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: Rapidly progressive respiratory failure
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):
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 But it has limitations: 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: Clinical hallmarks:
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. 3. Authors of the studies willing to share data and collaborate
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):

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
Guidot DM, Hart CM. Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association. J Investigative Med ; 53:

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 Jul;279(1):L

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 Respir Crit 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 (Nicotinamide Phosphoribosyltransferase)
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:

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:
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:
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:

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

51. No significant difference between the two groups in :
Mortality
ICU days
Ventilator-free days
Organ-failure free days

52. High PEEP trials
Meade MO, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers and high positive end- expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA ; 299:
N=385 No mortality difference. No difference with recruitment maneuvers
Mercat A, et al. Positive end-expiratory pressure setting in adults with aculte lung injury and acutre respiratory distress syndrome: a randomized controled trial. JAMA. 2008; 299:
N=382 No mortality difference

53. But for the sake of argument . . .
Meta analysis of previous trials
N=2299 patients with ARDS or ALI
No difference in hospital mortality overall
Small statistical difference in high PEEP group, specifically in subset with ARDS

55. Prone Position Multicenter RCT 342 patients
Stratified into moderate vs. severe based on PaO2:FIO2 ratio
Primary Outcome:
28 day mortality
Secondary:
6-month mortality
Organ dysfunction
Complication rate from prone positioning
Taccone P, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009; 302:

56. Prone Position Patients randomized into prone vs. supine
Prone patients remained prone for 20 hours/day until
Resolution of ARDS or
End of 28-day study period
Tidal volumes limited to 8cc/kg with max plateau pressures of 30 mmHg

59. Conclusions
Prolonged prone position not associated with survival advantage
No detectable difference in :
28 day mortality
6-month mortality
Ventilator free days
ICU length of stay
The incidence of many of the studied complications were higher in the prone group

60. NMBD Meta-analysis of 3 RCT N= 431 patients
48-hour infusions of cisatracurium in patients with ARDS
Outcomes:
Barotrauma
Duration of ventilation
ICU-acquired weakness
Alhazzanui W, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Critical Care. 2013;17

61. NMB Several previous small trials
#1 – improved oxygenation with continuous cisatracurium infusion
#2 – significant reduction in inflammatory mediators in blood and BAL fluid with patients on cisatracurium
#3 – no difference in crude hospital mortality rates

62. Findings: Cisatracurium infusion for 48 hours:
Reduced risk of death at 28 days
Reduced risk of death at ICU discharge
Reduced risk of death at hospital discharge
Reduced the risk of barotrauma
No effect on the the duration of mechanical ventilation
No effect on the risk of ICU weakness
These findings were strongly significant in terms of mortality reduction

64. Methylprednisolone Trial looking at persistent ARDS
Defined – ARDS of at least 7 days duration
N= 180 patients
Randomized to placebo or solumedrol
Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009; 302:

65. Methylprednisolone Primary – mortality at 60 days Secondary –
Ventilator-free days
Organ-failure free days
Inflammatory mediator levels
Infectious complications
Protocol – 2mg/kg bolus, then 0.5mg/kg Q6 hours for 14 days, then 0.5 mg/kg Q 12 hours for 7 days

66. Conclusions No beneficial effect on hospital mortality rate
Starting steroids 2 weeks or more after onset of ARDS increased mortality at 60 and 180 days

67. Conclusions
Steroids did improve cardiopulmonary physiology variables between days 3 and 7
Steroids increased the number of ventilator-free days, ICU-free days at day 28
Steroid patients were able to breathe without assistance earlier, but were more likely to require resuming of assisted ventilation
There was no difference in length of hospitalization between the two groups

68. Other Steroid Trials
Bernard GR, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. NEJM. 1987; 317:
No mortality difference
Meduri GU, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA ; 280:
Small mortality decrease
Meduri GU, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007: 131:
Slight reduction in duration of mechanical ventilation. No mortality difference

69. The BIG picture: ARDS is a complicated and multi-factoral process
Likely genetic and environmental components
Treatment strategies
Lung protective ventilation – HELPFUL
High PEEP – Likely not helpful, though maybe small benefit in ICU death rate in patients with ARDS
Prone – Likely not helpful,Possibly harmful
NMBD – Probably helpful
Steroids – Likely not helpful
Fluid conservative therapy – Possibly helpful

70. Citations:
1. Matthay M, Ware L, Zimmerman G. The acute respiratory distress syndrome. J Clin Invest. 2012; 122:
2. Rubenfeld MD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest. 2007; 131:
3. ARDS Definition Task Force. JAMA 2012;307:
4.Guidot DM, Hart CM. Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association. J Investigative Med ; 53:
5. Amato MB, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. NEJM ;338:
6. [No Author Listed]. Ventilation with lower tidal columes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. ARDS Network. NEJM. 2000; 342:

71. 7. Brower RG, et al. Higher versus lower positive end-expiratory pressure in patients with the acute respiratory distress syndrome. NEJM. 2004; 289:
8.Curley MA, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA. 2005; 294:
9. Taccone P, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009; 302:
10. Papazian L, et al. Neuromuscular blockers in early acute respiratory distress syndrome. NEJM. 2010; 363:
11.Alhazzanui W, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta- analysis of randomized controlled trials. Critical Care. 2013;17
12. Steinberg KP, et al. Efficacy and safety of corticosteroids for persistent acure respiratory distress syndrome. NEJM. 2006; 354:

72. 13. Meduri GU, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280:
14. Wiedemann HP, et al. Comparison of two fluid-management strategies in acute lung injury. NEJM. 2006;354:
15. Shariatpanahi ZV, et al. Effect of enteral feeding with ginger extract in acute respiratory distress syndrome. J of Crit Care