Introduction

The incidence of ARDS in at-risk populations is

prospective 1.5 to 12.9 cases per 100 000 people
per year depending on diagnostic criteria.
The most common cause of ARDS is severe
infection, (half of cases) may involve localized
disease (pneumonia) or systemic disease (SIRS,
sepsis and septic shock).
Sepsis-related conditions(particularly severe gramnegative infections) are associated with multiple
organ failure with or without progressive respiratory
failure.
The multiple organ failure syndrome is the major
cause of death in ARDS, and the mortality rate is
about 40%
ARDS, Ann Intern Med.
2004;141:460-470.

Risk factors

Am J RespirCritCare Med Vol149. pp 818-

Clinical principles

Physiologic principles

Acute severe respiratory

distress and 1 or more risk
factors (including
infection, aspiration,
pancreatitis, and trauma)
Impaired arterial
oxygenation (hypoxemia) :
- ALI : P/F ratio <300
- ARDS : P/F ratio <200
Bilateral pulmonary
infiltrates on chest
radiograph
No clinical evidence of
elevated left atrial
pressure (or pulmonary
artery occlusion pressure
18 mm Hg )

Physical or chemical injury or by

extensive activation of innate
inflammatory responses
(Neutrophil activation,
proinflammatory cytokines, VILI)
Cause damage to f the lungs
alveolar-capillary barrier and
decrease the lungs edema safety
factor by about half
Develope protein-rich alveolar
edema at low capillary pressures.
The alveolar flooding impairs
alveolar
ventilation, inactivates
surfactant, decreases lung
compliance, increases dispersion
of ventilation and perfusion, and
produces intrapulmonary shunt
( hypoxemia does not improve
despite oxygen administration)
but hypoxemia in ARDS does
respond to positive end-expiratory
ARDS, Ann Intern Med.
pressure
2004;141:460-470.

What causes ARDS?

The innate genetic immune system identifies a few
pattern of the receptors recognizing microbes and
endogenous ligands (fibronectin and hyaluronic acid), and
recognize the lipid A portion of lipopolysaccharide, which
produces a pathogen-associated molecular pattern.
Receptors CD14-recognizing and -binding lipopolysaccharide
directly , and Toll-like receptor 4 (TLR4), recognize
complexes generated by a pathogen-associated molecular
pattern (the complex of lipopolysaccharide with CD14 and
lipopolysaccharide-binding protein).
This transmembrane receptors after stimulation with
lipopolysaccharide, prokaryotic DNA, and other microbial
products activate proinflammatory transcription factors
(nuclear transcription factor-B and activator protein-1) in
cells
ARDS, Ann Intern Med.
2004;141:460-470.

What causes ARDS?

The polymorphisms TLR4 gene are associated with
lipopolysaccharide hyporesponsiveness , but not all
that
are hyporesponsive to lipopolysaccharide have TLR4
polymorphisms and not all TLR4 polymorphisms are
hyporesponsive.
TLR4 polymorphisms identify only a few individuals with
severe gram-negative sepsis.
Some responses to lipopolysaccharide are modulated by
MHC class II genes, such as those in macrophages ,
and by other TLR4-associated proteins (MyD88 and MD2).
Activation of such innate responses generates the
inflammatory mediators of ARDS
ARDS, Ann Intern Med.
2004;141:460-470.

Cellular and molecular events that interfere with gas exchange

in the acute respiratory distress syndrome.

These events include endothelial activation, recruitment of

inflammatory cells, activation of coagulation, and inhibition of
ARDS, Ann Intern Med.
fibrinolysis.
2004;141:460-470.

Capillary fluid filtration described by the Starling equation.

Pulmonary capillaries filter fluid (Jv) in proportion to the net capillary filtration pressure
minus the net osmotic pressure across the vessel wall. The hydraulic conductance (Kf,c) is
the capacity to filter fluid as filtration pressure increases relative to number and size of
endothelial openings perunit surface area. The osmotic reflection coefficient (d) determines
osmotic permeability to specific proteins (0 is permeable and 1 is impermeable).
Capillary damage in the acute respiratory distress syndrome may increase Kf,c
and decreased d, increasing capillary fluid flux at constant hydrostatic pressure.
Pc mean capillary hydrostatic pressure; Pi mean interstitial
hydrostatic
pressure;
ARDS,
Ann Intern
Med. ip

The lungs edema safety factor in the acute

respiratory distress syndrome.

