anti-inflammatory mediators, including cytokines such as IL-10 and IL-11.

Proposed important components of the pathogenesis of ARDS include:

1.Inflammation in the pulmonary parenchyma, particularly with neutrophils

2.Activation of the vascular endothelium and expression of leukocyte adhesion molecules

3.Release of multiple cytokine mediators, proteases, and oxidants

4.Release of procoagulants and activation of the coagulation system

Activation of complement is just one of multiple potential mechanisms for recruiting and sequestering neutrophils in the lungs. Other important factors include various cytokines and other mediators that influence neutrophil trafficking in the lungs. Vascular endothelial cells, particularly in the pulmonary vascular system, also become activated, express leukocyte adhesion molecules, and lead to accumulation of neutrophils within the pulmonary vasculature.

Another important process appears to be activation of the coagulation system. Several factors are responsible for what has been called a “procoagulant state,” including release of procoagulant tissue factors, a decreased concentration of factors with anticoagulant activity (e.g., protein C and protein S), and increased activity of proteins that inhibit fibrinolysis (e.g., plasminogen activator inhibitor-1). The result is increased production of thrombin and fibrin, as well as evidence of thrombosis within pulmonary capillaries.

Despite extensive research efforts over the past decades to explain the mechanisms of acute lung injury, a complete understanding of ARDS remains elusive. Recently, potential roles for the innate immune system (including alveolar macrophages and dendritic cells), toll-like receptors, and mitochondrial damage–associated molecular patterns (DAMPs) are actively being investigated. Further clarification of pathogenesis and the importance of various pathways and mediators will be critical to the development of effective forms of prevention and therapy.

Pathology

Despite the number of etiologic factors in ARDS, the pathologic findings are relatively similar regardless of the underlying cause. As observed by the pathologist, this pattern of injury accompanying ARDS is labeled diffuse alveolar damage.

Pathologic features of ARDS:

1.Damage to alveolar type I epithelial cells

2.Interstitial and alveolar fluid

3.Areas of alveolar collapse

4.Inflammatory cell infiltrate

5.Hyperplasia of alveolar type II epithelial cells

6.Hyaline membranes

7.Fibrosis

8.Pulmonary vascular changes

Injury to type I alveolar epithelial cells and pulmonary capillary endothelial cells appears to be the

primary factor in pathogenesis. Type I epithelial cells frequently appear necrotic and may slough from the surface of the alveolar wall. Damage to capillary endothelial cells is generally more difficult if not impossible to recognize with light microscopy; electron microscopy may be necessary to appreciate their subtle ultrastructural changes.

Early in the course of ARDS, often called the exudative phase, fluid can be seen in the interstitial space of the alveolar septum as well as in the alveolar lumen. Scattered bleeding and regions of alveolar collapse, which are at least partly related to inactivation of surfactant (by protein-rich alveolar exudates) and decreased surfactant production resulting from injury to alveolar type II epithelial cells, are seen. The lung parenchyma shows an influx of inflammatory cells, both in the interstitial space and often in the alveolar lumen. The cellular response is relatively nonspecific, consisting of neutrophils and macrophages. Fibrin and cellular debris may be seen in or around alveoli.

A characteristic finding in the pathology of ARDS is the presence of hyaline membranes. They are not true “membranes” in the biological sense; rather, these findings represent the protein-rich edema fluid that has filled the alveoli. Hyaline membranes are composed of a combination of fibrin, cellular debris, and plasma proteins that are deposited on the alveolar surface. Although they are nonspecific, their presence suggests that alveolar injury and increased capillary permeability, rather than elevated hydrostatic pressures, are the cause of pulmonary edema.

After approximately 1 to 2 weeks, the exudative phase evolves into a proliferative phase. As an important part of the reparative process that occurs during the proliferative phase, alveolar type II epithelial cells replicate in an attempt to replace the damaged type I epithelial cells. The resulting overabundance of type II epithelial cells often figures quite prominently in the pathologic picture of ARDS.

