The Acute Respiratory Distress Syndrome: An update of the current literature

1. The Acute Respiratory Distress Syndrome: An update of the current literature Judson Mehl, DO Tulane University School of Medicine Department of Anesthesiology

2. Key Points • History of acute respiratory distress syndrome (ARDS) in adults • Past and current definitions • Incidence of ARDS • Risk factors for ARDS • Current understanding of pathophysiology • Interventions – what has worked, and what has not • Ongoing research

3. What is ARDS? • A common and life-threatening condition • May be lone insult or complication of: • Critical Illness • Sepsis • Pneumonia • Trauma • Other • Lung inflammation, micro and macroatelectasis, hypoxemia • Ventilator dyssynchrony, frequent barotrauma

4. History: • First recognized as a clinical syndrome in 1967 • Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute Respiratory Distress in Adults. Lancet. 1967; 2(7511):319-323 • Rapidly progressive respiratory failure • Noncardiogenic pulmonary edema • Severe arterial hypoxemia • Requiring mechanical ventilation

5. 1994 American-European Consensus Conference • Simplified definitions • Current treatment strategies • Future research

6. 1994 AECC Consensus Definition: • Definitions based on PaO2/FiO2 ratio • ALI vs. ARDS • Absence of left atrial hypertension • PEEP requirements not considered in stratification

7. AECC • AECC definition has been widely adopted • Allowed for clinical and epidemiologic data gathering on ARDS and ALI • Has led to improved outcomes and better care But it has limitations: • Timing – “acute” undefined • ALI – confusing terminology • Oxygenation – does not account for PEEP • Radiograph criteria – unclear; poor intraobserver reliability • PAWP – High PAWP and ARDS may coexist;

8. The Berlin Definition • JAMA June 2012 • Commissioned by the European Society of Intensive Care Medicine • Endorsed by the American Thoracic Society and Society of Critical Care Medicine • Assess the predictive value of ancillary variables using empirical data • Refine the definition

9. Starting Point: • Conceptual model: • Acute, diffuse inflammatory injury • Increased vascular permeability • Increased lung weight • Loss of aerated lung tissue • Clinical hallmarks: • Hypoxemia • Bilateral chest radiograph opacities • Increased venous admixture • Increased dead space • Decreased lung compliance

10. Consensus proposed changes: • Definition: • 3 mutually exclusive categories: • Mild, Moderate, Severe • Ancillary variables to characterize “severe” • Further empirical evaluation of these variables • Timing – Symptoms within one week of known clinical insult or worsening respiratory symptoms • Chest Imaging – Retained definition of bilateral opacities • Proposed “Severe” variable for emperical evaluation: More extensive opacity (3 or 4 quadrants of the radiograph)

11. Consensus proposed changes: • Pulmonary edema: • PAWP criteria removed from the definition • Patient meets ARDS criteria if they have respiratory failure not fully explained by cardiac failure or volume overload • Oxygenation: • Remove ALI from the definition • Proposed “Severe” variable for emperical evaluation: Minimum PEEP level of 10 cmH20

12. Consensus proposed changes: • Additional Measurements: • Minute Ventilation standardized to a PaC02 of 40 mmHg • Surrogate measure for lung dead space, increased mortality • VECORR = (minute ventilation X (PaCO2)/40) • Respiratory System Compliance • (< 40mL/cm H20)

13. Cohort Assembly • Thorough review of the literature presented at consensus meeting • Study eligibility criteria: • 1. Large, multicenter prospective cohorts or smaller, single-center prospective studies with unique radiologic or physiologic data which enrolled patients meeting the AECC definition of both ARDS and ALI

14. Cohort Assembly • Thorough review of the literature presented at consensus meeting • Study eligibility criteria: • 2. Data collection sufficient to apply the individual criteria of both the Berlin Definition and the AECC Definition • 3. Authors of the studies willing to share data and collaborate • 7 Distinct data sets identified with sufficient information • 4 multi-center clinical studies (Clinical database) • 3 single-center physiologic studies (Physiologic database) • 4188 Patients

15. Variables • 90-day mortality • Ventilator-free days at 28 days following the diagnosis of ALI • Duration of mechanical ventilation • Progression between stages

18. 4 Ancillary Variables • “Severe ARDS” • PaO2/FIO2 ratio of 100 or less • 3 or 4 quadrant opacities on radiograph • PEEP 10cmH20 or higher • CRS less than 40 mL/cm/H2O or . . . • VECORR greater than 10 L/min Would these variables identify a group of patients with higher mortality than the high risk group simplified to : PaO2/FiO2 <100 ?

