Adult Respiratory Distress Syndrome
Case presentation
• A 45-year-old man develops ARDS after sustaining
multiple broken bones in an automobile accident.
The man weighs 70 kg. Mechanical ventilation is
initiated in the AC mode with the following settings:
(PEEP), 10 cm H2O; (FiO2), 70%; respiration rate,
12/min.
• The most appropriate Tidal volume at this point:
A.
B.
C.
D.
E.
1000 ml
420 ml
500 ml
560 ml
700 ml
ARDS Definition

The 1994 North American-European Consensus
Conference (NAECC) criteria:
Onset - Acute and persistent
 Radiographic criteria - Bilateral pulmonary infiltrates
consistent with the presence of edema
 Oxygenation criteria - Impaired oxygenation regardless of
the PEEP concentration, with a Pao2/Fio2 ratio  300 torr
(40 kPa) for ALI and  200 torr (27 kPa) for ARDS
 Exclusion criteria - Clinical evidence of left atrial
hypertension or a pulmonary-artery catheter occlusion
pressure of  18 mm Hg.

Bernard GR et al., Am J Respir Crit Care Med 1994
Stratification System of Acute Lung Injury
GOCA
Letter
G
O
C
A
Meaning
Scale
Gas exchange
0
1
2
3
A
B
C
D
Pao2/Fio2  301
Pao2/Fio2 200 -300
Pao2/Fio2 101 – 200
Pao2/Fio2  100
Spontaneous breathing, no PEEP
Assisted breathing, PEEP 0-5 cmH2O
Assisted breathing, PEEP 6-10 cmH2O
Assisted breathing, PEEP  10 cmH2O
Organ failure
A
B
C
D
Lung only
Lung + 1 organ
Lung + 2 organs
Lung +  3 organs
Cause
1
2
3
Unknown
Direct lung injury
Indirect lung injury
0
1
No coexisting disease that will cause death within 5 yr
Coexisting disease that will cause death within 5 yr but not within 6 mo
Coexisting disease that will cause death within 6 mo
Gas exchange
(to be combined with
the numeric
descriptor)
Associated diseases
Definition
2
Artigas A, et al. Am J Respir Crit Care Med. 1998.
The ARDS Lung
ARDS
Focal
Patchy
Diffuse
Chest x-ray
(zero PEEP)
Focal heterogeneous loss
of aeration in caudal and
dependent lung region
Bilateral and diffuse x-ray
densities respecting lung
apices
Bilateral and diffuse
hyperdensities
“White lungs”
Chest CT scan
(zero PEEP)
Loss of aeration
Upper lobes normally
aerated despite a regional
excess of lung tissue –
Lower lobes poorly or non
aerated
Lower lobes massively
nonaerated – The loss of
aeration involves partially
the upper lobes
Massive, diffuse and
bilateral non- or poorly
aerated lung regions – No
normally aerated lung
region
Response to PEEP
±
PEEP <10-12 cmH2O
Risk of overinflation of the
aerated lung regions
++++
Recruitment of non
aerated lung unit
Low potential for
recruitment
++++
Lung recruitment curve
Open lung concept
±
High potential for
recruitment
Rouby JJ, et al. Eur Respir J. 2003.
Rouby JJ, et al. Anesthesiology. 2004.
The ARDS Lung
Early phases of ARDS
Direct insult of the lung
Primary pulmonary ARDS
“Indirect” insult of the lung
Secondary extrapulmonary ARDS
Pathologic changes
Lung tissue consolidation
Severe intra-alveolar damage
(Edema, fibrin, collagen
neutrophil aggregates, red cells)
Microvascular congestion
Interstitial edema
Alveolar collapse
Less severe alveolar damage
End-expiratory lung volume
EELV


Static elastance of the total
respiratory system Est,rs


Static elastance of the chest
wall Est,w / Static lung
elastance Est,L
 / 
 / 
Intra-abdominal pressure


