ARDS
The Fundamentals
Objectives
• Know the epidemiologic risk factors for ARDS
• Understand the pathogenesis of lung
dysfunction in ARDS
• Know how to diagnose ARDS
• Understand the pathophysiology of ARDS
• Know the principles of management in ARDS
• Plan mechanical ventilation in ARDS
Features of ARDS
• Definition: clinically defined hypoxemic
respiratory failure
• Causes: multiple
• Pathophysiology: heterogeneous process
mediated by inflammatory pathways
• Treatment: identify and treat underlying cause
and provide supportive care
Definition
American-European Consensus Conference
(1994)
• Require:
– 1)Acute onset and persistence of respiratory
symptoms
– 2) Frontal chest radiograph w/bilateral infiltrates
– 3) No clinical evidence of left atrial hypertension
(pulmonary capillary wedge <18 mm Hg)
• Define:
– ALI:
P/F ratio <300 mm Hg
– ARDS: P/F ratio <200 mm Hg
Bernard GR et al., Am J Respir Crit Care Med 1994
Problems with the Definition
• Broad definition that does not address cause
• What is acute??
• Radiology criteria unspecific
• P/F ratio does not account for PEEP or MAP
• P/F ratio has not been shown to correlate
with the severity of the lung injury, the
clinical course, or mortality
Epidemiology
• Mortality decreasing
– > 50% in mid 80’s
– 36% in mid 90’s
UpToDate
Mortality is still significant
Causes
Multifactorial
• Direct Lung Injury
– Aspiration / chemical pneumonitis
– Infectious PNA
– Trauma – contusions, penetrating injury, inhalation injury
– Near drowning
– Fat embolism
• Indirect Injury
– Inflammation, sepsis
– Multiple trauma, burns
– Shock, hypoperfusion
– Acute pancreatitis
– Bypass
– Transfusion related
Causes: Children
• Shock, sepsis, drowning seem to be top three
• In single institution:
– Highest incidence (12%) for ARDS was for those with
sepsis/viral pneumonia/smoke inhalation/drowning
– 2.7% of all admissions developed ARDS.
Risk Factors of Poor Outcome
• Clinical
– Severity of illness (APACHE)
– Other organ involvement, comorbid conditions
• Specifically liver dysfunction
– Sepsis
• Plasma Markers
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Acute inflammation (IL-6, IL-8)
Endothelial injury (von Willebrand factor antigen)
Epithelial type II cell molecules (Surfactant protein-D)
Adhesion molecule (Intercellular adhesion molecule-1 (ICAM-1))
Neutrophil-endothelial interaction (Soluble TNF receptors I and II)
Procoagulant activity (Protein C)
Fibrinolytic activity (Plasminogen activator inhibitor-1)
Ware LB. Crit Care Med. 2005
Early deaths (within 72 hours) are caused by
the underlying illness or injury, whereas late
deaths are caused by sepsis or multiorgan
dysfunction
Pathophysiology of ARDS
Insult
↓
Activation of inflammatory mediators and cellular
components
↓
cytokines (TNF, IL-1, IL-6, IL-8)
neutrophil infiltration
↓
damage to capillary endothelial and
alveolar epithelial cells
Pathophysiology of ARDS
• Starling forces fall out of balance
– Increased in capillary hydrostatic pressure
– Diminished oncotic pressure gradient
• Exudative fluid in both the interstitium and alveoli
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impaired gas exchange
decreased compliance
increased pulmonary arterial pressure
Type II pneumocyte damage  decreased surfactant
Loss of aeration (mainly in caudal and dependent lung
regions in patients lying supine)
A Picture is Worth a Thousand Words?
