Transcript Recruitment manoeuvres and open lung ventilation

ACUTE RESPIRATORY
DISTRESS SYNDROME
Dr.J.R.Prajwala Reddy
DEFINING A SYNDROME
The first definition of ARDS dates to Ashbaugh
and colleagues in 1967 when they described 12
patients with severe acute respiratory failure .
 These patients had severe hypoxemia that was
refractory to supplemental oxygen, but which in
some cases was responsive to the application of
PEEP.
 Widespread pulmonary inflammation, edema,
and hyaline membranes were observed on
autopsy.
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In 1994, a joint American-European Consensus
Conference (AECC) met to refine the definition of
ARDS to standardize clinical research trials for
the disease.
The definition has subsequently been widely
employed to define patient enrollment in a broad
range of ARDS therapeutic trials.
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The ARDS Definition Task Force (the Berlin
definition) has recently revised the long-standing
1994 American– European Consensus Conference
(AECC) definition.
BERLIN
DEFINITION
RISK FACTORS
PATHOPHYSIOLOGY
The pathogenesis of ARDS starts with a
pulmonary or systemic insult that triggers an
inflammatory response within the lungs.
 The resulting “non cardiogenic, increased
permeability” form of pulmonary edema follows a
predictible clinical and pathological course that
has been separated into 3 clinically meanifull
phases.
 EXUDATIVE PHASE: occurs immediately and
lasts appx. 3-7days.
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Pathologically, it is characterized by “ diffuse
alveolar damage”, the cardinal features of which
are
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Accumulation of extravascular lung water ,protein,
and inflammatory cells( primarily neutrophils) in the
interstitial space and alveolar spaces, precipitates of
which result in the characteristic intra-alveolar
“hyaline membranes”.
Type I alveolar cell necrosis, and
Intra-alveolar hemorrhage .
PROLIFERATIVE PHASE: it overlaps with late
exudative phase
Lasts for 2-3 weeks, and it is characterized by
increased numbers of typeII pneuocytes, clearing of
alveolar edema and debris, improving gas exchange
,and eventually liberation from ventilator.
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FIBROTIC PHASE: some patient may progress
after 2-3 weeks to a clinically obvious fibrotic
phaser.
These patients develop progressive interstitial
and alveolar fibrosis, occasionally with large
emphysematous bullae prone to rupture, and
prolonged ventilator dependency with increased
morbidity and mortality.
CLINICAL MANAGEMENT OF ARDS
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The factors leading to ARDS must be promptly and
appropriately treated.
This includes diagnosis and treatment of infection with
drainage of collections and appropriate antimicrobial
agents, recognition and rapid resuscitation from shock,
splinting of fractures, and careful supportive care.
Prevention of deep venous thrombosis, stress
ulceration, nosocomial infection, and malnutrition,
often with enteral nutrition, must all be considered.
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Early mobilisation of mechanically ventilated patients
accompanied by appropriate levels of analgesia and
sedation is feasible and safe, and offers shorter
duration of ventilation, reduced delirium, ICU and
hospital length of stay, and improved mortality and
functional outcomes.
However, this must be balanced with strategies such
as use of neuromuscular blockers in the first 48 hours
of mechanical ventilation in ARDS, which reduced
mortality, possibly through prevention or reduction of
asynchronous ventilatory effort.
MECHANICAL VENTILATION
Acute hypoxaemic respiratory failure,and an
increase in the work of breathing, usually
mandates mechanical ventilation.
 The role of non-invasive ventilation in ARDS is
contentious; there are no large definitive studies,
and although some groups report encouraging
results these are usually in patients with mild
ARDS.
 Failure of NIV is common, associated with
greater complication rates and mortality,
perhaps due to delayed intubation.
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The method and delivery of ventilatory support
must take into account both the pathophysiology
of ARDS and ventilator-induced lung injury
(VILI).