Response to PEEP
Est,rs  [Est,L >> Est,w]
Stretching phenomena
Est,rs  [Est,L  Est,w]
Recruitment of previously closed alveolar
spaces
Lung recruitment
±
++++
Gattinoni L, et al. Am J Respir Crit Care Med. 1998.
ARDS Mortality Trend
28%
Crit Care Med 2009 Vol. 37, No. 5
Crude 60-day mortality among Acute Respiratory Distress
Syndrome (ARDS) Network patients, 1996–2005.
24%
Baby Lung Concept
• In acute lung injury/acute respiratory distress
syndrome, the normally aerated tissue has the
dimensions of the lung of a 5- to 6- year-old
child (300–500 g aerated tissue)
• What appears dangerous is not the VT/kg ratio
but instead the VT/”baby lung” ratio.
• The practical message is straightforward: the
smaller the “baby lung,” the greater is the
potential for unsafe mechanical ventilation.
ARDS: Baby lungs
The amount of normally aerated tissue, measured at end-expiration, was in the
order of 200–500 g in severe ARDS, i.e., roughly equivalent to the normally
aerated tissue of a healthy boy of 5/6 years.
Stiff or Small?
• ARDS lung is not “stiff” at all, but small
• The elasticity of the residual inflated lung is
nearly normal, as indicated by:
– The specific tissue compliance:
(compliance/normally aerated tissue)
• “baby lung” was a healthy anatomical
structure, located in the nondependent
regions of the original lungs
Ventilating ARDS with Normal VT
Straining of the “baby lung”
Supine
Prone
Supine
Sponge Lung Concept
The densities in the dependent lung regions are in fact due not to an increase in the
amount of edema but to a loss of alveolar gases, as the result of the compressive
gravitational forces, including the heart weight
Baby lung at end-inspiration
Spectrum of Regional Opening Pressures
Opening pressure
Superimposed
Pressure
Inflated
0
Small Airway
Collapse
10-20 cmH2O
Alveolar Collapse
(Reabsorption)
20-60 cmH2O
Consolidation
=
Lung Units at Risk for Tidal
Opening & Closure
(from Gattinoni)

Baby Lung and VILI
Elastic fibers (spring)
Collagen fibers (string).
Transpulmonary Pressure
Ventilator Induced Lung Injury
Recognized Mechanisms of Airspace
Injury
Airway Trauma
“Stretch”
“Shear”
Pathways to VILI
End-Expiration
Extreme Stress/Strain
Rupture
Tidal Forces
Moderate Stress/Strain
(Transpulmonary and
Microvascular Pressures)
Signaling
Mechano signaling via
integrins, cytoskeleton, ion channels
inflammatory cascade
Cellular Infiltration and Inflammation
Marini / Gattinoni CCM 2004
Stress distribution
homogeneous system
FT
min
max
L. Gattinoni, 2003
Mead J et al. J. Appl. Physiol. 28(5):596-608 1970
Stress distribution
High Stiffness Zone
min
max
L. Gattinoni, 2003
Mead J et al. J. Appl. Physiol. 28(5):596-608 1970
Ventilator-induced lung injury is initiated by
the application of excessive stress
Gattinoni, L. et al. CMAJ 2008;178:1174-1176
Copyright ©2008 Canadian Medical Association or its licensors
NEJM 2000;342:1334-1349
NEJM 2000;342:1334-1349
ARDS
Volutrauma
Atelectrauma
PEEP = 5 mbar
Pinsp = 40 mbar
Cytokines, complement,
prostanoids, leukotrienes, O2Proteases
Biotrauma
Barotrauma
MV and MODS: A Possible Link
Biophysical
Injury
Biochemical Injury
(Biotrauma)
Epithelium/
