TABLE 29.2

Categories of Pulmonary Edema

In the second mechanism by which fluid accumulates, hydrostatic pressures are normal, but the permeability of the capillary endothelial and alveolar epithelial barriers is increased as a result of damage to one or both of these cell populations. Movement of proteins out of the intravascular space occurs as a consequence of the increase in permeability. Due to the increase in permeability to large molecules, the fluid that leaks out has a relatively high protein content, often close to that found in plasma. This second mechanism is the one operative in ARDS. Because an elevation in pulmonary capillary pressure from cardiac disease is not involved, this form of edema is called noncardiogenic pulmonary edema.

Although cardiogenic and hydrostatic pulmonary edema are mentioned here, subsequent parts of this chapter focus on noncardiogenic edema (i.e., ARDS). However, it is important to remember that hydrostatic pressures still have an important impact on fluid movement, even when the primary problem is a defective permeability barrier. Specifically, higher pulmonary capillary hydrostatic pressures result in more fluid leaking through an abnormally permeable pulmonary capillary endothelium than occurs at lower pressures. At the extreme, some patients with a permeability defect of the pulmonary capillary bed simultaneously have a grossly elevated pulmonary capillary pressure due to concurrent left ventricular failure. In these cases, the permeability defect and the elevated hydrostatic pressure work synergistically in contributing to leakage of fluid out of the pulmonary vasculature. Not only is the fluid leak compounded, but when both factors are involved, sorting out the relative importance of each and thus determining the optimal treatment priorities in a given patient can be difficult.

Etiology

Numerous and varied disorders are associated with the potential to produce ARDS (Table 29.3). What these diverse etiologic factors in ARDS have in common is their ability to cause diffuse injury to the pulmonary parenchyma. Beyond that, defining other features that link the underlying causes is difficult based on our present knowledge. Even the route of injury varies. Some etiologic factors involve inhaled injurious agents; others appear to mediate their effects on the lungs via the circulation rather than the airway.

In some cases, a liquid is responsible; examples include gastric contents, salt or fresh water, and hydrocarbons. With acidic gastric contents, especially when pH is lower than 2.5, patients sustain a “chemical burn” to the pulmonary parenchyma, resulting in damage to the alveolar epithelium. In the case of near drowning in either fresh or salt water, not only does the inhaled water fill alveolar spaces, but secondary damage to the alveolar-capillary barrier causes fluid to leak from the pulmonary vasculature. Because salt water is hypertonic to plasma, it draws fluid from the circulation as a result of an osmotic pressure gradient. Fresh water, on the other hand, is hypotonic to plasma and cellular contents and thus may enter pulmonary parenchymal cells, with resulting cellular edema. In addition, fresh water appears to inactivate surfactant, a complicating factor discussed in more detail under Pathophysiology. Finally, aspirated hydrocarbons can be toxic to the distal parenchyma, perhaps in part because they also inactivate surfactant and cause significant changes in surface tension.

A number of inhaled gases have been identified as potential acute toxins and precipitants of ARDS. Nitrogen dioxide is one example, as are some chemical products of combustion when smoke inhalation occurs. A more recently described cause is e-cigarette or vaping use-associated lung injury (EVALI), in which inhaled vaporized chemicals initiate the development of ARDS among susceptible individuals, particularly if vitamin E acetate is among the inhaled agents. A high concentration of inhaled oxygen, particularly when given for prolonged periods, can contribute to alveolar injury. The mechanism of O2 toxicity is believed to be the generation of free radicals and superoxide anions, byproducts of oxidative metabolism that are toxic to pulmonary epithelial and endothelial cells. It is ironic that O2 can contribute to lung injury, given that it is so important in supportive treatment of ARDS. Chapter 30 discusses an additional way in which treatment of ARDS may worsen alveolar damage through overdistention and/or cyclic opening and closing of alveoli induced by mechanical ventilation.

Infectious agents may produce injury via airway access to the pulmonary parenchyma. Bacterial pneumonia is a common underlying clinical problem associated with development of ARDS. Another important cause of ARDS is viral pneumonia such as COVID-19 or influenza pneumonia, which damages parenchymal cells and adjacent endothelial cells, thus altering alveolar-capillary permeability. In the initial decade of the AIDS epidemic, pneumonia due to Pneumocystis jiroveci became a common cause of ARDS. However, with the advent of highly active antiretroviral therapy in the mid-1990s and the availability of effective prophylactic regimens against Pneumocystis, it is now an uncommon cause of ARDS.

