1

.INTRODUCTION
ARDS is a severe lung disease caused by a variety of direct and indirect
issues. It is characterized by inflammation of the lung parenchyma leading to impaired gas
exchange with concomitant systemic release of inflammatory mediators causing inflammation,
hypoxemia and frequently resulting in multiple organ failure. This condition is often fatal,
usually requiring mechanical ventilation and admission to an intensive care unit. A less severe
form is called acute lung injury (ALI).
ARDS formerly most commonly signified adult respiratory distress syndrome
to differentiate it from infant respiratory distress syndrome in premature infants. However, as
this type of pulmonary edema also occurs in children, ARDS has gradually shifted to mean acute
rather than adult. The differences with the typical infant syndrome remain.
ACUTE RESPIRATORY DISTRESS SYNDROME
Acute respiratory distress syndrome (ARDS) is a sudden and progressive form of
acute respiratory failure in which alveolar membrane becomes damaged and more permeable to
intra vascular fluid.
It is also known as respiratory distress syndrome (RDS) or adult respiratory distress
syndrome (in contrast with IRDS) is a serious reaction to various forms of injuries to the lung
HISTORICAL BACKGROUND
Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et
al. Initially there was no definition, resulting in controversy over incidence and mortality. In
1988 an expanded definition was proposed which quantified physiologic respiratory impairment.
During respiratory distress the patients lungs collapse, intubation is required.
The aveolar are ineffective in providing for adequate gas exchange, so acidosis occurs as the
CO2 accumulates systemically indicating the need to provide carbonate fluids to reverse
respiratory acidosis. Respiratory distress is a medical emergency and intubation should be
2

attempted at the first possible sign of respiratory distress as the esophagus will begin to swell and
close off the airway completely.
In 1994 a new definition was recommended by the American-European
Consensus Conference Committee. It had two advantages: 1 it recognizes that severity of
pulmonary injury varies, 2 it is simple to use
ARDS was defined as the ratio of arterial partial oxygen tension (PaO
2
) as
fraction of inspired oxygen (FiO
2
) below 200 mmHg in the presence of bilateral alveolar
infiltrates on the chest x-ray. These infiltrates may appear similar to those of left ventricular
failure, but the cardiac silhouette appears normal in ARDS. Also, the pulmonary capillary wedge
pressure is normal (less than 18 mmHg) in ARDS, but raised in left ventricular failure.
A PaO
2
/FiO
2
ratio less than 300 mmHg with bilateral infiltrates indicates acute lung injury
(ALI). Although formally considered different from ARDS, ALI is usually just a precursor to
ARDS.
Consensus after 1967 and 1994
ARDS is characterized by
Acute onset
Bilateral infiltrates on chest radiograph sparing costophrenic angles
Pulmonary artery wedge pressure < 18 mmHg (obtained by pulmonary artery
catheterization), if this information is available; if unavailable, then lack of clinical
evidence of left ventricular failure suffices
if PaO
2
:FiO
2
< 300 mmHg (40 kPa) acute lung injury (ALI) is considered to be present
if PaO
2
:FiO
2
< 200 mmHg (26.7 kPa) acute respiratory distress syndrome (ARDS) is
considered to be present
To summarize and simplify, ARDS is an acute (rapid onset) syndrome (collection of symptoms)
that affects the lungs widely and results in a severe oxygenation defect, but is not heart failure
3

EPI DEMI OLOGY
The annual incidence of ARDS is 1.513.5 people per 100,000 in the general
population. Its incidence in the intensive care unit (ICU), mechanically ventilated population is
much higher. Brun-Buisson et al. (2004) reported a prevalence of acute lung injury (ALI) (see
below) of 16.1% percent in ventilated patients admitted for more than 4 hours. More than half
these patients may develop ARDS.
Mechanical ventilation, sepsis, pneumonia, shock, aspiration, trauma
(especially pulmonary contusion), major surgery, massive transfusions, smoke inhalation, drug
reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or
pulmonary embolectomy may all trigger ARDS. Pneumonia and sepsis are the most common
triggers, and pneumonia is present in up to 60% of patients. Pneumonia and sepsis may be either
causes or complications of ARDS.
Elevated abdominal pressure of any cause is also probably a risk factor for the
development of ARDS, particularly during mechanical ventilation.
The mortality rate varies from 30% to 85%. Usually, randomized controlled trials
in the literature show lower death rates, both in control and treatment patients. This is thought to
be due to stricter enrollment criteria. Observational studies generally report 50%60% mortality.
ETIOLOGY
Causes of Acute Respiratory Distress Syndrome (ARDS)
There are a number of underlying conditions that can lead to ARDS. However,
in most cases, people with these conditions do not develop ARDS. It is not clear why some
people are at a higher risk than others.
Direct lung injury
-Common causes
Aspiration of gastric contents or other substances
4