The safety factor prevents airspace flooding during increases in filtration (hydrostatic)
pressure (arrow). The safety factor has 3 components arranged in a series (squares 1, 2, and
3). As filtration pressure increases, dilute fluid is forced into the interstitial space, which
increases the absorption force (arrowhead) opposing it (square 1). The increase in interstitial
fluid volume causes perivascular swelling (square 2), and interstitial fluid is removed at a
greater rate (square 3) by lung lymphatics (Ly). A breech of the alveolar epithelium allows
plasma and interstitial fluid to leak into the airspaces faster than
saltAnn
andIntern
water Med.
can be
ARDS,

 The acute respiratory

distress syndrome is a
group of diverse processes
that produce widespread
lung damage causes
alveolar damage:
- fluid to leak across the
alveolarcapillary
barrier
(despite relatively
normal
pulmonary circulatory
pressures)
- produce enough
alveolar
edema to cause the
cardinal physiologic
manifestation of the
refractory hypoxemia
ARDS, Ann Intern Med.

Pulmonary edema formation in congestive heart failure

(CHF) and the acute respiratory distress syndrome (ARDS).

In CHF, the edema safety factor prevents pulmonary edema fluid

accumulation
until pulmonary capillary pressure is elevated to approximately 22 mm
Hg. In ARDS, an increase in capillary permeability produces edema at
ARDS,
Ann
Intern
normal capillary pressures and greatly increases
the
rate
of Med.
edema

 In ARDS : the effects of inflammatory mediators

airway , vascular smooth-muscle tone bronchial
and vascular functions are altered increases in
the dispersion of both alveolar ventilation and
cardiac output gas exchange is affected
.
As lung compliance decreases, the work to expand
the lungs to maintain the arterial PCO2 level must
also increase.
Alveolar edema in the acute phase creating areas
of low VA/Q ratio and shunt hypoxemia; the latter
cannot be overcome by oxygen administration
because of the absence of alveolar ventilation.
ARDS, Ann Intern Med.
2004;141:460-470.

LUNG PROTECTIVE VENTILATION

STRATEGIES IN ARDS
Ventilator-induced lung injury occurs by several mechanisms, all of
which exacerbate inflammation, including oxygen toxicity, lung
overdistention, and destructive cycles of alveolar opening and closure
Life-threatening problem of ARDS is hypoxemia due to
intrapulmonary shunt, which must be alleviated by recruiting and
stabilizing nonventilated alveoli
Protective ventilation involved
- a recruitment maneuver,
- positive end expiratory pressures above the lower inflection point
on the
static P-V curve,
- a TV of less than 6 mL/kg,
- driving pressures of less than 20 cmH2O above the PEEP value, - permissive hypercapnia, and
- preferential use of pressure-limited ventilatory modes.

ARDS, Ann Intern Med.

2004;141:460-470.

The effects of alveolarcapillary leak and positive end-expiratory

pressure (PEEP) on pulmonary gas exchange.

The right half of the diagram illustrates the effect of PEEP, which stabilizes alveoli
that are then better able to exchange gas because they have more surface area.
ARDS, Ann Intern Med.

LUNG PROTECTIVE VENTILATION

STRATEGIES IN ARDS
Positive end-expiratory pressure improves
oxygenation in ARDS by stabilizing damaged alveoli
and improving areas of low VA/Q ratio and shunt
Use of PEEP in general, 5 to 20 cm of H2O and
plateau pressures 35 cm of H2O provides a
reasonable balance among the potential effects.
Higher levels of PEEP may open more collapsed
alveoli at the expense of cardiac output and
overdistending already recruited alveoli
Other adverse effects of PEEP include :
increases in lung water; dead space; resistance in
the bronchial circulation; and lung stretch during
inspiration, which may exacerbate lung injury.
ARDS, Ann Intern Med.
2004;141:460-470.

The open lung concept

ARDS multiple atelectasis, % of recruitable lung varied
widely, from negligible to >50%
The treatment for alveolar collapse is lung recuitment, the
open lung concept (OLC)
The goal of OLC collapse atelectasis and optimal gas
exchange :
Initial inspiratory pressure recruit collapse alveoli,
then minimal pressure prevent lung from collapsing
- Early OLC ( < 72hrs ) higher response rate, this probably
related to the change from exudate to a fibroproliferative
process

The Law of Laplace links the pressure applied by the

ventilator to
the alveolar pressure (P), which relates surface
tension (T) and radius (R):

