Pathophysiology

The pathophysiology of ARDS is complex and multifaceted. It may be considered as 3 distinct

components, which are the nature of the stimulus that initiates or causes ARDS, the host
response to this stimulus, and, finally, the role that iatrogenic damage plays in the progression
and outcome of this condition. There are 3 pathohistologic stages of ARDS which are further
discussed under histology.

An initiating stimulus leads to a cascade of effects, the most immediate of which is an increase
in alveolar and pulmonary capillary permeability. Protein-rich fluid engulfs the alveolus, activated
neutrophils and macrophages follow, and an inflammatory cascade is initiated. This cascade
involves the release of interleukins (ILs), tumor necrosis factor, and other inflammatory
mediators. Neutrophils release oxidants, leukotrienes, and various proteases. The net effect at a
cellular level is massive cell damage, alveolar denudation, and sloughing of cell debris into the
lumen of the alveolus. Furthermore, surfactant is markedly inactivated.

Meanwhile, in the pulmonary capillary, endothelial cells swell, platelets aggregate, and a
procoagulant cascade may arise, leading to small-vessel thrombosis. At a physiologic level, the
consequences of the reactions outlined above are myriad.

Surfactant depletion, alveolar flooding, cellular debris within the alveoli, and increased airway
resistance all lead to increased work of breathing. Surfactant loss leads to alveolar collapse
because of increased surface tension, which is analogous to the situation observed in
premature infants with infant RDS (IRDS). As alveoli collapse, closing lung volume decreases
below the patient's functional residual capacity (FRC), further increasing the work of breathing.
This is reflected as reduced compliance; that is, additional pressure is required to generate a
unit volume.

A widened interstitial space between the alveolus and the vascular endothelium decreases
oxygen-diffusing capacity. Hypoxia arises as a result of the change described above. Collapsed
alveoli result in either low ventilation-perfusion (V/Q) units or a right-to-left pulmonary shunt. The
end result is marked venous admixture, the process whereby deoxygenated blood passing
through the lungs does not absorb sufficient oxygen and causes a relative desaturation of
arterial blood when it mixes with blood that is oxygenated adequately. Hence, relatively
deoxygenated arterial blood attempts to supply respiratory muscles that are working harder than
usual. These muscles become fatigued; the body is unable to maintain such sustained work of
breathing, and respiratory failure ensues.

In addition, hypoxia, hypercarbia, and small-vessel thrombosis combine to elevate pulmonary

artery pressures, leading to increased right ventricular work, increased right ventricular filling,
and, ultimately, a septal shift toward the left ventricle. These changes, in turn, may decrease
cardiac output, further reducing oxygen delivery to the tissues.
Iatrogenic problems may further complicate the patient's clinical picture. High-inspired oxygen
concentration (FiO2>95%) may cause absorption atelectasis, further reducing the number of
patent alveoli. Oxygen toxicity can be seen with FiO2 more than 60% over time, leading to
additional inflammation secondary to free radical damage.

High mean airway pressures during attempts to maintain adequate oxygenation and ventilation
may decrease cardiac output. In addition, high peak airway pressures may cause air leaks (eg,
pneumothoraces), which may acutely compromise cardiac and respiratory function. Ventilator-
induced lung injury (VILI), discussed in detail below, may further complicate and accelerate
disease progression.

Finally, fluid resuscitation may lead to further alveolar and pulmonary interstitial flooding, with
worsening compliance and oxygenation.