19. P<.001 comparing mortality across stages of ARDS for draft and final definitions

21. However, • Because the Berlin Definition has just been introduced into clinical practice . . . • The literature which follows will still utilize the nomenclature ALI vs. ARDS under the previously stated AECC definitions.

22. Incidence • Annual incidence ranges 140,000 to 190,000 cases per year in the US adult population • Mortality rate ranges between 26-58% Rubenfeld DG, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005; 353 (16): 1685-1693

23. Across the World:

24. Risk Factors for ARDS • Gastric Aspiration • Sepsis • Trauma • Multiple blood transfusions • Many others suggested • Still being studied

25. Risk Factors • Risk factors for increased mortality • From multicenter epidemiologic cohorts: • Older age • Worse severity of illness • Shock on hospital admission • Increased radiographic opacity • Immunosuppression

26. Emerging research • Role of chronic alcohol abuse • Role of genetics • Role of environmental factors • Treatment strategies

27. Chronic Alcohol Review of several previous articles: Alcoholics more likely to suffer from: trauma pneumonia gastric aspiration sepsis pancreatitis Alcohol is an independent risk factor for development of ARDS Alcohol increases risk for multiorgan dysfunction in association with ARDS • GuidotDM, Hart CM. Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association. J Investigative Med. 2005; 53: 235-245

28. Animal Model • Rats fed 20% ethanol in drinking water for 5 weeks • In ex-vivo lung preparation, ethanol exposed rats had more edema than control rats after induced endotoxemia • Type II alveolar epithelial cells from ethanol-exposed rats had decreased ability to synthesize and secrete surfactant • More susceptible to oxidant-induced cell death when exposed to hydrogen peroxide Guidot DM, et al. Ethanol ingestion via glutathione depletion impairs alveolar epithelial barrier function in rats. Am J Physiol Lung Cell Mol Physiol. 2000 Jul;279(1):L127-35.

29. Animal Model • Alveolar epithelial permeability to radiolabeled albumin was 5x greater in isloates from ethanol-fed rats than the control • Alveolar epithelium from ethanol-fed rats had increased expression of apical sodium channels • Counteract increased paracellular leak • Maintains balance in the absence of further oxidative stress • These compensatory mechanisms are overwhelmed in the face of an inflammatory challenge • Result is proteinaceous fluid leak

30. The role of Glutathione • The role of glutathione depletion in alcohol-induced hepatic injury is well established • The concept of glutathione depletion in lung tissue is novel • Several animal studies demonstrate that ethanol ingestion decreases glutathione levels by • 80% in epithelial lung fluid • 90% in lung epithelial cells • Subsequent studies demonstrate that supplementation of glutathione in the experimental diet prevents ethanol-mediated defects in lung epithelium.

31. Human Correlate • When compared with non-alcoholic controls: • Otherwise healthy alcoholic subjects have dramatically decreased levels of glutathione in lung lavage fluid • These decreases correlate proportionally with that seen in the animal model Moss M, Guidot DM, Wong-Lambertina M, et al. The effects of chronic alcohol abuse on pulmonary glutathione homeostasis. Am J RespirCrit Care Med 2000; 161:414-9

32. To be continued . . . • Studies on glutathione supplementation in alcoholics with ARDS are ongoing

33. Genetics • As with any disease, the genetics of ARDS are complicated • Over 25 separate genes have been identified and studied in regards to clinical outcome • These genes tend to regulate • Inflammation • Coagulation • Endothelial cell function • Reactive oxygen species generation • Apoptosis

34. FAS Genetic Variation • FAS ligand binds to FAS receptor on cell surface • Cascade of inflammation and apoptosis • Increased levels of FAS ligand found in BAL fluid in previous studies • Are genetic polymorphisms of FAS associated with development of ALI?