P = 2T/R

Open lung units are more efficient and function at a lower pressure when alveolarradii are larger. The
opening pressure is higher when surface tension is elevated (e.g., curve T1 with less effective surfactant).
The pressure needed to keep the alveoli open is less when the lung volume indicated by functional
residual capacity at IV is compared to that at III and is unstable at I and II. The vertical dotted line labeled
PI ,III illustrates that it is easier for a partially opened alveolus (III) to be recruited than a closed alveolus (I)

The Open Lung Concept

The goal of is to minimize cycle
alveolar collapse and reopening.
Pressure-controlled ventilation is
used with a peak pressure of 40
60 cm H2O and a ratio of
inspiration-expiration is 1:1 to 2:1
The peak inspiratory pressure
(PIP) is adjusted to the lowest
pressure which keeps the lung
open (lowest pressure is when the
tidal volume remains stable and
the arterial blood gases are
constant)
The ideal pressure is generally 1 5
30 cm H2O lower than the
required recruitment pressure.
The positive end-expiratory
pressure (PEEP) is set at 10 20
cm of H2O to avoid alveolar
collapse.

OLC may be applied in at-risk patient during

shock
Recruitment at early stage of severe lung injury
dramatically improve oxygenation and
maintain the newly recruited lung tissue
The peak inspiratory pressure (PIP) is adjusted
to the lowest pressure, which keep the lung
open.
The ideal pressure is 15~30 cmH2O to prevent
alveolar collapse.

Lung Recruitment
Recruitment maneuver : reinflate collapsed
alveoli, a sustained pressure above the tidal
ventilation range is applied, and PEEP is used to
prevent derecruitment.
opening collapsed lung units
by transpulmonary pressure (PA-Ppl).
PEEP VT
continuous expansion and collapse of alveoli
barotrauma + volutrauma, surfactant
dysfunction
and cytokine release
activation of SIRS
High PEEP cytokine level.
Standard physiologic VT 5 to 7 cc/kg
ARDS, Ann Intern Med.
2004;141:460-470.

Performance of Recruitment Maneuvers:

1. Ensure hemodynamic stability.
2. Set the FiO2 to 1.0
3. Wait 10 minutes.
4. Recruit with 30 cmH2O CPAP for 30-40 seconds (or 10 cmH2O
above the plateau pressure level).
5. If unresponsive, wait 15 minutes and then recruit with 35
cmH2O CPAP for 30 to 40 seconds.
6. If unresponsive, wait 15 minutes and then recruit with 40
cmH2O
CPAP for 30 to 40 seconds.
7. If unresponsive, wait 15 minutes and then recruit with
20cmH2O
pressure control and 40 cmH2O CPAP for 2 minutes.
8.
If the patient remains unresponsive, consider prone positioning .

CCM, Kacmarek and Schwartz

(2000):

Relative contra-indication
is extensive
apical
bullous lungHospital
disease
General Intensive
Care Unit,
Johannesburg
(barotrauma). Johannesburg, South Africa.
Secondary' ARDS (abdominal sepsis) are tmore likely to respond
favourably to the maneuver
2.Position the patient prone
Prone positioning for recruitment is to have a pillow under the upper
chest, and another beneath the pelvic area, so the abdomen hangs down
somewhat in between the two pillows.
3.The patient must be fully monitored
Monitoring : invasive arterial blood pressure monitoring, pulse oximetry
and ECG.
The patient must also be completely paralysed with non-depolarising
neuromuscular blockade,
A baseline arterial blood gas analysis (ABG) should be obtained after the
FiO2 100%.
4.Administer 40cm H2O of PEEP for 90s
Set the ventilator to an effective rate of zero (with no machine breaths)
and then immediately raise the PEEP to 40cm H2O for 90s., then reinstitute ventilation as before.
5.Wait and recheck the ABG
Wait for a 5 minutes, in the prone position, and obtain a blood gas
analysis. If the PaO2 is 300mmHg, then repeating the maneuver at
PEEPs of 45mmHg and 50mmHg, for 90 s.
6.Prevent 'de-recruitment'

Patient Centred Acute Care Training (PACT),

European Society of Intensive Care. Respiratory
failure. Oct 2002

Recruitm
ent
Maneuver
ICU-RSHS

Severe acute respiratory distress syndrome,

Lung Injury Score

Lung injury score 3 (score is the sum of all

components/number of components).

Failing a lung-protective ventilation strategy because

of any one of the following clinical parameters:
-refractory hypoxemia (O2 saturation 90% for at least 1
hr on FIO2 0.80);
-refractory respiratory acidosis (pH 7.10 for at least 1
hr);
-persistently elevated plateau airway
pressures
30
Crit Care
Med 2010of
Vol.
38, No.

