the acute respiratory distress syndrome: an update of the current literature
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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 - PowerPoint PPT PresentationTRANSCRIPT
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.