35. FAS Genetic Variation • 14 FAS polymorphisms evaluated • Healthy controls vs. FACTT patients 3 polymorphisms identified. These halotypes had higher levels of blood FAS mRNA and increased mortality vs. controls

36. Other inflammatory pathways also involved: • FAS is not alone. Other studies have identified associations with ALI/ARDS with deregulated inflammation in other pathways: • NFKBIA (Nuclear Factor of Kappa Light Chain Enhancer in B-Cell Inhibitor) • LTA (lymphotoxin alpha) • MYLK (myosin light chain kinase) • ACE (angiotensin conversion enzyme) • NAMPT (NicotinamidePhosphoribosyltransferase) • Associations shown with mortality, duration of mechanical ventilation

37. Other polymorphisms currently under review: • T-46C polymorphism in the promoter region of Duffy Antigen chemokine receptor (DARC) • Associated with a 17% increase in mortality, specifically in African American patients in ARDS-Network clinical trials • And others: • PPFIA1 shown to increase susceptibility for ALI after major trauma • Polymorphisms in other receptors showed worse outcomes with specific infectious agents: pneumococci, Legionella, virus • Key point: Genetics of both the host and the microbe are likely both highly important in the degree of inflammation and subsequent development of ARDS

38. Pathogenesis • Central concepts: • Dysregulated inflammation • Uncontrolled activation of coagulation pathways • Inappropriate accumulation of leukocytes, platelets • Disrupted alveolar endothelial barriers • Inflammatory mechanisms necessary for pathogen clearance • Controlled vs. excessive • Leukocyte protease release • Generation of reactive oxygen species • Abundant synthesis of chemokines, cytokines • Toll-like receptor engagement

39. Toll-Like receptor: A major player • Pattern-recognition receptor • “Pathogen-associated molecular patterns” • Single-spanning non-catalytic receptor molecule • Highly expressed on macrophages and dendritic cells • Innate immune response activation • Work in tandem with Interleukin-1 receptor

40. Vascular endothelial Cadherin • Adherens protein critical for integrity of endothelial barrier in lung microvasculature • Bonds between proteins • Bonds destabilized by TNF, Thrombin, VEGF, leukocyte signaling molecules and even anti-VE-Cadherin-Ab • Experimental manipulation of the stability of VE-Cadherin bonds alter the leukocyte transmigration through cellular junctions • In LPS challenged mice, stabilization of these bonds decreased BAL protein contend and leukocyte content

41. What do the clinical trials show? • Research focused on: • Lung-protective ventilation • High PEEP • Prone positioning • NMBD • Steroids • Fluid conservative vs. liberal • ECMO • Also, APC, GM-CSF, inhaled beta agonists, nitric, omega-3 FA none of which have showed mortality difference

42. I will present the largest and most thorough of the trials currently published • Again, research relating to treatment of ARDS is a very active and ongoing field

43. Lung-protective ventilation • 861 patients enrolled • Randomized to • 12ml/kg predicted body weight • Plateau pressures up to 50 • 6ml/kg predicted body weight • Plateau pressures up to 30 • Primary outcomes: Mortality prior to discharge • Secondary outcomes: Ventilator-free days through hospital day 1-28 ARDS Definition Task Force. JAMA 2012;307:2526 -2533

44. Enrollment • Patients admitted to ARDS-NET hospitals • PaO2:FiO2 ratio of 300 or less • Bilateral pulmonary infiltrates • No evidence of LA hypertension • PCWP less than 18mmHg (if measured) • Exclusion criteria: • >36 hours since meeting criteria • Pregnant • Less than 18 y.o. • Burns • Increased ICP • Other conditions with estimated 6-month mortality>50%

47. Other LPV trials • Amato MB, et al. Effects of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. NEJM 1998; 338: 347-354 • N=53 Decreased mortality • Villar J, Kacmarek RM, Perez L. A high positive end-expiratory pressure, low tidal volume ventilator strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Critical Care Medicine 2006; 34:1311-1318 • N=103 Decreased mortality

48. High PEEP trials • 549 patients • Meeting ARDS criteria • Randomized to high vs. low PEEP • Ventilator settings per protocol • Brower RG, et al. Higher versus lower positive end-expiratory pressure in patients with the acute respiratory distress syndrome. NEJM. 2004; 289:2104-2112

49. Mean age in the higher PEEP group was significantly higher PaO2:FiO2 in high PEEP group was significantly lower

50. Protocol change after 170 patients enrolled Trial stopped after 549 patients based on pre-determined futility stopping rule