The Acute Respiratory Distress Syndrome: An update of the

current literature

Judson Mehl, DOTulane University School of Medicine

Department of Anesthesiology

Key PointsHistory of acute respiratory distress syndrome

(ARDS) in adultsPast and current definitionsIncidence of ARDSRisk factors for ARDSCurrent understanding of pathophysiologyInterventions – what has worked, and what has notOngoing research

What is ARDS?A common and life-threatening conditionMay 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 failureNoncardiogenic pulmonary edemaSevere arterial hypoxemiaRequiring 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

AECCAECC definition has been widely adopted Allowed for clinical and epidemiologic data gathering

on ARDS and ALIHas led to improved outcomes and better care

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;

But it has limitations:

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 weightLoss of aerated lung tissue

Clinical hallmarks:HypoxemiaBilateral chest radiograph opacities Increased venous admixture Increased dead spaceDecreased 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 AssemblyThorough review of the literature presented at

consensus meetingStudy eligibility criteria:

1. Large, multicenter prospective cohortsor

smaller, single-center prospective studies with unique radiologic or physiologic data

whichenrolled patients meeting the AECC definition of both

ARDS and ALI

Cohort AssemblyThorough review of the literature presented at

consensus meetingStudy 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

Variables90-day mortalityVentilator-free days at 28 days following the

diagnosis of ALIDuration of mechanical ventilationProgression between stages

4 Ancillary Variables“Severe ARDS”

PaO2/FIO2 ratio of 100 or less3 or 4 quadrant opacities on radiographPEEP 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.

IncidenceAnnual incidence ranges 140,000 to 190,000

cases per year in the US adult populationMortality 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 ARDSGastric AspirationSepsisTraumaMultiple blood transfusionsMany others suggested

Still being studied

Risk FactorsRisk factors for increased mortality

From multicenter epidemiologic cohorts: Older age Worse severity of illness Shock on hospital admission Increased radiographic opacity Immunosuppression

Emerging researchRole of chronic alcohol abuseRole of geneticsRole of environmental factorsTreatment strategies

Chronic Alcohol Review of several previous articles:

Alcoholics more likely to suffer from:

traumapneumoniagastric

aspirationsepsispancreatitis

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. 2005; 53: 235-245

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.

Animal ModelAlveolar 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 channelsCounteract increased paracellular leakMaintains balance in the absence of further oxidative stress

These compensatory mechanisms are overwhelmed in the face of an inflammatory challengeResult is proteinaceous fluid leak

The role of GlutathioneThe role of glutathione depletion in alcohol-induced

hepatic injury is well establishedThe 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 CorrelateWhen 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 complicatedOver 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 Variation14 FAS polymorphisms evaluatedHealthy 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 inflammationUncontrolled activation of coagulation pathways Inappropriate accumulation of leukocytes, plateletsDisrupted alveolar endothelial barriers

Inflammatory mechanisms necessary for pathogen clearanceControlled vs. excessiveLeukocyte protease releaseGeneration of reactive oxygen speciesAbundant synthesis of chemokines, cytokinesToll-like receptor engagement

Toll-Like receptor: A major playerPattern-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 CadherinAdherens protein critical for integrity of

endothelial barrier in lung microvasculatureBonds 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 ventilationHigh PEEPProne positioningNMBDSteroidsFluid conservative vs. liberalECMO

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 ventilation861 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

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 trials549 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

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 pre-determined futility stopping rule

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

days

High PEEP trialsMeade 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. 2008; 299:637-645N=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: 646-655N=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

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; 302:1977-1984

Prone Position

Patients randomized into prone vs. supineProne 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

ConclusionsProlonged prone position not associated with

survival advantageNo 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

NMBDMeta-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

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 daysReduced risk of death at ICU dischargeReduced risk of death at hospital dischargeReduced the risk of barotraumaNo effect on the the duration of mechanical ventilationNo effect on the risk of ICU weakness

These findings were strongly significant in terms of mortality reduction

MethylprednisoloneTrial 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; 302:1977-1984

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 rateStarting 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 processLikely genetic and environmental components

Treatment strategiesLung protective ventilation – HELPFULHigh PEEP – Likely not helpful, though maybe small

benefit in ICU death rate in patients with ARDSProne – Likely not helpful,Possibly harmfulNMBD – Probably helpfulSteroids – Likely not helpfulFluid 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 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; 354:1671-1684

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.