Viral/bacterial pneumonia
-Less common causes
Chest trauma
Embolism;fat,air,amniotic fluid
Inhalation of toxic substances
Near-drowning
O
2
toxicity
Radiation pneumonitis
Indirect lung injury
-Common causes
Sepsis(especially gram negative infection)
Severe massive trauma
-Less common causes
Acute pancreatitis
Anaphylaxis
Cardio pulmonary bypass
Disseminated intravascular coagulation
Multiple blood transfusions
Narcotic drug overdose(eg;heroin)
Nonpulmonary systemic diseases
Severe head injury
Shock states
ARDS can occur within 24 to 48 hours of an injury (trauma, burns, aspiration, massive
blood transfusion, drug/alcohol abuse) or an acute illness (infectious pneumonia, sepsis,
acute pancreatitis
5

Injury to the Alveoli
About 90% of the cells that make up the alveoli are very thin "type I
epithelial cells" across which actual gas exchange takes place. Oxygen normally diffuses
very easily through this layer of cells into the capillaries where it binds with the
hemoglobin in the red blood cells
The alveolar epithelial cells normally form a very tight barrier around the
alveolar space, preventing any fluid from entering and disrupting gas exchange. In
ARDS, the alveolar epithelial barrier breaks, allowing flooding of the alveolar space and
making it difficult or impossible for oxygen to diffuse into the capillaries.
ARDS also can affect the "type II alveolar cells". Type II cells are
thicker, square-shaped cells and the main function of these cells is to produce surfactant.
Surfactant plays an essential role in preventing the alveoli from collapsing. The flooding
through the broken type I cell barrier and the diminished production of surfactant by the
type II cells collapse the alveoli.
Alveolar damage is increased by the activity of immune system
cells (neutrophils) that rush to the site of injury, ironically, to help out. The activity of
these cells and the inflammation they cause create a cascade of further injury that may
extend into the capillaries as well.
Injury to the Alveolar Capillaries
If the original injury is in the alveolar capillaries that lie just beneath
the alveoli, chemical mediators (usually cytokines) that the immune system releases in
response, rush to the site of the injury, damaging and causing inflammation to the cells
that line the capillaries (i.e., the capillary endothelium).
As a result, cells and fluid leak through the capillaries and into the
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alveolar spaces; the capillaries become blocked with cellular debris and fibrin (i.e.,
protein that makes up blood clots); surfactant production ceases; and the alveoli collapse.
PATHOPHYSIOLOGY

A pathohistological image of ARDS.
ARDS is a clinical syndrome associated with a variety of pathological
findings. These include pneumonia, eosinophilic pneumonia, cryptogenic organizing pneumonia,
acute fibrinous organizing pneumonia, and diffuse alveolar damage (DAD). Of these, the
pathology most commonly associated with ARDS is DAD.
DAD is characterized by a diffuse inflammation of lung parenchyma. The
triggering insult to the parenchyma usually results in an initial release of cytokines and other
inflammatory mediators, secreted by local epithelial and endothelial cells.
Neutrophils and some T-lymphocytes quickly migrate into the inflamed
lung parynchema and contribute in the amplification of the phenomenon.
Typical histological presentation involves diffuse alveolar damage
and hyaline membrane formation in alveolar walls.
Although the triggering mechanisms are not completely understood,
recent research has examined the role of inflammation and mechanical stress.
7

Inflammation
Inflammation alone, as in sepsis, causes endothelial dysfunction, fluid
extravasation from the capillaries and impaired drainage of fluid from the lungs. Dysfunction of
type II pulmonary epithelial cells may also be present, with a concomitant reduction in surfactant
production. Elevated inspired oxygen concentration often becomes necessary at this stage, and
they may facilitate a 'respiratory burst' in immune cells.
In a secondary phase, endothelial dysfunction causes cells and inflammatory exudate to enter the
alveoli. This pulmonary edema increases the thickness of the alveolo-capillary space, increasing
the distance the oxygen must diffuse to reach blood. This impairs gas exchange leading to
hypoxia, increases the work of breathing, eventually induces fibrosis of the airspace.
Moreover, edema and decreased surfactant production by type II pneumocytes may cause whole
alveoli to collapse, or to completely flood. This loss of aeration contributes further to the right-
to-left shunt in ARDS. As the alveoli contain progressively less gas, more blood flows through
them without being oxygenated resulting in massive intrapulmonary shunting.
Collapsed alveoli (and small bronchi) do not allow gas exchange. It is not uncommon to see
patients with a PaO
2
of 60 mmHg (8.0 kPa) despite mechanical ventilation with 100% inspired
oxygen.
The loss of aeration may follow different patterns according to the nature of the underlying
disease, and other factors. In pneumonia-induced ARDS, for example, large, more commonly
causes relatively compact areas of alveolar infiltrates. These are usually distributed to the lower
lobes, in their posterior segments, and they roughly correspond to the initial infected area.
In sepsis or trauma-induced ARDS, infiltrates are usually more patchy and diffuse. The posterior
and basal segments are always more affected, but the distribution is even less homogeneous.
Loss of aeration also causes important changes in lung mechanical properties. These alterations
are fundamental in the process of inflammation amplification and progression to ARDS in
mechanically ventilated patients.
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Mechanical stress
Mechanical ventilation is an essential part of the treatment of ARDS.
As loss of aeration (and the underlying disease) progress, the work of breathing (WOB)
eventually grows to a level incompatible with life. Thus, mechanical ventilation is
initiated to relieve respiratory muscles of their work, and to protect the usually obtunded
patient's airways.
However, mechanical ventilation may constitute a risk factor for the
development, or the worsening, of ARS
]