Therapeutic strategies for severe acute lung

injury
Initial Interventions:
Low tidal volume , low inspiratory pressure ventilation and at low compliance
may require the use of high respiratory rates, as long as intrinsic PEEP is not
generated, and permissive hypercapnea.
PEEP is set at moderate levels by using the PaO2/FIO2 (used in the
Respiratory Management in ALI/ARDS trial) the goal is to obtain an oxygen
saturation of approximately 90%.
Tidal volumes as low as 4 mL/kg may be necessary to reach the goal plateau
pressure of 30 cm H2O and avoid ventilator-associated lung injury.
A fluid-conservative hemodynamic management strategy should be instituted
if the patient is not in shock (MAP 60 mm Hg without vasopressor support)
Real-time echocardiography may assist in the evaluation and management of
acute cor pulmonale

Crit Care Med 2010 Vol. 38, No.

Management strategy for life-threatening

hypoxemia

Step 1. Measure plateau airway pressure. If 30 cm H2O,

then proceed to Step 2a.
If 30, then proceed to Step 2b.
Step 2a. Implement a recruitment maneuver and/or high
positive end-expiratory pressures alone.
Step 2b. Implement the prone position or high-frequency
oscillatory ventilation.
Step 3. Evaluate effects on oxygenation, static compliance,
and dead-space ventilation. If there is significant
improvement, then continue with therapy. If there is no
significant improvement, then proceed to the next
intervention.
Step 4. Administer inhaled nitric oxide; if no response within
several hours, then proceed to the next intervention.
Step 5. Consider administration of glucocorticoids
(methylprednisolone at low doses 1 mg/kg/day); weigh the
At risks
each step,
is critical to
evaluate
effectspatients.
on oxygenation, static
anditbenefits
for
individual
and pulmonary dead space ventilation. If there is significant
compliance,
Step 6. Consider extracorporeal life support. Candidates
improvement, then continue with therapy. If there is no significant
should not
receive
high-pressure
ventilation
days
Crit for
Care 7
Med
2010 Vol. 38, No.
improvement,
then
proceed
to the next intervention.

 Prone positioning
promotes
recruitment of
dependent,
atelectatic lung
regions most
affected by ARDS
by :
- relieving external
compressive
forces,
- improving
ventilationperfusion
matching without

Dependent areas are poorly aerated at

end-expiration caused by compressing
hydrostatic pressures.
-At end-inspiration,patent alveoli may
become
over-stretched (A)
-Excessive stresses may be generated
at the
boundary between aerated and
nonaerated l

Prone Positioning (c,d)

Placing patients prone for a total of at least 20 hrs per

day is associated with greater benefit .
If there is no improvement in oxygenation then do not
continue with prone positioning

High-Frequency Oscillatory
Ventilation
High-frequency
oscillatory ventilation
(HFOV) uses high mean
airway
pressure to achieve lung
recruitment an
oscillating piston that
creates cycles of
pressure above and
below the mean airway
pressure at a
high frequency (180
Potential
900/min), disadvantages are hemodynamic deterioration,
barotraumas,
or the need for heavy sedation and
in small tidal volumes
neuromuscular
(between 1 andblockade to reduce ventilator asynchrony.
In
a large clinical trial, HFOV was not associated with
2.5mL/kg).
more frequent episodes of intractable hypotension, air
leak, or mucous plugging

HFOV is
recommended early
in the course of
severe ARDS
patients with severe
hypoxemia and/or
elevated plateau
airway pressures
HFOV should not be
used in
patients with shock,
severe airway
obstruction,
intracranial
Fessler HE, Derdak S, Ferguson ND, et al: A
hemorrhage,
or ventilation
protocol for high-frequency oscillatory
in adults: results from a roundtable discussion.

