., Manaker, S. Swan-Ganz Catheterization: Indications and Complications. 2006. www.utdol.com.