The 3 Pathologic Phases of
ARDS
• Exudative Phase
– diffuse alveolar damage
• Proliferative Phase
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–
–
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pulm edema resolves
myofibroblasts infiltrate the
interstitium
collagen begins to deposit
• Fibrotic Phase
– obliteration of normal lung architecture
– diffuse fibrosis and cyst formation
Principles of Management
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Identify and treat underlying process
Offer supportive care
Improve gas exchange
Trial unproven last ditch therapies
No effective modalities to intervene
the only therapy that has been proven to be
effective at reducing mortality in ARDS in a large,
randomized, multi-center, controlled trial is a
protective ventilatory strategy
Supportive Care
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Sedatives and neuromuscular blockade
Hemodynamic management
Nutritional support
Control of blood glucose levels
VAP and other nosocomial infection
prevention
• Prophylaxis against DVT and GI bleeding
Sedatives and NMBs
• improve tolerance of mechanical ventilation
• decrease oxygen consumption
BUT
• routinely wake patients each day
• use intermittent doses when possible
• follow a sedation and analgesia protocol
Paralysis: improved oxygenation
vs. prolonged neuromuscular
weakness
• multicenter RCT of ARDS patients - N=340
• cisatracurium vs. placebo drip x 48 hrs
• statistically significant decrease in 90-day
mortality for subset of patients with P/F < 120
• there was no difference in the frequency of
ICU-acquired neuromuscular weakness
Papazian L , et al. Neuromuscular blockers in early acute respiratory distress syndrome. NEJM. 2010
Sep;363(12):1107-16
Hemodynamic Management
• Decrease oxygen consumption
– Because of pulmonary shunting, increasing SvO2 may increase
SaO2
– Avoid fever
– Avoid anxiety and pain
– Avoid excessive use of respiratory muscles
• Improve oxygen delivery
– CO x (SaO2 x Hgb x 1.34)
Nutrition
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ARDS is a catabolic state
Use gut when able
Avoid overfeeding
Keep HOB 30 degrees upright for reflux precautions in
intubated patients
• Arginine: inhibit platelet aggregation, improve wound
healing, changes into NO
• Glutamine: fuel for mucosa, lymphocytes, macrophages
• PolyUnsaturated Fatty Acids: affect immune balance
VAP
• Pulmonary edema is an excellent growth medium
for bacteria
• Pneumonia is difficult to diagnose
• Proven strategies
– keep HOB elevated
– avoid unnecessary antibiotics
– good mouth care
– wean vent timely
– avoid excessive sedation
– vent circuit change per protocol
– routine vent tubing care
Improve Gas Exchange
• Mechanical ventilator strategies
• Use of high fractions of inspired oxygen
• Prone positioning
There’s no free lunch!
VILI
• Pulmonary edema
– Mechanical ventilation alters the alveolar-capillary barrier
permeability
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Increased transmural vascular pressure
Surfactant inactivation
Mechanical distortion and disruption of endothelial cells
Regional activation of inflammatory cells
• Lung inflammation
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Repetitive opening /collapse of atelectatic lung units
Surfactant alterations
Loss of alveoli-capillary barrier function
Bacterial translocation
Overinflation of healthy lung regions
Normal – 5 min – 20 min of 45 cmH2O
Dreyfuss, Am J Respir Crit Care Med 1998;157:294-323
ARDS Network Study
ARDS Network Study
ARDS Network Study – Other
Findings
• No difference in their supportive care
requirements (vasopressors-IV fluids-fluid
balance-diuretics-sedation)
• ~10% mortality reduction
• Less organ failures
• Lower IL-6 and IL-8 levels
Physiologic Effects of
Hypercapnia
• Resp
– Benefits: Improves oxygenation by
• Enhancing hypoxic pulmonary vasoconstriction and decreasing intrapulmonary
shunting
• right-shift of oxygen-hemoglobin dissociation curve
– Dangers:
• Low PaO2. For a constant FIO2, as the PaCO2 ↑, PAO2 ↓ (alveolar gas equation).