The ARDS Network randomised 861 ALI patients
from 75 ICUs to receive either a tidal volume
(VT) of 12 or 6mL/kg predicted body weight.
Mortality was reduced by 22%, from 40% to 31%,
in the lower VT group.
There was a strict PEEP and FiO2 protocol, and
patients were ventilated with assist-control ventilation
to avoid excessive spontaneous VT.
 Similar data with improved long-term survival are
found in routine clinical practice; however, it is the
concept of lung protection rather than an exact VT
formula that is important.
 As Hager and colleagues found that lower VT
ventilation was protective across all quartiles of
plateau pressure (Pplat) in the ARDS Network trial,
with no safe upper limit of Pplat, it appears that the
key variable is lower VT rather than control of static
airway pressure.
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AVOIDANCE OF OVERSTRETCH AND
INADEQUATE RECRUITMENT
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The increase in dependent lung density found on
chest CT, due to non-aerated and poorly aerated
lung, reduces the volume of aerated lung
available for tida inflation (baby lung).
Both PEEP and tidal recruitment will increase
aeration of some of these air spaces, but a VT
that is not reduced in proportion to the reduction
in aerated lung may lead to overstretch of
aerated lung parenchyma and further diffuse
alveolar damage.
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This is termed volutrauma as increased airway
pressure (Paw) despite low VT, due to decreased chest
wall compliance, causes minimal damage compared
with high VT, high Paw ventilation.
Atelectrauma refers to injury due to repeated opening
and closing of air spaces during tidal inflation.
Both volutrauma and atelectrauma result in alveolar
inflammation and elevated alveolar cytokines
(biotrauma), which may ‘spill’ into the systemic
circulation.
OVERSTRETCH
The normal lung is fully inflated at a
transpulmonary pressure of ∼25–30cmH2O.
 Consequently, a maximum Pplat, an estimate of
the elastic distending pressure, of 30cmH2O has
been recommended.
 However, overinflation may occur at much lower
elastic distending pressures (18–26cmH2O).
 Inspiratory muscle contraction through reduction
of intrapleural pressure lowers Pplat, potentially
avoiding simple detection of an excessive
transpulmonary pressure.
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This is particularly common when pressure
support ventilation is used as a primary mode of
ventilatory support; VT that would produce an
unacceptably high Pplat during mechanical
ventilation will produce the same volutrauma
during a spontaneous or supported mode of
ventilation, and should be avoided.
 Provided the same VT is generated, spontaneous
ventilation does not reduce VILI compared to
controlled ventilation.
 Consequently, unless particular expertise is
available, VT limitation is currently the most
practical approach
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ADEQUATE PEEP
PEEP improves PaO2 by recruiting alveoli and
increasing functional residual capacity.
 Because PEEP may reduce cardiac output by
impairing venous return, Suter and coworkers
suggested that at best PEEP the oxygen delivery
(oxygen content × flow) was highest, and that
this coincided with greatest compliance.
 PEEP is commonly titrated to a particular
PaO2/FiO2 ratio such as the ARDS Network
protocol.
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The lower inflection point of a volume–pressure
curve has been used to set PEEP; early studies
suggested that this reflected recruitment of
collapsed alveoli.
 However, in patients with ARDS, recruitment
occurs well above the lower inflection point, often
along the entire volume–pressure curve and
above the upper inflection point.
 Meta-analysis of major clinical trials using
protective VT and comparing higher and lower
PEEP scales did not find an overall improvement
in outcome with higher PEEP, although rescue
therapies were required less often.
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However, patients with mild ARDS tended to have
worse outcomes with higher PEEP, and those with
moderate to severe ARDS had better outcomes.
 These data suggest individual patients may benefit
from a tailored approach.
 Although routine CT analysis has been advocated by
some, it is cumbersome and has not been shown to
influence outcome; non-invasive bedside alternatives
are under investigation.
 Consequently, PEEP titration is often a compromise
aiming to minimise both atelectrauma and
volutrauma.