Aside from the infectious complications arising from invasive ventilation
with tracheal intubation, positive-pressure ventilation directly alters lung mechanics
during ARDS. The result is higher mortality, i.e. through baro-trauma, when these
techniques are used.
In 1998, Amato et al. published a paper showing substantial improvement
in the outcome of patients ventilated with lower tidal volumes (V
t
) (6 mL kg
1
).This
result was confirmed in a 2000 study sponsored by the NIH.Although both these studies
were widely criticized for several reasons, and although the authors were not the first to
experiment lower-volume ventilation, they shed new light on the relationship between
mechanical ventilation and ARDS.
One opinion is that the forces applied to the lung by the ventilator
may work as a lever to induce further damage to lung parenchyma. It appears that shear
stress at the interface between collapsed and aerated units may result in the breakdown of
aerated units, which inflate asymmetrically due to the 'stickiness' of surrounding flooded
alveoli. The fewer such interfaces around an alveolus, the lesser the stress.
9

Indeed, even relatively low stress forces may induce signal
transduction systems at the cellular level, thus inducing the release of inflammatory
mediators.
This form of stress is thought to be applied by the transpulmonary
pressure (gradient) (P
l
) generated by the ventilator or, better, its cyclical variations. The
better outcome obtained in patients ventilated with lower V
t
may be interpreted as a
beneficial effect of the lower P
l
. Transpulmonary pressure, is an indirect function of the
V
t
setting on the ventilator, and only trial patients with plateau pressures (a surrogate for
the actual P
l
) were less than 32 cmH
2
O (3.1 kPa) had improved survival.
The way P
l
is applied on alveolar surface determines the shear stress to
which lung units are exposed. ARDS is characterized by a usually inhomogeneous
reduction of the airspace, and thus by a tendency towards higher P
l
at the same V
t
, and
towards higher stress on less diseased units.
The inhomogeneity of alveoli at different stages of disease is further
increased by the gravitational gradient to which they are exposed, and the different
perfusion pressures at which blood flows through them. Finally, abdominal pressure
exerts an additional pressure on inferoposterior lung segments, favoring compression and
collapse of those units.
The different mechanical properties of alveoli in ARDS may be
interpreted as having varying time constants (the product of alveolar compliance
resistance). A long time constant indicates an alveolus which opens slowly during tidal
inflation, as a consequence of contrasting pressure around it, or altered water-air interface
inside it (loss of surfactant, flooding).


10


Slow alveoli are said to be 'kept open' using positive end-
expiratory pressure, a feature of modern ventilators which maintains a positive airway
pressure throughout the whole respiratory cycle. A higher mean pressure cycle-wide
slows the collapse of diseased units, but it has to be weighed against the corresponding
elevation in P
l
/plateau pressure. Newer ventilatory approaches attempt to maximize mean
airway pressure for its ability to 'recruit' collapsed lung units while minimizing the shear
stress caused by frequent openings and closings of aerated units.
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prone position also reduces the inhomogeneity in alveolar time
constants induced by gravity and edema. If clinically appropriate, mobilization of the
ventilated patient can assist in achieving the same goal
Mediators of Acute Lung Injury
Complement component CSa
eutrophil products, induding proteases and O
2
radicals
Monocyte and macrophage products, induding tumor necrosis
factor, interleukin-I, and colony-stimulating factor
Arachidonic acid metabolites, induding prostaglandins and
leukotrienes
Coagulation products, induding kallikreins, kinins, fibrin degra-
dation products, and plasminogen-activating factor
Histamine
Serotonin
Endotoxin
Elastase
Collagenase
The pathophysiologic changes in ARDS are divided into three phases:
(I) injury or exudative phase,
(2) reparative or proliferative phase, and
(3) fibrotic phase.
Injury or Exudative Phase. The injury or exudative phase occurs
approximately I to 7 days (usually 24 to 48 hours) after the initial direct lung injury or
host insult. eutrophils adhere to the pulmonary microcirculation, causing damage to the
12