Nitric Oxide
Inhaled nitric oxide
(NO) induces
vasodilatation
in aerated
portions of the
lung, which may
cause blood flow to
redistribute
toward ventilated
areas, which
results in improved
oxygenation.
Crit Care 1998; 2:917

NO attenuate the activation of

polymorphonuclear leukocytes
and platelet aggregation .
NO dissolved in alveolar fluid may
react with reactive oxygen
species to form reactive nitrogen
species, and cytotoxic to
epithelial cells.
Initiate inhaled NO at 1 ppm and
titrate up every 30 mins until an
improvement in oxygenation, but
not to exceed 10 ppm.
If there is no immediate
response,
then gradually discontinue
If there is a response, then the
dose
should be decreased daily to the
lowest
Crit Care 1998; 2:917
dose necessary to maintain the

Steroid Therapy
Glucocorticoids could
halt the progression
to severe and
persistent ALI/ARDS
by :
inhibiting neutrophil
activation, fibroblast
proliferation, and
collagen deposition
Two small, randomized
trials have examined
the effects of
corticosteroids in
early hypoxemic
respiratory failure
attributable to
ARDS (n 91) and
severe pneumonia (n
46) and reported

Steroid Therapy
Consider corticosteroids for life-threatening
hypoxemia that has failed previous
therapies.
Corticosteroids should be initiated before
day 14 except who require neuromuscular
blockade.
It recommend the administration of
methylprednisolone
at low doses 1 mg/kg/ day (Meduri et al
trial)
Assess PaO2/FIO2, compliance, and PaCO2
at baseline and on a daily basis.
If no improvement after 3 days, then
discontinue treatment.

Stepwise management strategy for severe

respiratory acidosis

Step 1. Increase respiratory rates to 35x/min,

ensuring that intrinsic positive endexpiratory
pressure is not increased, using conventional
humidifiers. If severe respiratory acidosis persists,
then proceed to Step 2.
Step 2. Administer buffer therapy. Trishydroxymethyl aminomethane may be preferable to
bicarbonate if renal function allows. If severe
respiratory acidosis persists, then proceed to Step
3.
Step 3. Evaluate for renal replacement therapy,
especially if there are other indications. If severe
respiratory acidosis persists, then proceed to Step
4.
Step 4. Consider extracorporeal life support.
Candidates should not receive high-pressure

Crit Care Med 2010 Vol. 38, No.

Tris-hydroxymethyl aminomethane (THAM)

Permissive hypercapnea is a well-accepted practice

from achieving the targets of a low-volume, lowpressure lung-protective ventilation strategy, but
varying thresholds for pH levels depending on the
presence of shock or multiorgan failure.
THAM is a nonbicarbonate buffer that does not
increase CO2 production and in a small observational
study improved pH and PaCO2 in patients with
ALI/ARDS and severe acidosis.
THAM infusion is contraindicated in renal
insufficiency; its risks include volume overload,
hypoglycemia, and hyperkalemia.
THAM dose is based on the base deficit, is given at a
mean dose of 0.55 mmol/kg/h (0.3 to 0.6 mmol/kg/h
for 5-10 d) and glucose and potassium levels should
be monitored.
Am J Respir Crit Care Med
Renal replacement therapies may be2000;
considered to
161(4 Pt 1):11491153
assist with management of acidosis

Stepwise management strategy for

elevated plateau airway pressures (30
35 cm H2O) when
tidal volume is set at 6 mL/kg
Step 1. Decrease tidal volumes to 4 mL/kg. If
plateau airway pressure remains at 3035 cm H2O,
then proceed to Step 2.
Step 2. Implement prone position and/or highfrequency oscillatory ventilation alone.
If plateau airway pressure remains at 3035 cm
H2O, then proceed to Step 3.
Step 3. Consider extracorporeal life support.
Candidates should not receive high-pressure
ventilation for 7 days before extracorporeal life
support.

Crit Care Med 2010 Vol. 38, No.

ECLS
ECLS uses a venovenous life-support
circuit that removes
blood from the
patient and
circulates it
through a
membrane
oxygenator to
relieve the lungs
from
Two
typestheir
of ECLSmain
that have been used to manage ARDS:
- extracorporeal
membrane oxygenation (ECMO), a high-flow
function
of gas
extracorporeal
membraneoxygenation
circuit, and
exchange
and
allow
- extracorporeal carbon dioxide removal, a low-flow, mostly
the
lungs to heal
extracorporeal CO2-removal circuit

CONCLUSIONS AND
RECOMMENDATIONS
The goals of using unproven therapies for
severe ARDS are to sustain life, minimize
additional lung injury, and avoid placing the
patient at excess risk for other
nonpulmonary complications
Recognition of patients with severe disease
(lung injury score 3) who have lifethreatening hypoxemia, respiratory
acidosis, or consistently elevated plateau
airway pressures develop should trigger the
early use of an rescue (unproven) therapy.
If no benefit is evident, then the therapy
should be discontinued to minimize harm
and delay in the initiation of another
therapy.