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Reasonable approaches to PEEP titration include:
 The use of a scale similar to the ARDS Network
protocol,
 Titration of PEEP to PaO2 aiming for a PEEP of
∼15cmH2O, or
 Measuring elastic mechanics at the bedside.
 In patients at risk for ARDS prophylactic
PEEP(8cmH2O) was not protective.
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RECRUITMENT MANOEUVRES AND OPEN
LUNG VENTILATION
Open lung ventilation refers to an approach
where the lung is maximally recruited, usually
through application of higher PEEP, recruitment
manoeuvres, and efforts to minimise
derecruitment.
 In theory increased lung volume will result in
less tidal overinflation, and improved outcome.
 The recruitment manoeuvre may be followed by a
marked improvement in oxygenation; however,
this is not a consistent finding, and hypotension
may occur due to reduced venous return if there
is inadequate fluid loading.
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During a typical recruitment manoeuvre a high level
of CPAP (30–40cmH2O) is applied for 30–40 seconds
in an apnoeic patient, followed by return to a lower
level of PEEP and controlled ventilation.
This may be suboptimal; an alternative for example is
a staircase recruitment manoeuvre where airway
pressure is sequentially increased every 2 minutes,
and then decreased until oxygenation deteriorates.
A number of small trials have shown improvement in
oxygenation following recruitment manoeuvres;
however, the largest clinical trias failed to show an
effect.
Grasso and colleagues found that recruitment
manoeuvres were effective only early in ARDS and
with lower levels of baseline PEEP, which probably
explains the variable responses reported
In addition to physical recruitment of alveoli,
lung stretch above resting VT is the most
powerful physiological stimulus for release of
pulmonary surfactant from type II cells.
 This is associated with a decrease in lung
elastance and improved PaO2 in the isolated
perfused lung.
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MODE OF VENTILATION
Non-invasive ventilation should not be routinely
used in ARDS and most patients require
intubated mechanical ventilation.
 Following intubation, controlled ventilation
allows immediate reduction in the work of
breathing, and application of PEEP and a
controlled FiO2.
 Later in the clinical course assisted or supported
modes of ventilation may allow better patient–
ventilator interaction, and possibly improved
oxygenation through better V/Q mismatch as a
result of diaphragmatic contraction.
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An advantage of assist-control ventilation (as used
in the ARDS Network study) is that spontaneous
effort generates a controlled VT.
Care should be taken with synchronised intermittent
mandatory ventilation (SIMV), particularly if
pressure support is added to SIMV, as excessive VT
may occur during supported breaths.
There is an increasing tendency to use pressure
controlled ventilation (PC) or pressure-regulated
volume control (PRVC) as Ppk is lower than volume
controlled (VC) ventilation with constant inspiratory
flow pattern
Both oxygenation, haemodynamic stability and
mean airway pressure are no different between
PC and VC, and a moderate-sized randomised
study found no difference in outcome.
 However, there may be differences in lung stress
due to greater viscoelastic build-up with VC.
 Inverse ratio ventilation, often together with
PC, has been used in ARDS.
 However, when PEEPi and total PEEP are taken
into account, apart from a small decrease in
PaO2, there are no advantages with inverse ratio
ventilation.
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Mean airway pressure is higher with a greater
risk of both haemodynamic consequences, and
regionalhyperinflation.
 Consequently, an inspiratory to expiratory ratio
greater than 1:1 is recommended
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HIGH FREQUENCY OSCILLATORY
VENTILATION (HFOV)
HFOV encapsulates the main principles of lung
protection: it delivers extremely small tidal
volumes around a relatively high mean airway
pressure, at high respiratory frequencies (3-15
Hz), with the goal of avoiding tidal overstretch
and recruitment/ derecruitment.
 Despite the strong physiological rationale and
preliminary human studies showing
improvement in oxygenation two recent large
clinical trials in patients with moderate/severe
ARDS failed to show any improvement in
survival.