• Low pH. (HendersonHasselbalch equation)
• Decreased ventilatory reserve. Small changes in
alveolar ventilation  big change in CO2 when
unhealthy
Physiologic Effects of
Hypercapnia
• Renal: Worsens perfusion by
– direct renal vasoconstriction from acidosis and
sympathetic-meditated release of NE
– But, maintains pH with compensatory bicarb
reabsorption
• CV: Compromises hemodynamics
– Sympathetic stimulation with increased CO
• Increased HR and SV, decreased SVR
– Intracellular acidosis of cardiomyocytes
– When combined with high PEEP strategy, can lead to
severely decreased preload and cardiovascular
compromise
Permissive Hypercapnia
Is it worth it?
• Early adult ARDS trial showed a reduction
in expected mortality of 56% to an actual
Hickling, CCM, 1994
mortality of 26%
• Included in adult trauma patients protocol
for mechanical ventilation Nathens, J Trauma, 2005
• Several pediatric studies showing benefit
when used in conjunction with low TV and
Sheridan, J Trauma, 1995
high PEEP
Paulson, J Pediatr, 1996
PEEP
• Improves oxygenation by
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Increasing end-expiratory lung volume
Recruiting unventilated alveoli
Decreasing perfusion to unventilated alveoli
Improving V/Q matching
Decreasing intrapulmonary shunt
PVR Increases at Lung Volumes
Below and Above FRC
Lung Volume
What is adequate PEEP?
• Measuring P/V curve is
not practical clinically.
• A single inflation P/V
curve doesn’t represent
whole lung.
• The P/V curve for the
whole lung = sum of
multiple regional P/V
curves
• A lot of variation btwn
dependent and
nondependent lung
Recruitment Maneuvers
• inflating to 40 cm H2O for 15 - 26 seconds
• Intermittent increase of PEEP
• Sigh breaths
When alveolar recruitment is optimized by
increasing PEEP, recruitment maneuvers
are either poorly effective or deleterious
Proning
Proning 7 hrs/day x 10 days
Gattinoni, et al AJRCCM 164(9), 1701-11 (2001)
Effects from changes in position
• End expiratory views, PEEP 10
• supineprone  supine
• Relatively quick change in alveolar
gas distribution
Gattinoni, et al AJRCCM 164(9), 1701-11 (2001)
Proning
How does it work?
• Increases FRC
• Improves ventilation of previously dependent regions
• Redistribute tidal volume to atelectatic dorsal region
• Difference in diaphragm movement: when supine,
dorsal and ventral move symmetrically, when prone,
dorsal > ventral
Mechanical Ventilation Summary
• Avoid
overdistension
(limit tidal volume and
plateau pressure)
• Avoid
derecruitment
(adequate PEEP)
Unproven Therapies for
Times of Desperation
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Inhaled vasodilators: iNO
Steroids
Beta Agonists
Surfactant
Liquid Ventilation
ECMO
Role of Nitric Oxide in Lung Injury
• Optimizes V/Q
matching
• Inhibits neutrophil
adhesion
• Effects on long term
lung disease unclear
Role of Nitric Oxide in Lung Injury
Steroids in ARDS
• Theoretical anti-inflammatory, anti-fibrotic benefit
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Inhibit transcriptional activation of various cytokines
Inhibit synthesis of phospholipase A2 : cycloxygenase
Reduced prod. of prostanoids, PAF
 fibrinogenesis
• 2 meta-analyses
– High dose methylpred for < 48 hrs (30 mg/kg/d)
– In early ARDS no benefit
LEFERING et al CCM 1995
CRONIN et al., CCM 1995
Steroids in ARDS
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Randomized, double-blind, placebo-controlled trial
Adult ARDS ventilated for > 7 days without improvement
No evidence of untreated infection
Randomized:
– Placebo
– Methylprednisolone 2 mg/kg/day x 14 days, tapered
over 1 month
Meduri et al, JAMA, 1998