vascular endothelium and increased capillary permeability. In the earliest phase of
injury, there is engorgement of the peribronchial and perivascular interstitial space,
which produces interstitial edema. Next, fluid from the interstitial space crosses the
alveolar epithelium and enters the alveolar space. Intrapulmonary shunt develops
because the alveoli fill with fluid, and blood passing through them cannot be oxygenated
Alveolar type I and type II cells (which produce surfactant) are damaged
by the changes caused by ARDS. This damage, in addition to further fluid and protein
accumulation, results in surfactant dysfunction. The function of surfactant is to maintain
alveolar stability by decreasing alveolar surface tension and preventing alveolar
collapse. Decreased synthesis of surfactant and inactivation or existing surfactant cause
the alveoli to become unstable and collapse (atelectasis). Widespread atelectasis further
decreases lung compliance, compromises gas exchange, and contributes to hypoxemia.
Also during this stage, hyaline membranes begin to line the alveoli. The
hyaline membrane is composed of necrotic cells, protein, and fibrin and lies adjacent to
the alveoli wall. These hyaline membranes are thought to result from the exudation of
high-molecular-weight substances (particularly fibrinogen) in the edema fluid. Hyaline
membranes contribute to the development of fibrosis and atelectasis, leading to a
decrease in gas exchange capability and lung compliance.
The primary pathophysiologic changes that characterize the injury or
exudative phase of ARDS are interstitial and alveolar edema (noncardiogenic pulmonary
edema) and atelectasis." Severe V/Q mismatch and shunting of pulmonary capillary blood
result in hypoxemia unresponsive to increasing concentrations of O
2
(termed refractory
hypoxemia). Diffusion limitation, caused by hyaline membrane formation, further
contributes to the severity of the hypoxemia. As the lungs become less compliant
because of decreased surfactant, pulmonary edema, and atelectasis, the patient must
generate higher airway pressures to inflate "stiff" lungs. Reduced lung compliance
greatly increases the patient's work of breathing.

13



Hypoxemia and the stimulation of juxta capillary receptors in the
stiff lung parenchyma (J reflex) initially cause an increase in respiratory rate and
decrease in tidal volume. This breathing pat- tern increases CO
2
removal, producing
respiratory alkalosis. Cardiac output increases in response to hypoxemia, a
compensatory effort to increase pulmonary blood flow. However, as atelectasis,
pulmonary edema, and pulmonary shunt increase, compensation fails, and
hypoventilation, decreased cardiac output, and de- creased tissue O
2
perfusion eventually
occur.
Reparative or Proliferative Phase. The reparative or
proliferative phase of ARDS begins I to 2 weeks after the initial lung injury. During this
phase, there is an influx of neutrophils, monocytes, and lymphocytes and fibroblast
proliferation as part of the inflammatory response. The injured lung has an immense
regenerative capacity after acute lung injury. The proliferative phase is complete when
the diseased lung becomes characterized by dense, fibrous tissue. Increased pulmonary
vascular resistance and pulmonary hypertension may occur in this stage because
fibroblasts and inflammatory cells destroy the pulmonary vasculature. Lung compliance
continues to decrease as a result of interstitial fibrosis. Hypoxemia worsens because of
14

the thickened alveolar membrane, causing diffusion limitation and shunting. If the
reparative phase persists, widespread fibrosis results. If the reparative phase is arrested,
the lesions resolve.
Fibrotic Phase. The fibrotic phase of ARDS occurs approximately 2 to
3 weeks after the initial lung injury. This phase is also called the chronic or late phase of
ARDS. By this time, the lung is completely remodeled by sparsely collagenous and
fibrous tissues. There is diffuse scarring and fibrosis, resulting in decreased lung
compliance. In addition, the surface area for gas exchange is significantly reduced
because the interstitium is fibrotic, and therefore hypoxemia continues. Pulmonary
hypertension results from pulmonary vascular destruction and fibrosis.

CLINICAL PROGRESSION
Progression of ARDS varies among patients. Some persons
survive the acute phase of lung injury; pulmonary edema resolves and complete recovery
occurs in a few days. The chance [or survival is poor in patients who enter the fibrotic
(chronic or late) stage,which requires long-term mechanical ventilation. It is not known
why injured lungs repair and recover in some patients, and in others ARDS progresses.
Several factors seem to be important in determining the course of ARDS, including the
nature of the initial injury, extent and severity of coexisting diseases, and pulmonary
complications.
If the underlying disease or injurious factor is not removed, the amount of
inflammatory mediators released by the lungs in ARDS may result in a systemic inflammatory
response syndrome (or sepsis if there is lung infection) The evolution towards shock and/or
multiple organ failure follows paths analogous to the pathophysiology of sepsis.
This adds up to the impaired oxygenation which is the central problem of
ARDS, as well as to respiratory acidosis, which is often caused by ventilation techniques such as
permissive hypercapnia which attempt to limit ventilator-induced lung injury in ARDS.
15