Injury via pulmonary circulation

For causes of ARDS that do not involve inhaled agents or toxins, the pulmonary circulation is believed to be the route of injury. However, in most cases a specific circulating factor has not been identified with certainty, even though several possibilities have been proposed. One of the most common precipitants for ARDS is sepsis, in which microorganisms or their products (especially endotoxin) circulating through the bloodstream initiate a sequence of events resulting in toxicity to parenchymal cells.

Although the term shock lung was used many years ago to describe what is now called ARDS, the presence of hypotensive shock alone is probably insufficient for development of ARDS. Patients in whom ARDS develops seemingly as a result of hypotension usually have complicating potential etiologic factors (e.g., trauma, sepsis) or have received therapy (e.g., blood transfusions) associated with cellular damage. Patients with the coagulation disorder known as disseminated intravascular coagulation (DIC) appear

to have the potential for development of ARDS. In DIC, patients have ongoing activation of both the clotting mechanism and the protective fibrinolytic system that prevents clot formation and propagation. Like ARDS, DIC is a syndrome and can occur because of a variety of primary or underlying causes; although these two problems are frequently associated, whether and exactly how one causes the other is

uncertain.

When fat or amniotic fluid enters the circulation, the material is transported to the lungs, resulting in the clinical problems of fat embolism and amniotic fluid embolism, respectively. Presumably these materials are toxic to endothelial cells of the pulmonary capillaries, and the development of ARDS is well described in these clinical settings.

A variety of drugs, many of which fall into the class of narcotics, are potential causes of ARDS. In most cases an overdose of the drug has been taken, although this is not always the situation. One of the agents most frequently recognized has been heroin, and the name “heroin pulmonary edema” sometimes is used. In addition to heroin and other narcotics, several other drugs occasionally cause ARDS, including aspirin and thiazide diuretics. Although the syndrome of drug-induced pulmonary edema has been well described, the mechanism by which it occurs is not certain.

Some patients with acute pancreatitis develop a clinical picture consistent with noncardiogenic pulmonary edema. In this situation, enzymes released into the circulation from the damaged pancreas have been proposed to directly injure pulmonary parenchymal cells or initiate other indirect pathways, resulting in injury.

Certain disorders of the central nervous system, particularly trauma and intracerebral bleeding associated with increased intracranial pressure, are known to be associated with development of ARDS. Similarly, ARDS occasionally occurs after generalized seizures. An interesting and commonly accepted hypothesis to explain this so-called neurogenic pulmonary edema is that intense sympathetic nervous system discharge in response to intracranial hypertension produces vasospasm and extremely high pulmonary capillary pressures, resulting in mechanical damage to the endothelium and subsequent exudation of fluid out of the intravascular space.

Pathogenesis

How do these diverse clinical problems all result in the syndrome of increased pulmonary capillary permeability in ARDS? One important factor appears to be injury to pulmonary capillary endothelial and alveolar epithelial cells (primarily type I epithelial cells, the cytoplasmic processes of which provide most of the surface area lining the alveolar walls). Given the wide variety of insults that can damage these cell types, it seems unlikely that a single common mechanism is operative for all kinds of injury.

The initial injury in ARDS affects alveolar epithelial (type I) cells, capillary endothelial cells, or both.

In the discussion of some specific causes of ARDS, brief mention was made of a few of the theories of pathogenesis for individual disorders. Here the more generalized cellular and biochemical mechanisms that are operative during the course of injury to the pulmonary epithelial and capillary endothelial cells are considered. A particularly important component of the pathogenesis of acute lung injury and ARDS appears to be recruitment of inflammatory cells to the lungs, especially neutrophils. An early theory explaining recruitment of neutrophils to the lungs focused on the complement pathway. When complement is activated by sepsis, C5a is released and is responsible for aggregation of neutrophils within the pulmonary vasculature. These neutrophils may release a variety of substances that are potentially destructive to cellular and noncellular components of the alveolar wall. Superoxide radicals, other byproducts of oxidative metabolism, an array of cytokines, and various proteolytic enzymes all can be released by neutrophils and may be important pathogenetically in producing structural and functional injury to the alveolar wall. Examples of specific mediators include endotoxin, products of arachidonic acid metabolism, and cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-8, endothelin, and

transforming growth factor (TGF)-β. An inflammatory response also can be augmented by a reduction in

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