Steroids in ARDS
• By day 10, steroids
improved:
– PaO2/FiO2 ratios
– Lung injury scores
– Static lung compliance
• 24 patients enrolled; study
stopped due to survival
difference
100
90
80
70
60
50
40
30
20
10
0
Steroid
Placebo
ICU
survival
Hospital
survival
P< 0.01
Meduri et al, JAMA, 1998
Steroids in ARDS
ARDSNET 2006:354(16) 1671-83
• N = 180
• Methylpred vs. placebo
• > 14 days into course
Steroids showed no benefit
and some potential adverse
effects
NOT recommended
Exogenous Surfactant
• Multicenter trial-uncontrolled, observational
P = 2T/r
• Calf lung surfactant (Infasurf) - intratracheal
• Immediate improvement and weaning in 24/29 children
with ARDS and 14% mortality
Wilson et al, CCM, 24:1996
• In several other studies, there is no evidence for sustained
benefit from Surfactant administration
Wilson et al, JAMA, 2005
Liquid Ventilation
• Fill the lungs with liquid – Perfluorocarbon: colorless,
odorless, inert, high vapor pressure, oxygen rich liquid
• Anti-inflammatory properties
(↓ TNF, IL-1 and IL-8, inhibits neutrophil activation and
chemotaxis)
• Reduces surface tension
• ↑ surfactant phospholipid synthesis and secretion
• 2 published adult trials of PLV in ARDS have confirmed
its safety but not efficacy over HFOV
Hirschl et al JAMA 1996, 275; 383-389
Gauger et al, CCM 1996, 24; 16-24
ECMO for Severe Lung Injury
• Alternative means for
gas exchange
• Allows lung rest
• May be beneficial in
fluid removal
• High risk/ high cost
venture
Issues with use of ECMO
• Is the disease process potentially reversible?
– Is there a diagnosis?
• Are the pre-ECMO therapies harmful?
– Can we prevent iatrogenic complications?
– Have we created hemodynamic instability?
• Are there other complicating comorbidities?
– Will these increase the risk of ECMO?
• Requires balancing the risks and benefits
Combination Therapies
Now to look at RCTs of combination
therapies ….
Just kidding 
Summary
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Clinically defined
Multiple causes
Mediated by inflammatory pathways
Heterogeneous process
Identify and treat underlying cause
Do no harm
Supportive interventions
Decrease in ARDS mortality in recent years largely due to
improved CCM capabilities rather than ARDS-specific
therapies
References
•
ARDS Clinical Trial Network. 2006. Comparison of Two Fluid-Management Strategies in
Acute Lung Injury. N Engl J Med. 354 (24). pp 2564-75.
•
ARDS Clinical Trial Network. 2006. Pulmonary-Artery versus Central Venous Catheter to
Guide Treatment of Acute Lung Injury. N Engl J Med. 354 (21). pp 2213-24.
•
Fan, E., Needham, D.M., Stewart, T.E. Ventilatory Management of Acute Lung Injury and
Acute Respiratory Distress Syndrome. 2005. JAMA. 294 (22). pp. 2889-96.
•
Hansen-Flaschen, J., Siegel, M.D. Acute Respiratory Distress Syndrome: Definition;
Epidemiology; Diagnosis; and Etiology. 2006. www.utdol.com.
•
Heresi, G.A., Arroligo, A.C., Weidemann, H.P., Matthay, M.A. 2006. Pulmonary Artery
Catheter and Fluid Management in Acute Lung Injury and the Acute Respiratory Distress
Syndrome. Clin Chest Med. 27. pp 627-628.
•
Marino, P.L. The ICU Book. 3rd Ed. Lippincott Williams & Wilkins. Philadelphia. pp. 41935.
•
Petty, T.L. Acute Respiratory Distress Syndrome: Consensus, Definitions, and Future
Directions. 1996. Crit Care Med. 24(4). pp 555-556.
•
Rouby, J-J., Puybasset, L., Nieszkowska, A., Lu, Q. Acute Respiratory Distress Syndrome:
Lessons form Computed Tomography of the Whole Lung. 2003. Crit Care Med. 31(4S). pp.
S285-95.
•
Weinhouse, G.L., Manaker, S. Swan-Ganz Catheterization: Indications and Complications.
2006. www.utdol.com.