The result is a critical illness in which the 'endothelial disease' of severe
sepsis/SIRS is worsened by the pulmonary dysfunction, which further impairs oxygen delivery.
CLINICAL MANIFESTATIONS
The initial presentation of ARDS is often insidious. At the time of the
initial injury, and for several hours to I to 2 days afterward, the patient may not
experience respiratory symptoms, or the patient may exhibit only dyspnea, tachypnea,
cough, and restlessness. Chest auscultation may be normal or reveal fine, scattered
crackles. ABGs usually indicate mild hypoxemia and respiratory alkalosis caused by
hyperventilation. Respiratory alkalosis results from hypoxemia and the stimulation of
juxtacapillary receptors. The chest x-ray may be normal or exhibit evidence of minimal
scattered interstitial infiltrates. Edema may not show on the x-ray until there is a 30%
increase in fluid content in the lung.
The symptoms of ARDS develop suddenly and include the following:
Dyspnea (audible, labored breathing, shortness of breath)
Tachypnea (abnormally rapid breathing)
Severe hypoxaemia (decreased oxygen concentration in the blood)
Pulmonary hypertension (high blood pressure in the pulmonary arteries)
Cyanosis (bluish discoloration of the skin due to poor oxygenation of the blood)
Presence of abnormal deposits in the lungs (detected by chest x-rays)
As ARDS progresses, symptoms worsen because of increased fluid
accumulation and decreased lung compliance. Respiratory di'~omfort becomes evident
as the work of breathing increases. Tachypnea and 1Tlterc stal and suprasternal
retractions may be present . Pulmonary function tests in ARDS reveal decreased
copliance and decreased lung volumes, particularly a decreased functional residual
capacity (FRC). Tachycardia, diaphoresis, changes in sensorium with decreased
mentation, cyanosis, and pallor may be present. Chest auscultation usually reveals
16

scattered to diffuse crackles and rhonchi. The chest x-ray demonstrates dif- fuse and
extensive bilateral interstitial and alveolar infiltrates. A pulmonary artery catheter may
be inserted. Pulmonary artery wedge pressure does not increase in ARDS because the
cause is non cardiogenic (not related to cardiac function).
Hypoxemia and a PaO/FI0
2
ratio below 200 despite increased
FI0
2
by mask, cannula, or endotracheal tube are hallmarks of ARDS. ABGs may initially
demonstrate a normal or decreased PaC0
2
despite severe dyspnea and hypoxemia.
Hypercapnia signifies that hypoventilation is occurring, and the patient is no longer able
to maintain the level of ventilation needed to provide optimum gas exchange.
As ARDS progresses it is associated with profound respiratory
distress requiring endotracheal intubation and positive pressure ventilation (PPY). The
chest x-ray is often termed whiteout or white tung, because consolidation and coalescing
infiltrates are widespread throughout the lungs, leaving few recognizable air spaces.
Pleural effusions may also be present. Severe hypoxemia, hypercapnia, and metabolic
acidosis, with symptoms of target organ or tissue hypoxia, may ensue if prompt therapy
is not instituted.
DIAGNOSTIC MEASURES
An arterial blood gas analysis and chest X-ray allow formal diagnosis by the
aforementioned criteria. Although severe hypoxemia is generally included, the appropriate
threshold defining abnormal PaO
2
has never been systematically studied. Note though, that a
severe oxygenation defect is not synonymous with ventilatory support. Any PaO
2
below 100
(generally saturation less than 100%) on a supplemental oxygen fraction of 50% meets criteria
for ARDS. This can easily be achieved by high flow oxygen supplementation without ventilatory
support.
Any cardiogenic cause of pulmonary edema should be excluded. This can be
done by placing a pulmonary artery catheter for measuring the pulmonary artery wedge pressure.
However, this is not necessary and is now rarely done as abundant evidence has emerged
17

demonstrating that the use of pulmonary artery catheters does not lead to improved patient
outcomes in critical illness including ARDS.
Plain chest X-rays are sufficient to document bilateral alveolar infiltrates in the
majority of cases. While CT scanning leads to more accurate images of the pulmonary
parenchyma in ARDS, it has little utility in the clinical management of patients with
ARDS, and remains largely a research tool


In summary, no precise criteria define ARDS. ARDS is considered to be
present if the patient has (I) refractory hypoxemia, (2) a chest x-ray with new bilateral
interstitial or alveolar infiltrates, (3) a pulmonary artery wedge pressure of 18 mm Hg or
less and no evidence of heart failure, and (4) a predisposing condition for ARDS within
48 hours of clinical manifestations
Refractory Hypoxemia
Pa0
2
<50 mm Hg on FI0
2
>40% with PEEP >5 em H
2
0 PaOz/FI0
2
ratio <200
Chest X-ray New bilateral interstitial and alveolar infiltrates
Pulmonary Artery Wedge Pressure :</=18 mm Hg and no evidence of heart failure
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Predisposing Condition
Identification of a predisposing condition for ARDS within 48 hours of clinical
manifestations
MANAGEMENT
*RESPIRATORY THERAPY
Oxygen administration
primary goal of O2 therapy is to correct hypoxemia .O2 administered via
a simple face mask or nasal cannula is usually inadequate to treat refractory hypoxemia
that is associated with ARDS.Masks with high flow systems that deliver higher O2
concentrations are initially used to maximize O2 delivery.The general standard for O2
administration is to give the patient the lowest concentration that results in a PaO2 of 60
mmHg or greater When the FiO2 exceeds 60% for more than 48 hrs, the risk for O2
toxicity increases.The patients with ARDS commonly need intubation with mechanical
ventilation because the PaO2 cannot otherwise be maintained at acceptable levels.
Commonly used supportive therapy includes particular techniques of
mechanical ventilation and pharmacological agents whose effectiveness with respect to the
outcome has not yet been proven. It is now debated whether mechanical ventilation is to be
considered mere supportive therapy or actual treatment, since it may substantially affect survival.
Mechanical ventilation
Acute respiratory distress syndrome is usually treated with mechanical
ventilation in the Intensive Care Unit. Ventilation is usually delivered through oro-tracheal
intubation, or tracheostomy whenever prolonged ventilation (2 weeks) is deemed inevitable.
The possibilities of non-invasive ventilation are limited to the very early period
of the disease or, better, to prevention in individuals at risk for the development of the disease
(atypical pneumonias, pulmonary contusion, major surgery patients).
Further information: Pressure Regulated Volume Control
19

