Syn: Acute Respiratory Distress
The most important cause of diffuse alveolar damage is the acute respiratory distress syndrome (ARDS).
In this syndrome, a patient with apparently normal lungs suffers an insult
and then develops rapidly progressive respiratory failure, characterized
by hypoxia and extensive radiologic opacities in both lungs.
Acute Respiratory Distress
is characterized by diffuse alveolar capillary damage, leading to severe
pulmonary edema, respiratory failure and arterial hypoxemia refractory to
Diagnostic studies in patients with acute
respiratory distress syndrome.
unresponsive to oxygen therapy, develops with diffuse bilateral
infiltration on x-ray and frequent superimposed infections, resulting in
death (more than 50 %).
Over the years there has been much debate
about the term ARDS.
Some feel that the definition of rapidly progressive
respiratory failure in a patient with apparently normal lungs is too
broad, since it obviously encompasses many conditions in which a more
specific diagnosis can be made, such as pneumonia of any sort, fat
embolism, pulmonary thromboembolism, aspiration, inhalation of toxic
Others have doubted the existence of ARDS related to
trauma and have held that the pulmonary lesions are due to known causes,
such as oxygen toxicity or hemodynamic
However, there is
now little doubt that ARDS is a useful term and that it is not simply due to
oxygen or hemodynamic
should be recognized that the syndrome of ARDS exists and is
multifactorial and that it is appropriate to qualify the
term as ARDS due to specific conditions, such as nonthoracic trauma,
inhalation of toxic gases, aspiration etc. In addition, oxygen toxicity produces similar lesions, and an idiopathic category should also
The overall medical costs are
enormous, since mangement requires high technology and intensive care.
The syndrome was first recognized as an entity during the Vietnam War as a
result of effective resuscitation techniques for seriously injured combatants.
nonthoracic trauma or infection leads to hemodynamic shock,
from which the patient is resuscitated.
However, recovery is inturrupted
by respiratory symptoms (Example: tachypnea, dyspnea, and
hypoxemia) and a chest radiograph shows diffuse bilateral infiltrates,
which progresses to virtually complete opacification.
The patient requires ventilatory assistance and increasing amounts of oxygen.
The lungs become
stiff (decreased compliance), and increasing end-expiratory pressures are
required, until the patient needs 100% oxygen to maintain tissue
of all patients with Acute
Respiratory Distress Syndrome (ARDS) die.
been studied in patients and in animal models.
The important early event is
leakiness of endothelial capillaries, with morphologic loosening of the
intercellular junctions. At this stage respiratory failure is not
Then, 24 to
48 hours after the initial insult, pulmonary edema and resultant hypoxemia
ensue in the exudative phase.
The next stage is diffuse alveolar damage,
in which necrosis of type I epithelial cells and hyaline membranes that
line the air spaces are prominent.
In the proliferative phase, type II cells multiply to
reconstitute the alveolar lining and an interstitial
inflammatory infiltrate of mononuclear cells is accompanied by
proliferation of fibroblasts.
All these conditions are present
4 to 7 days after the insult, and the patient usually dies in severe
If the patient survives, the lesions may heal with resorption of the alveolar exudates and hyaline membranes and restitution
of the normal alveolar epithelium.
Fibroblastic proliferation ceases and
the extra collagen is metabolized.
It is well documented that patients
with ARDS who recover have normal pulmonary function.
Alternatively, more fibrous
tissue is laid down and the lung then becomes remodeled to produce the
“honeycomb lung” - multiple cyst-like spaces throughout the lung,
separated from each other by fibrous tissue and lined by type II cells,
bronchiolar epithelium, or squamous cells. The
resemblance of the honeycomb lung to the end stage of fibrosing alveolitis
is rarely more than superficial.
Following ARDS there is more active
fibroblastic proliferation and less dense scarring. Bronchiolar epithelium
lining is less promonent and secretions are not present in the spaces.
Occasionally, an appearance
similar to bronchopulmonary dysplasia develops.
In ARDS produced by the
inhalation of toxic gases or near-drowning, the damage
occurs primarily at
the alveolar epithelial surface.As indicated, the alveolar epithelial
junctions are usually very tight ; damage to the epithelium results in
exudation of fluid and proteins from the interstitium into the alveolar
spaces. Endothelial damage may or may not occur in ARDS that is due to
inhalation of toxic substances, but the sequence of events is similar to
that due to endothelial damage in ARDS that follows trauma or septicemia.
Mechanism of injury:
1. Oxygen-derived free radicals, especially in the toxicity induced by prolonged exposure (e.g. in
respirators) to high concentrations of oxygen or other toxins (e.g.- paraquat).
Aggregation of activated neutrophils in the pulmonary vasculature.
have shown that a reduced number of neutrophils in the blood of
patients with risk factors for ARDS is a good predictor for the
development of the syndrome. This finding suggests that increased numbers
of neutrophils are sequestered in the pulmonary capillary bed. These neutrophils damage
epithelium by secreting several types of injurious factors, including
oxygen-derived free radicals and lysosomal enzymes (proteases). It also
secretes arachidonic acid metabolites that induce neutrophil aggregation.
3. Activation of lung
which release oxidants, proteases and proinflammatory
cytokines (e.g. IL-8).
4. Loss or damage to surfactant,
contributing to atelectasis, which (in combination with pulmonary edema)
results in the stiff lungs characteristic of ARDS.
The basic lesion is diffuse
damage to the alveolar wall, initially involving the capillary endothelium
but eventually the epithelium as well.
Damage leads to the acute stage of ARDS with increased capillary permeability and edema, fibrin exudation,
formation of hyaline membrane (composed of necrotic epithelial cell debris
and exuded proteins), and septal inflammation.
In the acute stage:
Gross features: lungs are
diffusely firm, red, boggy, and heavy.
Microscopic features: Shows
diffuse alveolar damage with interstitial and intra-alveolar edema,
hyaline membranes and acute inflammation.
In the proliferative/organizing
There are patchy areas of intersititial fibrosis and type-II epithelial proliferation, frequently,
in fatal cases with superimposed bacterial infection.
The Adult Respiratory Distress Syndrome:
- In ARDS, Type1 cells die as a
result of diffuse alveolar damage.
- Intra-alveolar edema
follows, after which there is formation of hyaline membrane
composed of proteinaceous exudate and cell debris.
- In the acute phase the
lungs are markedly congested and heavy.
- Type II cells multiply
to line the alveolar surface.
inflammation is characteristic.
- The lesion may
or progress to interstitial fibrosis.
Before 1992, the acronym ARDS represented the adult respiratory
distress syndrome. The American-European Consensus Committee on ARDS
standardized the definition in 1994 and renamed it acute rather than
adult respiratory distress syndrome because it occurs at all ages. The
term acute lung injury (ALI) was also introduced at that time. The
committee recommended that ALI be defined as "a syndrome of
inflammation and increased permeability that is associated with a
constellation of clinical, radiologic, and physiologic abnormalities
that cannot be explained by, but may coexist with, left atrial or
pulmonary capillary hypertension.
of the American-European consensus conference on ARDS: definitions,
mechanisms, relevant outcomes and clinical trial coordination.
Intensive Care Med 1994;20:225-32.