interstitium
cytokines,
complement,
PGs, LTs, ROS,
proteases
mf
• shear
• overdistention
• cyclic stretch
• D intrathoracic
pressure
bacteria
? sFasL
 alveolar-capillary
permeability
 cardiac output
 organ perfusion
neutrophils
Distal Organ Dysfunction
DEATH
Slutsky, Tremblay Am J Resp Crit Care Med. 1998;157:1721-5
PRINCIPLES AND GOALS OF
MECHANICAL VENTILATION IN ARDS
Respiratory Pressure/Volume (P/V) Curve
Healthy subject
In normal healthy volunteers, the P/V curve explore
the mechanical properties of the respiratory system
(lung + chest wall)
ARDS
RV, Residual volume; FRC, Functional residual capacity; TLC, Total lung capacity; UIP, Upper
inflection point; LIP, Lower inflection point. The critical opening pressure above which most of the
collapsed units open up and may be recruited - CLIN Compliance of the intermediate, linear segment
of the P/V curve
Maggiore SS, et al. Eur Respir J. 2003. Rouby JJ, et al. Eur Respir J. 2003.
Ventilator-induced Lung Injury (VILI)
Upper
Deflection point
Lower
Inflection point
Principles and Goals of MV in ARDS
• Appropriate oxygenation (PO2 = 55-60)
• Accept hypercapnea and mild acidosis (pH~ 7.3)
• Limit distending pressure=limit transpulmonary
pressure: Pplateau <28 cm H2O
• Limit tidal volume: 4-6 ml/Kg
• Best PEEP: 10-16 cm H2O
Preventing Overdistention and
Under-Recruitment Injury
“Lung Protective” Ventilation
10-16 cm H2O
V
O
L
U
M
E
Add PEEP
< 28 cm H2O
4-6 mL/kg
Limit VT
Limit Distending Pressure
Transpulmonary Pressure= Airway
Pressure-Pleural Pressure
Pressure
Lung protective ventilatory strategy
CT at end-expiration
Pelosi P et al, AJRCCM 2001;164:122-130
Lung Protective Ventilator
Strategies
volutrauma
zone of
overdistension
V
zone of derecruitment
and atelectasis
"safe"
window
LIP
atelectrauma
P
UIP
DON’T EVEN
THINK
OF PARKING
HERE
1998
53 patients
28 day mortalityControl
Intervention
Intervention
TV
<6 ml/Kg
PEEP
>PFlex
38%
Control
TV (10-12
ml/Kg)
Lowest
PEEP
71%
ARMA Trial
28861
daypatients
mortality
Intervention
TVP(4-6
ml/Kg)
31%
plateau <30
PEEP 8.5
Control
TV P
(10-12
ml/Kg)
40%
plateau <50
PEEP 8.6
NIH ARDS Network trial
NEJM 2000;342:1301
ARDS net mortality
Reducing from 12 to 6 ml/kg VT saved lives
NIH ARDS Network trial
NEJM 2000;342:1301
Low TV High TV
Mortality
Days of
free MV
Days free
of organ
failure
P=
31
40
0.007
12
10
0.007
15
12
0.006
Reducing from 12 to 6 ml/kg VT saved lives
Tradeoffs with 6 ml/kg
Crs also better in the HIGH Vt group
ARDS Network:
Improved Survival with Low VT
1.0
Proportion of Patients
0.9
0.8
0.7
0.6
0.5
Lower tidal volumes
Survival
Discharge
Traditional tidal values
Survival
Discharge
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
100
120
Days after Randomization
ARDS Network. N Engl J Med. 2000.
140
160
180
Randomized Trials of MV
in ARDS
1990s
1996-9
10-16
20-26
25-32
29-38
Tidal hyperinflation during Low TV
ventilation in ARDS
• 30 patients with ARDS
• Ventilatory strategy (ARMA protocol)
– 6 ml/Kg IBW
• BAL ► cytokine measurements
• CT scan on mechanical ventilation
 Hyperinflated
 Normally aerated
 Poorly aerated
 Non-aerated
Tidal hyperinflation during low TV
ventilation in ARDS