The overall goal is to maintain acceptable gas exchange and to minimize
adverse effects in its application. Three parameters are used: PEEP (positive end-expiratory
pressure, to maintain maximal recruitment of alveolar units), mean airway pressure (to promote
recruitment and predictor of hemodynamic effects) and plateau pressure (best predictor of
alveolar overdistention).
Conventional therapy aimed at tidal volumes (V
t
) of 12-15 ml/kg. Recent
studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma
(secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a landmark trial
that showed improved mortality when ventilated with a tidal volume of 6 ml/kg compared to the
traditional 12 ml/kg. Low tidal volumes (V
t
) may cause hypercapnia and atelectasis
[1]
due to their
inherent tendency to increase dead space.
Low tidal volume ventilation was the primary independent variable associated
with reduced mortality in the NIH-sponsored ARDSnet trial of tidal volume in ARDS. Plateau
pressure less than 30 cm H
2
O was a secondary goal, and subsequent analyses of the data from the
ARDSnet trial (as well as other experimental data) demonstrate that there appears to be NO safe
upper limit to plateau pressure; that is, regardless of plateau pressure, patients fare better with
low tidal volumes (see Hager et al., American Journal of Respiratory and Critical Care Medicine,
2005).
APRV (Airway Pressure Release Ventilation) and ARDS / ALI
No particular ventilator mode is known to improve mortality in ARDS. The
landmark ARDSNet trial used a volume controlled mode and showed decrease mortality with
smaller volumes. However, other modes of ventilation have not been directly compared to
volume controlled ventilation.
Some practitioners favor airway pressure release ventilation (APRV). Advantages to APRV
ventilation include: decreased airway pressures, decreased minute ventilation, decreased dead-
space ventilation, promotion of spontaneous breathing, almost 24 hour a day alveolar
recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized
arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive
20

effect on cardiac output (due to the negative inflection from the elevated baseline with each
spontaneous breath), increased organ and tissue perfusion, potential for increased urine output
secondary to increased renal perfusion.
A patient with ARDS on average spends 8 to 11 days on a mechanical
ventilator; APRV may reduce this time significantly and conserve valuable resources.
A study is needed to evaluate whether APRV will reduce patient mortality
when compared to the ARDSNet protocol. However, there seems to be little political will, within
the medical community, to address the need for this study, in spite of the clinical successes seen
with APRV.
Positive end-expiratory pressure
Positive end-expiratory pressure (PEEP) is used in mechanically-
ventilated patients with ARDS to improve oxygenation. In ARDS, three populations of alveoli
can be distinguished. There are normal alveoli which are always inflated and engaging in gas
exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas
enchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas
exchange under certain ventilatory regimes. The recruitable aveoli represent a continuous
population, some of which can be recruited with minimal PEEP, and others which can only be
recruited with high levels of PEEP. An additional complication is that some or perhaps most
alveoli can only be opened with higher airway pressures than are needed to keep them open.
Hence the justification for maneuvers where PEEP is increased to very high levels for seconds to
minutes before dropping the PEEP to a lower level. Finally, PEEP can be harmful. High PEEP
necessarily increases mean airway pressure and alveolar pressure. This in turn can damage
normal alveoli by overdistension resulting in DAD.
The 'best PEEP' used to be defined as 'some' cmH
2
O above the lower
inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent
research has shown that the LIP-point pressure is no better than any pressure above it, as
recruitment of collapsed alveoli, and more importantly the overdistension of aerated units, occur
throughout the whole inflation. Despite the awkwardness of most procedures used to trace the
21