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Both trials compared HFOV to a lung protective
strategy that employed low tidal volume and
higher PEEP levels to fully recruit the lung.
 In the OSCAR study 398 patients were
randomized to HFO and 397 patients to a
conventional lung protective strategy.
 There was no difference in mortality between the
two groups (HFOV 42% vs. conventional
ventilation 41%).
 In the OSCILLATE study, an excess mortality
was reported in the HFOV arm and the trial was
stopped early after enrolling 548 patients instead
of planned 1,200 patients.
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Possible factors that might explain this excess
mortality in the HFOV arm are a greater use of
sedation, neuromuscular blocker use, and longer
and higher rates of vasoactive drugs.
 In light of these considerations, the results of
these two studies preclude the routine use of this
strategy in patients with ARDS.
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EXTRACORPOREAL MEMBRANE OXYGENATION
(ECMO)
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In patients with severe hypoxemic and/or
hypercapnic respiratory failure, extracorporeal
lung support (ECLS) techniques, including
extracorporeal membrane oxygenation (ECMO),
have been considered to be possible rescue
therapies.
The aim of this strategy is to overcome severe
hypoxemia and respiratory acidosis while
keeping the lung completely at rest.
Despite earlier negative trials , the CESAR study
suggested the benefit of ECLS in patients with
severe ARDS.
 In this RCT, 180 patients were randomized to
receive veno-venous ECMO (after transfer to a
specialized center) or conventional mechanical
ventilation (in regional centres).
 The former group had a better 6 months survival
than the latter one, but critics argue that the
ECMO patients received a best practice
treatment in specialized centers, while the
control group treatment was left to the discretion
of physicians in multiple non-specialized
hospitals.
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AIRWAY PRESSURE RELEASE VENTILATION
(APRV)
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APRV uses high continuous airway pressure to
promote alveolar recruitment and to maintain
adequate lung volume, and a time-cycled release
phase to a lower pressure in supplementing
spontaneous minute ventilation.
By allowing unrestricted spontaneous breathing
throughout the ventilator cycle, APRV allows for
better ventilation of dependent lung regions;
spontaneous breathing reduces atelectasis.
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These modes of ventilation may lead to ventilation
with a low tidal volume leading to hypercapnia,
which is termed “permissive hypercapnia” as it is a
necessity for safe ventilation.
Permissive hypercapnia should probably be used with
caution in patients with heart disease and is
relatively contraindicated in those with elevated
intracranial pressure.
TARGET BLOOD GASES
Oxygenation targets and FiO2
 There must be a compromise between the major
determinants of oxygenation including the extent
of poorly or non-aerated lung, hypoxic pulmonary
vasoconstriction and mixed venous oxygen
saturation, and the target PaO2.
 The association between cognitive impairment
and arterial saturation (SaO2 ) <90% suggests
that a SaO2 > 90%, usually PaO2 >60mmHg, is
a reasonable target.
 Because positive-pressure ventilation may reduce
cardiac output it is also important to consider
tissue oxygenation.
In addition to PEEP, increased FiO2 is used to
improve SaO2.
 However, high FiO2 may also cause tissue injury
including diffuse alveolar damage. The balance
between increased airway pressure and FiO2 is
unknown, but high FiO2 is generally regarded as
being less damaging.
 A reasonable compromise is to start ventilation
at a FiO2 of 1 and to titrate down, aiming for a
FiO2 >0.6.
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Carbon dioxide target
 Low VT strategies will result in elevations in
PaCO2 unless minute ventilation is augmented
by an increase in respiratory rate.
 The ARDS Network protocol aimed at
normocapnia, with a maximum respiratory rate
of 35, to minimise respiratory acidosis.
 This exposes the lung to more repeated tidal
stretch, and may result in dynamic
hyperinflation due to a shortened expiratory
time.