Another component of the proliferative phase is accumulation of fibroblasts in the pulmonary parenchyma. In some severe and prolonged cases of ARDS, this fibroblastic response becomes progressive and a fibrotic phase occurs. In these cases, the damaged lung parenchyma is not repaired but goes on to develop significant scar tissue (fibrosis). Often accompanying the fibrosis are changes in the pulmonary vasculature, which include extensive remodeling and compromise of the lumen of small vessels by intimal and medial proliferation and by the formation of in situ thrombi.

Pathophysiology

Effects on gas exchange

Most of the clinical consequences of ARDS follow in reasonably logical fashion from the presence of interstitial and alveolar edema. The most striking early problem is alveolar flooding, which effectively prevents ventilation of affected alveoli, even though perfusion may be relatively preserved. These alveoli, perfused but not ventilated, act as regions where blood is shunted from the pulmonary arterial to pulmonary venous circulation without being oxygenated. This type of shunting is one of the mechanisms of hypoxemia (see Chapter 1), and there is perhaps no better example of intrapulmonary shunting than ARDS.

Pathophysiologic features of ARDS:

1.Shunt and mismatch

2.Secondary alterations in function of surfactant

3.Increased pulmonary vascular resistance

4.Decreased pulmonary compliance

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5. Decreased FRC

In ARDS, there are regions of not only true shunt but also ventilation-perfusion mismatch. To some extent, this phenomenon results from a nonuniform distribution of the pathologic process within the lungs. In areas where the interstitium is more edematous or where more fluid is present in the alveoli, ventilation is more impaired (even though some ventilation remains) than in areas that have been relatively spared. Changes in blood flow do not necessarily follow the same distribution as changes in ventilation, and thus ventilation-perfusion mismatch results.

In addition to the direct effects of interstitial and alveolar fluid on oxygenation, other changes appear to be secondary to alterations in the production and effectiveness of surfactant. Chapter 8 refers to surfactant as a mixture of lipids, specific proteins, and carbohydrates responsible for decreasing surface tension and maintaining alveolar aeration. When surfactant is absent, as is seen in the respiratory distress syndrome of neonates, there is extensive collapse of alveoli. In ARDS, surfactant production is adversely affected by injury to alveolar type II epithelial cells. In addition, the high protein fluid within the alveoli makes surfactant dysfunctional and therefore less effective in preventing alveolar collapse.

In terms of oxygenation, both ventilation-perfusion mismatch (with regions of low ventilation-perfusion ratio) and true shunt (ventilation-perfusion ratio = 0) contribute to hypoxemia. Insofar as shunt is responsible for much of the drop in PO2, supplemental O2 alone may not restore oxygenation to normal. In practice, PO2 does rise somewhat with administration of 100% O2, but not nearly to the level expected after such high concentrations of O2. Considering the nature of the problem of ARDS, this response to supplemental O2 should not be surprising. Oxygen improves the component of hypoxemia that is due to ventilation-perfusion mismatch, but it is ineffective for a true shunt.

On the other hand, the absolute level of ventilation in the patient with ARDS initially remains intact or even increases. As a result, the patient typically does not have difficulty with CO2 retention, except in very severe disease or in the presence of another underlying pulmonary process. Even though substantial amounts of what is effectively dead space may be present (as part of the overall ventilation-perfusion mismatch), the patient with early ARDS is able to increase total ventilation to compensate for the regions of maldistribution. If the patient progresses to the later stages of ARDS, dead space is increased, pulmonary fibrosis ensues, and CO2 elimination may be impaired.

Changes in pulmonary vasculature

The pulmonary vasculature is subject to changes resulting from the overall pathologic process. Pulmonary vascular resistance increases, probably for a variety of reasons. Hypoxemia produces vasoconstriction within the pulmonary arterial system, and fluid in the interstitium may increase interstitial pressure, resulting in a decrease in size and an increase in resistance of the small pulmonary vessels. The lumen of small vessels may be compromised by microthrombi and proliferative changes in vessel walls (discussed earlier under Pathogenesis and Pathology).

One consequence of the pulmonary vascular changes is alteration in the normal distribution of pulmonary blood flow. Blood flows preferentially to areas with lower resistance, which often do not correspond to the regions receiving the most ventilation. Hence ventilation-perfusion mismatch again results, with some areas having high and other areas low ventilation-perfusion ratios.

Effects on mechanical properties of the lungs

When considering the mechanical properties of the lungs in ARDS, we must recognize that computed