pressure-volume curve, it is still used by some to define the minimum PEEP to be applied to their
patients. Some of the newest ventilators have the ability to automatically plot a pressure-volume
curve. The possibility of having an 'instantaneous' tracing trigger might produce renewed interest
in this analysis.
PEEP may also be set empirically. Some authors suggest performing a
'recruiting maneuver' (i.e., a short time at a very high continuous positive airway pressure, such
as 50 cmH
2
O (4.9 kPa), to recruit, or open, collapsed units with a high distending pressure)
before restoring previous ventilation. The final PEEP level should be the one just before the drop
in PaO
2
(or peripheral blood oxygen saturation) during a step-down trial.
Intrinsic PEEP (iPEEP), or auto-PEEP, first described by John Marini of St.
Paul Regions Hospital, is a potentially unrecognized contributor to PEEP in patients. When
ventilating at high frequencies, its contribution can be substantial, particularly in patients with
obstructive lung disease. iPEEP has been measured in very few formal studies on ventilation in
ARDS patients, and its contribution is largely unknown. Its measurement is recommended in the
treatment of ARDS patients, especially when using high-frequency (oscillatory/jet) ventilation.
A compromise between the beneficial and adverse effects of PEEP is inevitable.
Extracorporeal Membrane Oxygenator (ECMO) and extracorporeal CO2
removal(ECCO2R)
These pass blood across a gas exchanging membrane outside the
body and then return oxygenated blood back to the body.ECCO2Rwith low frequency
PPV allows the lung to heal while the lung is not functional.
The extracorporeal membrane oxygenator (ECMO) is essentially an
artificial lung. It is an appropriately cased artificial membrane which is attached to the
patient externally (extracorporeally), through a vein or artery. Although the best
substitute for a diseased lung that cannot handle gas exchange adequately is a healthy
human lung, such substitution is often not possible. Circulating the patient's blood
22

through the ECMO offers another approach. Gas exchange using ECMO keeps the
patient alive while the damaged lungs have a chance to heal.
In 1974, the National Heart, Lung, and Blood Institute (NHLBI)
organized a carefully designed clinical trial, to determine the effectiveness of ECMO for
patients with acute respiratory distress syndrome. In this study, ECMO appeared to be no
more useful than conventional therapy. On the other hand, ECMO seems to be an
effective option in some infants with respiratory failure when treatment with mechanical
ventilation fails. However ECMO is expensive, is associated with nonrespiratory
complications, and is available only in a few specialized centers.
Positioning strategies
Prone position

Distribution of lung infiltrates in acute respiratory distress syndrome is non-
uniform. Repositioning into the prone position (face down) might improve oxygenation by
relieving atelectasis and improving perfusion(PaO270 mmHg-supine,PaO2 90 mmHg-
prone)with no change in inspired O2 concentration. However, although the hypoxemia is
overcome there seems to be no effect on overall survival

Lateral rotation therapy
23

The purpose of this therapy is to provide continuous slow side to side turning of
the bed by rotating actual bed time.The lateral movement of the bed is maintained for18 of every
24 hr to stimulate postural drainage and help mobilate pulmonary secretions.The bed may also
contain a vibrator pack that can provide chest physiotherapy.

Fluid management
Several studies have shown that pulmonary function and outcome are better in patients that lost
weight or pulmonary wedge pressure was lowered by diuresis or fluid restriction.
[1]

Pharmacological Therapy
Appropriate antibiotic therapy must be administered as soon as microbiological
culture results are available. Empirical therapy may be appropriate if local microbiological
surveillance is efficient. More than 60% ARDS patients experience a (nosocomial) pulmonary
infection either before or after the onset of lung injury.
24

Corticosteroids
A Meduri et al. study has found significant improvement in ARDS using
modest doses of corticosteroids. The initial regimen consists of methylprednisolone 2 mg/kg
daily. After 35 days a response must be apparent. In 12 weeks the dose can be tapered to
methylprednisolone 0.5-1.0 mg daily. Patients with ARDS do not benefit from high-dose
corticosteroids This was a study involving a small number of patients in one center. A recent
NIH-sponsored multicenter ARDSnet LAZARUS study of corticosteroids for ARDS
demonstrated that they are not efficacious in ARDS.
Nitric oxide
Inhaled nitric oxide (NO) potentially acts as selective pulmonary vasodilator.
Rapid binding to hemoglobin prevents systemic effects. It should increase perfusion of better
ventilated areas. There are no large studies demonstrating positive results. Therefore its use must
be considered individually.
Almitrine bismesylate stimulates chemoreceptors in carotic and aortic bodies. It has been used to
potentiate the effect of NO, presumably by potentiating hypoxia-induced pulmonary
vasoconstriction. In case of ARDS it is not known whether this combination is useful.
Maintenance of cardiac output and tissue perfusion-
crystalloids,colloids/to lower PEEP in decreased cardiac output.use dopamine
and dobutamine also.
Surfactant therapy
To date no prospective controlled clinical trial has shown a significant mortality
benefit of exogenous surfactant in ARDS
surgical management
25

The origin of infection, when surgically treatable, must be operated on. When
sepsis is diagnosed, appropriate local protocols should be enacted.
COMPLICATIONS
Complications may develop as a result of ARDS itself or its treatment. The
major cause of death in ARDS is MODS, often accompanied by sepsis. The vital organs
most commonly involved are the kidneys, liver, and heart. The organ systems most often
involved are the CNS, hematologic system, and gastrointestinal system.
Infection -Catheter-related infection
Nosocomial pneumonia
Sepsis (bacteremia)
Respiratory Complications O
2
toxicity
Pulmonary barotrauma (e.g, pneumothorax, pneumomediastinum, subcutaneous
emphysema)
Pulmonary emboli
Pulmonary fibrosis
Gastrointestinal Complications Paralytic ileus
Pneumoperitoneum
Stress ulceration and hemorrhage
Renal Complications
Acute renal failure
Cardiac Complications Arrhythmias
Decreased cardiac output
Disseminated intravascular coagulation
Thrombocytopenia
Hematologic Complications
Anemia
Disseminated intravascular
26

coagulation
Thrombocytopenia
ET Intubation Complications Laryngeal ulceration
Tracheal malacia
Tracheal stenosis
Tracheal ulceration