Hyperinflated
Normally aerated
Less protected


Poorly aerated
Non-aerated
More protected
Despite the use of protective ventilatory
strategy (6 ml/Kg) …..





30 % of patients hyperinflated
Plateau Pressure:
– Protected (25.5  0.5) vs. unprotected (28.9  0.9)
Higher inflammatory cytokines in unprotected
Number of ventilator-free days:
– Protected (7  8) vs. unprotected (1  2)
Mortality:
– Protected (30%) vs. unprotected (40%)
Limit plateau pressure to < 28
Neuromuscular Blockers in
Early Acute Respiratory
Distress Syndrome
340 patients
Cisatracurium besylate
Placebo
# of Patients
178
162
TV
6-8 ml/Kg
6-8 ml/Kg
PEEP
>5
>5
90 day mortality
31.6%
40.7%
Papazian L et al. N Engl J Med 2010;363:1107-1116
p= 0.08
Neuromuscular Blockers in
Early Acute Respiratory
Distress Syndrome
Hazard Ratio: 0.68 (95% confidence interval
[CI], 0.48 to 0.98; P = 0.04)
Papazian L et al. N Engl J Med 2010;363:1107-1116
Possible Mechanisms by Which Neuromuscular
Blocking Agents Might Lead to improved Survival
Possible Mechanisms by Which Neuromuscular
Blocking Agents Might Lead to improved Survival
zone of derecruitment
and atelectasis
volutrauma
zone of
overdistension
UIP
"safe"
window
V
Optimal
PEEP
atelectrauma
LIP
P
The PEEP Effect
NEJM 2006;354:1839-1841
Higher vs. Lower PEEP
Overinflated
Recruitment
Positive End-Expiratory Pressure Setting in Adults With Acute
Lung Injury and Acute Respiratory Distress Syndrome
(EXPRESS)
Ventilation Strategy Using Low Tidal Volumes, Recruitment Maneuvers,
and High Positive End-Expiratory Pressure for Acute Lung Injury and Acute
Respiratory Distress Syndrome
“LOVS”
ALVEOLI
1998
53 patients
28 day mortalityControl
Intervention
Intervention
TV
<6 ml/Kg
PEEP
>PFlex
38%
Control
TV (10-12
ml/Kg)
Lowest
PEEP
71%
50 patients
53 Patients
Intervention
Control
TV
5-8 ml/Kg
9-11 ml/Kg
PEEP
Pflex + 2 cm H2O
>5 cm H2O
ICU Mortality
32%
53%
P= 0.04
Crit Care Med 2006. 34l 1311
Positive End-Expiratory Pressure Setting in Adults With Acute
Lung Injury and Acute Respiratory Distress Syndrome
(EXPRESS)
385 patients
382 Patients
Intervention
Control
TV
6 ml/Kg
6 ml/Kg
PEEP
Plateau 28-30
16±3 cm H2O
5-9 cm H2O
ICU Mortality
NS
Mercat A, Richard JM, Vielle B, et al. (EXPRESS). JAMA. 2008;299:646-655
ALVEOLI
549 patients
Low PEEP
High PEEP
TV
6 ml/Kg
6 ml/Kg
PEEP
8.3 ± 3.2
13.2 ± 3.5
ICU Mortality
24.9%
27.5%
NS
N E J Med 2004. 351: 327
Ventilation Strategy Using Low Tidal Volumes, Recruitment Maneuvers, and
High Positive End-Expiratory Pressure for Acute Lung Injury and Acute
Respiratory Distress Syndrome
LOVS
475 patients
508 Patients
Intervention
Control
TV
6 ml/Kg
6 ml/Kg
PEEP
Pplat < 40
PEEP 20 cm H2O
RM
Pplat < 30
Low PEEP
ICU Mortality
36.4%
40.4%
NS
Meade et al JAMA. 2008;299(6):637-645.
PEEP in ARDS
100%
Bad
75%
Overinflated
Normal
Atelectasis
50%
25%
Good
0%
PEEP 0
PEEP 10
PEEP 15
PEEP 40
JAMA, March 3, 2010—Vol 303, No. 9
Time to Unassisted Breathing for Higher and Lower Positive
End-Expiratory Pressure (PEEP) Stratified by Presence of
Acute Respiratory Distress Syndrome (ARDS) at Baseline
Time to Death in Hospital for Higher and Lower Positive EndExpiratory Pressure (PEEP) Stratified by Presence of Acute
Respiratory Distress Syndrome (ARDS) at Baseline
Optimal PEEP
PEEP Table by ARDSNet
• ARDS Network, 2000: Multicenter, randomized
861 patients
Principle for FiO2 and PEEP Adjustment
FiO2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PEEP
5
5-8
8-10
10
10-14
14
14-18
18-24
NEJM 2000; 342: 1301-1308
PV Curve
Best PEEP
Rotta, J Pediatr (Rio J0 2003:79(Suppl 2):S149
Issues with PV Curves
• Require sedation/paralysis
• Difficult to identify “inflection points”
• May require esophageal pressure to separate
lung from chest wall effects
• Pressure volume curves of individual lung
units are not known
Optimal PEEP by Compliance
• 15 normovolemic patients requiring MV
for ARF
• PEEP resulting in maximum oxygen
transport and the lowest dead space
fraction resulted in highest compliance
• Optimal PEEP varied from 0- to 15 cm
H2O
• Mixed venous PO2 increased from 0 PEEP
to the PEEP resulting in maximum oxygen
transport, but then decreased at higher
PEEP
• Conclusion: compliance may be used to
indicated the PEEP likely to result in
optimum cardiopulmonary function
Suter, N Eng J Med 1975:292:284
Concerns when using lung-protective
strategy…
•
•
•
•
•
•
•
Heterogeneous distribution
Hypercapnia
Auto-PEEP
Sedation and paralysis
Patient-ventilator dyssynchrony
Increased intrathoracic pressure
Maintenance of PEEP
Permissive Hypercapnia
• Low Vt (6ml/kg) to prevent over-distention