 In addition, allowing the PaCO2 to rise above
normal may not be harmful in many patients
If hypercapnic acidosis occurs slowly, intracellular
acidosis is well compensated, and the associated
increase in sympathetic tone may augment cardiac
output and blood pressure.
 Although the respiratory acidosis may worsen
pulmonary hypertension and induce myocardial
arrhythmias these effects are often small.
 In addition, in an ischaemia–reperfusion model of
ARDS, therapeutic hypercapnia reduced lung injury
and apoptosis.
 However, clinical studies of permissive hypercapnia
must be undertaken before therapeutic hypercapnia
is considered.
 Hypercapnia should be avoided in patients with or at
risk from raised intra-cranial pressure.
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ADDITIONAL MEASURES TO
IMPROVE OXYGENATION
PRONE POSTURE
 In ∼70% of patients with ARDS, prone positioning will
result in a significant increase in PaO2, with a modest
increase in PaO2 sustained in the supine position.
 The mechanisms involved include recruitment of dorsal
lung, with concurrent ventral collapse; however,
perfusion is more evenly distributed leading to better
V/Q matching.
 Recent meta-analysis did not show an improvement in
overall mortality; however, when studies only enrolling
patients with moderate and severe ARDS were examined,
prone position was associated with reduced ICU mortality
without increased airway complications.
Meta-regression revealed a trend to better results
with longer periods of prone position.
 These data support the use of prone positioning as
rescue therapy in life-threatening hypoxaemia.
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Inhaled vasodilators
 The recognized pulmonary hypertension, right heart
dysfunction, and severe hypoxemia which
characterizes ARDS has prompted investigators to
consider treatment strategies to address both
parameters.
 The most promising agents for treatment of
hypoxemia and pulmonary hypertension have been
inhaled vasodilators.
Systemic administration of vasodilators including
prostagladin based vasodilators and sildenafil
have been unable to show a therapeutic effect in
ARDS and are often associated with worsening of
oxygenation indices.
 In contrast, inhaled vasodilators reduce
pulmonary arterial pressure and redistribute
blood flow to well ventilated lung regions with
little to no systemic side effects.
 The two most frequently investigated agents are
inhaled nitric oxide and inhaled prostacyclin.
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PHARMACOLOGICAL THERAPY
Neuromuscular blocking agents (NMBS)
 Neuromuscular blocking agents (NMBS) are
frequently used in the management of ARDS patients
to facilitate patient-ventilator synchrony and improve
poor oxygenation when traditional sedation is not
adequate.
 Under these conditions, NMBA are frequently
effective.
 Less clear is their role in the management of ARDS
patients with less severe disease.
Given the frequent association of NMBA with
critical illness myopathy, understanding the
risk/benefit profile of these medications in the
treatment of ARDS patients is especially
important.
 Theoretically, short-term paralysis may facilitate
patient ventilator synchrony in the setting of lung
protective ventilation.
 Short-term paralysis would eliminate patient
triggering, active expiratory muscle activity, and
overventilation.
 In combination, these effects may serve to limit
regional overdistention (volutrauma) and cyclic
alveolar collapse (atelectrauma).
 Paralysis may also act to lower metabolism and
overall ventilatory demand.
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SURFACTANT REPLACEMENT THERAPY
 Surfactant dysfunction is an important and early
abnormality contributing to lung damage in ARDS.
 Pulmonary surfactant reduces surface tension
promoting alveolar stability, reducing work of
breathing and lung water.
 In paediatric ARDS, particularly that due to direct
lung injury, clinical trials have been promising.
 However, in adults results have been disappointing;
subgroup analysis of recombinant surfactant proteinC-based surfactant administered intratracheally
improved oxygenation in direct ARDS without an
improvement in mortality.
GLUCOCORTICOIDS
 Glucocorticoids may have a role in ARDS through
their reduction of the intense inflammatory response
and their potential to reduce fibroproliferation and
collagen deposition, by faster degradation of
fibroblast procollagen mRNA.
