The Acute Respiratory
Distress Syndrome: An update of the
current literature
Judson Mehl, DO
Tulane University School of Medicine
Department of Anesthesiology
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
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
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
 1994 American-European
Consensus Conference
 Simplified definitions
 Current treatment
strategies
 Future research
1994 AECC Consensus Definition:
 Definitions based on PaO2/FiO2 ratio
 ALI vs. ARDS
 Absence of left atrial hypertension
 PEEP requirements not considered in stratification
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;
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
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
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)
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
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)
)
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
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
Variables
 90-day mortality
 Ventilator-free days at 28 days following the diagnosis
of ALI
 Duration of mechanical ventilation
 Progression between stages
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 ?
P<.001 comparing mortality across
stages of ARDS for draft and final
definitions
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.
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
Across the World:
Risk Factors for ARDS
 Gastric Aspiration
 Sepsis
 Trauma
 Multiple blood transfusions
 Many others suggested
 Still being studied
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
Emerging research
 Role of chronic alcohol abuse
 Role of genetics
 Role of environmental factors
 Treatment strategies
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
Guidot DM, Hart CM. Alcohol abuse and acute lung
injury: epidemiology and pathophysiology of a recently
recognized association. J Investigative Med. 2005; 53:
235-245
Alcohol increases risk for
multiorgan dysfunction in
association with ARDS
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
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.
 More susceptible to oxidantinduced cell death when exposed
to hydrogen peroxide
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
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.
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
To be continued . . .
 Studies on glutathione supplementation in alcoholics
with ARDS are ongoing
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
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?
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
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
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
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
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
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
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
 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
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
ARDS Definition Task Force.
JAMA 2012;307:2526 -2533
 Secondary outcomes:
Ventilator-free days through
hospital day 1-28
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%
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
High PEEP trials
 549 patients
 Meeting ARDS criteria
 Randomized to high vs.
low PEEP
Brower RG, et al. Higher versus lower
positive end-expiratory pressure in
patients with the acute respiratory
distress syndrome. NEJM. 2004;
289:2104-2112
 Ventilator settings per
protocol
Mean age in the
higher PEEP group
was significantly
higher
PaO2:FiO2 in high
PEEP group was
significantly lower
 Protocol
change after
170 patients
enrolled
Trial stopped
after 549
patients based
on predetermined
futility stopping
rule
 No significant
difference between
the two groups in :
 Mortality
 ICU days
 Ventilator-free days
 Organ-failure free days
High PEEP trials
 Meade MO, et al. Ventilation strategy using low tidal
volumes, recruitment maneuvers and high positive endexpiratory pressure for acute lung injury and acute
respiratory distress syndrome: a randomized controlled
trial. JAMA. 2008; 299:637-645
 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: 646-655
 N=382 No mortality difference
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
Prone Position
 Multicenter RCT
 342 patients
 Stratified into moderate
vs. severe based on
PaO2:FIO2 ratio
 Primary Outcome:
 28 day mortality
Taccone P, et al. Prone positioning in
patients with moderate and severe acute
respiratory distress syndrome: a
randomized controlled trial. JAMA. 2009;
302:1977-1984
 Secondary:
 6-month mortality
 Organ dysfunction
 Complication rate from
prone positioning
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
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
NMBD
 Meta-analysis of 3 RCT
 N= 431 patients
 48-hour infusions of
cisatracurium in
patients with ARDS
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
 Outcomes:
 Barotrauma
 Duration of ventilation
 ICU-acquired weakness
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
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
Methylprednisolone
 Trial looking at
persistent ARDS
 Defined – ARDS of at
least 7 days duration
 N= 180 patients
Prone positioning in patients with moderate
and severe acute respiratory distress
syndrome: a randomized controlled trial.
JAMA. 2009; 302:1977-1984
 Randomized to
placebo or solumedrol
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
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
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
Other Steroid Trials
 Bernard GR, et al. High-dose corticosteroids in patients with
the adult respiratory distress syndrome. NEJM. 1987;
317:1565-1570
 No mortality difference
 Meduri GU, et al. Effect of prolonged methylprednisolone
therapy in unresolving acute respiratory distress syndrome: a
randomized controlled trial. JAMA. 1998; 280:159-165
 Small mortality decrease
 Meduri GU, et al. Methylprednisolone infusion in early severe
ARDS: results of a randomized controlled trial. Chest. 2007:
131: 954-963
 Slight reduction in duration of mechanical ventilation. No mortality
difference
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
Citations:
 1. Matthay M, Ware L, Zimmerman G. The acute respiratory distress
syndrome. J Clin Invest. 2012; 122:2731-2740
 2. Rubenfeld MD, Herridge MS. Epidemiology and outcomes of acute
lung injury. Chest. 2007; 131:554-562
 3. ARDS Definition Task Force. JAMA 2012;307:2526 -2533
 4.Guidot DM, Hart CM. Alcohol abuse and acute lung injury:
epidemiology and pathophysiology of a recently recognized
association. J Investigative Med. 2005; 53: 235-245
 5. Amato MB, et al. Effect of a protective-ventilation strategy on
mortality in the acute respiratory distress syndrome. NEJM.
1998;338: 347-354
 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;
342:1301-1308
 7. Brower RG, et al. Higher versus lower positive end-expiratory
pressure in patients with the acute respiratory distress syndrome.
NEJM. 2004; 289:2104-2112
 8.Curley MA, et al. Effect of prone positioning on clinical
outcomes in children with acute lung injury: a randomized
controlled trial. JAMA. 2005; 294:229-237
 9. Taccone P, et al. Prone positioning in patients with moderate
and severe acute respiratory distress syndrome: a randomized
controlled trial. JAMA. 2009; 302:1977-1984
 10. Papazian L, et al. Neuromuscular blockers in early acute
respiratory distress syndrome. NEJM. 2010; 363:1107-1116
 11.Alhazzanui W, et al. Neuromuscular blocking agents in acute
respiratory distress syndrome: a systematic review and metaanalysis 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;
354:1671-1684
 13. Meduri GU, et al. Effect of prolonged methylprednisolone
therapy in unresolving acute respiratory distress syndrome: a
randomized controlled trial. JAMA. 1998;280:159-165
 14. Wiedemann HP, et al. Comparison of two fluid-management
strategies in acute lung injury. NEJM. 2006;354:2564-2575
 15. Shariatpanahi ZV, et al. Effect of enteral feeding with
ginger extract in acute respiratory distress syndrome. J of Crit
Care. 2012.