• Increase respiratory rate to avoid very high level of
hypercapnia
• If Respiratory rate can’t be increased further then the
PaCO2 allowed to rise
• Accept PH > 7.25
• Usually well tolerated
• May be beneficial (shift oxygen dissociation curve to the
right)
• May use bicarb infusion till the kidney is able to retain
bicarb
Permissive Hypercapnia – When would you
NOT do it?
• Renal failure
• High intracranial pressures
• Cardiovascular problems
Conclusion
“Lung Protective” Ventilation
10-16 cm H2O
V
O
L
U
M
E
Add PEEP
< 28 cm H2O
4-6 mL/kg
Limit VT
Pressure
Limit Distending Pressure
Management of refractory hypoxemia
•
•
•
•
•
•
•
PEEP
Pee (diuresis)
Prone
Paralysis
Pleural evacuation (pleural effusion drainage)
Prostacyclin (or iNO)
More PEEP/recruitment maneuvers
What next?
Prone position
Inhaled nitric oxide
ECMO
High-frequency oscillation
Other Ventilator Strategies
• Lung recruitment maneuvers
• Prone positioning
• High-frequency oscillatory ventilation
(HFOV)
• ECMO
Recruitment Maneuvers
• Application of high airway pressure (3540cmH2O) for approximately 40 seconds.
• Most common methodology
– 40 cm H2O CPAP
– 40 seconds
• Employed to open atelectatic alveolar units that
occur with ARDS and particularly with any
disconnection from ventilator
• If successful, PaO2 will increase by 20% or more.
• Must use PEEP after procedure to keep recruited alveoli
open.
Effects of Recruitment Maneuvers to Promote Homogeneity within the Lung
Malhotra A. N Engl J Med 2007;357:1113-1120
Lung Recruitment
• To open the collapsed
alveoli
• A sustained inflation of
the lungs to higher
airway pressure and
volumes
– Ex.: PCV, Pi = 45 cmH2O,
PEEP = 5 cmH2O, RR = 10
/min, I : E = 1:1, for 2
minutes
NEJM 2006; 354: 1775-1786
ARDSnet protocol Vs open lung protocol
• ARDSnet protocol
• Experimental protocol
– Tv 6 ml/kg
– Tv 6 ml/kg
– Plateau pressure <30
– Plateau pressure <40
– Conventional PEEP
– Recruitment
(titrate for FIO2 <0.6)
maneuvers
– High PEEP (10-15)
JAMA, February 2008
ARDSnet protocol Vs open lung protocol
JAMA, February 2008
Lung Recruitment
NEJM 2006; 354: 1775-1786
Lung Recruitment
NEJM 2006; 354: 1775-1786
Lung Recruitment
• Potentially recruitable (PEEP 5  15 cmH2O)
– Increase in PaO2:FiO2
– Decrease in PaCO2
– Increase in compliance
Sensitivity : 71%
Specificity : 59%
• The effect of PEEP correlates with the percentage
of potentially recruitalbe lung
• The percentage of recruitable lung correlates with
the overall severity of lung injury
NEJM 2007; 354: 1775-1786
Lung Recruitment
• The percentage of potentially recruitable lung:
– Extremely variable,
– Strongly associated with the response to PEEP
• Not routinely recommended
Prone Position
Prone Position
• Mechanisms to improve
oxygenation:
– Increase in endexpiratory lung volume
– Better ventilationperfusion matching
– More efficient drainage
of secretions
Prone Position
 Improved gas exchange
 More uniform alveolar
ventilation
 Recruitment of atelectasis
in dorsal regions
 Improved postural
drainage
 Redistribution of perfusion
away from edematous,
dependent regions
Prone Positioning
Prone Position
NEJM 2001;345:568-573
Prone Position
NEJM 2001;345:568-573
Prone Position
• Improve oxygenation in about 2/3 of all
treated patients
• No improvement on survival, time on
ventilation, or time in ICU
• Might be useful to treat refractory hypoxemia
• Optimum timing or duration ?
• Routine use is not recommended
High-Frequency Oscillatory Ventilation
(HFOV)
HFV - the “ultimate” lung protective
strategy?
Over-distended
Protected
Under-recruit
HFOV
Frequency: 180-600 breaths/min (3-10Hz)
Effect of HFOV on gas exchange in ARDS
patients
AJRCCM 2002; 166:801-8
Survival difference of ARDS patients treated
with HFOV or CMV
30-day: P=0.057
90-day: P=0.078
AJRCCM 2002; 166:801-8
HFOV
• Complications:
– Recognition of a
pneumothorax
– Desiccation of secretions
– Sedation and paralysis
– Lack of expiratory filter
• Failed to show a mortality
benefit
• Combination with other
interventions ?
Chest 2007; 131:1907-1916
Acute Lung injury
• Decreased lung compliance results in high airway
pressures
• Low tidal volume 6-8 ml/kg ideal body weight
• Maintain IPP  30 cm H2O
• PEEP to improve oxygenation
Conclusions
• The only treatment that shows mortality
benefit:
– lung-protective ventilation strategy
– Low tidal volume (6ml/Kg), high PEEP, adequate
Pplat (<30 cmH2O)
• Modalities to improve oxygenation:
– Prone position, steroid, fluid treatment, steroid,
HFOV, NO
• Combining other treatments:
– Antibiotics, EGDT…etc
The University of Michigan