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Preventative steroids increase the incidence of ARDS
and, although there may be a greater number of
ventilator-free days and the possibility of a reduction
in mortality, neuromuscular complications, and
increased mortality when steroids are administered
more than 13 days after the onset of ARDS, argue
against their routine use.
KETOCONAZOLE
 Ketoconazole is an antifungal drug that also
inhibits thromboxane synthase and 5-lipooxygenase.
 However, promising results from small studies
in at-risk patients have not been confirmed in a
larger treatment trial.
THERAPEUTIC STRATEGIES FOR
HEMODYNAMIC MANAGEMENT
In addition to problems with gas exchange, ARDS
patients frequently have evidence for cardiovascular
failure.
 The Fluid and Catheter Treatment Trial (FACTT), as
part of the ARDSNetwork, compared specific
management protocols guided by either a PAC or
central venous catheter.
 This study showed no differences in clinical outcomes
with respect to 60-day survival, ventilator-free days,
renal function, need for hemodialysis, or vasopressor
therapy.
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This trial incorporated device specific estimates of
preload and fluid management.
 No differences in fluid management were noted with
the use of the respective monitoring devices
 ARDSNetwork published their findings from a
prospective, randomized controlled trial of fluid
conservative versus fluid liberal management
strategies in ARDS patients.
 The fluid conservative intervention was associated
with a net even fluid balance in the ARDS
population during the first week of therapy.
 This contrasted with the liberal treatment group
and, where net fluid balance approximates 1 liter
per day of hospitalization.
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FUTURE NON-VENTILATORY THERAPEUTIC
OPTIONS
Gene therapy for ARDS
 several in vitro and animal studies have previously
shown that beta agonist salbutamol activate β-2
receptors on alveolar type-1 and type-2 cells, which
increase intracellular cAMP, leading mainly to increased
AFC.
 In 2011 the ARDS-net sponsored the ALTA study in
which 280 patients with acute lung injury, as defined by
PaO2 and FiO2 ratio of 300 or less, were randomized to
receive aerosolized salbutamol (at dose of 5 mg) or
placebo every 4 hours for up to 10 days.
 Unfortunately, the trial was stopped earlier because the
primary end point, ventilator free days (VFDs), had
crossed predefined futility boundaries.
More recently, a large multicenter RCT,
performed across 46 ICUs in the United
Kingdom, showed that intravenous salbutamol is
even hazardous for patients with early and
severe ARDS .
 In fact, patients treated with salbutamol at dose
of 15 μg/kg ideal bodyweight/h had higher
mortality at 28 days and lower ventilator and
organ failure free days.
 The reason of these unfavorable outcomes seems
to be related to higher rates of side effects as
tachycardia, arrhythmias, and lactic acidosis in
the interventional arm.
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Based on the negative results of these large
RCTs, to overcome the problem of systemic side
effects of beta 2 receptors agonists, transfer of α2
subunit or β1 subunit of Na+/K+ ATPase has
been demonstrated to increase the expression of
Na+/K+ ATPase on alveolar epithelial cells and
to improve AFC.
 A number of studies have demonstrated the role
of growth factors in increasing AFC.
 In a mouse model of hyperoxia and oleic acid
induced acute lung injury, liposome transfer of
gene encoding keratinocyte growth factor
attenuated lung injury likely increasing the
proliferation of alveolar epithelial cells .
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Gene transfer of HO-1 provided lung protection
against hyperoxia, influenza virus pneumonia
and endotoxin mediated lung injury.
Mesenchymal stem cells:
 MSCs have several properties that make them
promising as a therapeutic approach in ARDS.
 MSCs differentiating into several cell types have
regenerative properties and may repair damaged
tissues.
 In addition, they can release many molecules,
which contribute to immunomodulatory and antiinflammatory effect.
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