Nosocomial Pneumonia.
A frequent complication of ARDS is nosocomial pneumonia, occurring
in as many as 68% of patients with ARDS. Risk factors include impaired host fenses,
contaminated medical equipment, invasive monitor devices, aspiration of gastrointestinal
contents, and pro Ion: mechanical ventilation, as well as colonization of the respirat tract.
Strategies to prevent nosocomial pneumonia include inltion control measures (e.g., strict
hand washing and sterile te nique during endotracheal suctioning) and elevating the head
of the bed 45 degrees or more to prevent aspiration."
Barotrauma.
Barotrauma may result from rupture overdistended alveoli during
mechanical ventilation. The high peak airway pressures that may be required in patients
with ARDS predispose to this complication. Barotrauma results in presence of alveolar
air in locations where it is not usually found. This can lead to pulmonary interstitial
emphysema, pneumothorax, subcutaneous emphysema, pneumoperitoneum, pneumor
diastinum, and tension pneumothorax. To avoid barotrauma, the patient with ARDS is
sometimes ventilated with smaller tidal volumes, resulting in higher PaC0
2
This method
of mechanical ventilan is termed permissive hypercapnia because the PaC0
2
is allowed
(permitted) to rise above normal limits."
Volu-pressure Trauma.
Volu-pressure trauma can occur in patients with ARDS when large tidal
volumes are used to Ventilate noncompliant lungs. volu-pressure trauma results in alveolar
27

fractures and movement of fluids and proteins into the alveolar spaces. To limit this
complication, it is recommended tl smaller tidal volumes or pressure ventilation be used
in patie with ARDS
Stress Ulcers.
Critically ill patients with acute respiratory failure are at high risk for
stress ulcers. Bleeding from stress ulcers occurs in 30% of patients with ARDS who
require PPV higher incidence than other causes of acute respiratory failure. Management
strategies include correction of predisposing conditions such as hypotension, shock, and
acidosis. Prophylcatic management includes antiulcer agents (e.g., famotidine) and early
intiation of enteral nutrition
Renal: acute renal failure (ARF),
Renal failure can occur from decreased renal tissue oxygenation as a result of
hypotension, hypoxemia or hypercapnia.Renal failure may also be caused by
administration of nephrotoxic drugs(eg;aminoglycosides), which are used to treat
infections associated withARDS.
Mechanical:
vascular, pneumothorax (by placing pulmonary artery catheter), tracheal
injury/stenosis (result of intubation and/or irritation by endotracheal tube.
Nutritional: malnutrition (catabolic state), electrolyte deficiency.








28


Vol 171. pp. 518-526, (2005)
2005 American Thoracic Society


NHLBI/CDC/NIAID Workshop
Clinical Issues and Research in Respiratory Failure from
Severe Acute Respiratory Syndrome
Mitchell M. Levy, Melisse S. Baylor, Gordon R. Bernard, Rob Fowler, Teri J. Franks,
Frederick G. Hayden, Rita Helfand, Stephen E. Lapinsky, Thomas R. Martin, Michael S.
Niederman, Gordon D. Rubenfeld, Arthur S. Slutsky, Thomas E. Stewart, Barbara A.
Styrt, B. Taylor Thompson and Andrea L. Harabin
ABSTRACT
The National Heart, Lung, and Blood Institute, along with the

Centers for Disease Control and
Prevention and the National

Institute of Allergy and Infectious Diseases, convened a panel

to
develop recommendations for treatment, prevention, and research

for respiratory failure from
severe acute respiratory syndrome

(SARS) and other newly emerging infections. The clinical and

pathological features of acute lung injury (ALI) from SARS appear

indistinguishable from ALI
from other causes. The mainstay of

treatments for ALI remains supportive. Patients with ALI
from

SARS who require mechanical ventilation should receive a lung

protective, low tidal
volume strategy. Adjuvant treatments recommended

include prevention of venous
thromboembolism, stress ulcer prophylaxis,

and semirecumbent positioning during ventilation.
Based on previous

experience in Canada, infection control resources and protocols

were
recommended. Leadership structure, communication, training,

and morale are an essential aspect
of SARS management. A multicenter,

placebo-controlled trial of corticosteroids for late SARS is

justified because of widespread clinical use and uncertainties

about relative risks and benefits.
Studies of combined pathophysiologic

endpoints were recommended, with mortality as a
secondary endpoint.

The group recommended preparation for studies, including protocols,

ethical
considerations, Web-based registries, and data entry

systems
29