The endothelium is composed of a monolayer of cells situated on the basement membrane (located between the endothelium and epithelium). The junctions between endothelial cells contain pores that allow the passage of water and ions. They act as a sieve for protein molecules. Of these molecules, only the smaller ones (i.e., albumin) can pass normally with relative freedom; large molecules (i.e., globulin, fibrinogen) cannot.

The alveolar epithelial cells, which are situated on the other side of the basement membrane, are composed of type 1 and 2 pneumocytes. Type 1 are large, flat cells that line the alveoli as a continuous sheet and have tight gaps (pores) in their junctions. Therefore, the alveolar wall is much less permeable than the endothelial wall. This also explains the cases in which pulmonary edema remains in the interstitium without filling the alveoli. Type 2 cells are cuboidal stem cells that produce surfactant.

The interstitium is the thin layer that lies between the endothelial and alveolar layers. This space contains fibrin, collagen matrix, pulmonary lymphatic vessels, and basement membrane. Its thicker component surrounds the large blood vessels and airways.

The lymphatic vessels are in the interstitium and drain the pulmonary microvascular filtrate.

Because of the vulnerability of the blood-gas barrier to stress failure when the capillary pressure rises, it is important to know what is responsible for the strength of the capillary wall. The thin side of the blood-gas barrier consists of the capillary endothelial layer, alveolar epithelial layer, and the extracellular matrix (ECM), which is made up of the fused basement membranes of the two cellular layers. There is strong evidence that most of the strength comes from the ECM, particularly the type IV collagen in the basement membranes. This suggests that the ECM is the strongest layer.⁴ The thickness of the capillary basement membranes is frequently related to the transmural pressure. For example, patients with mitral stenosis who have an increased pulmonary capillary pressure over several years have thickened basement membranes.⁵

Pulmonary edema is defined as an abnormal accumulation of fluid in the extravascular compartments of the lung. The relative amounts of intravascular and extravascular fluid in the lung are mostly controlled by the permeability of the capillary membrane, as well as the oncotic pressure.⁶ This relation is described by the Starling equation, which is used to determine the theoretic amount of fluid Q_filt filtered per unit area per unit of time:

In this equation, HP_iv and HP_ev represent the intravascular and extravascular hydrostatic pressure, and OP_iv and OP_ev represent the intravascular and extravascular oncotic pressure, respectively. K_filt represents the conductance of the capillary wall and expresses the water resistance created by the capillary endothelial cell junctions with changes in HP_iv and HP_ev, whereas t represents the oncotic reflection coefficient and indicates the permeability of the capillary membrane to macromolecules. The greater this reflection coefficient, the more the passage of macromolecules will be restricted, thereby decreasing overall fluid filtration. The net flow, F_net, is defined as Q_filt– Q_lymph, where Q_filt represents fluid transudation or exudation and Q_lymph represents lymphatic absorption. Pulmonary edema develops when the equilibrium between fluid transudation or exudation Q_filt and lymphatic absorption Q_lymph is disturbed. Therefore, although under normal conditions the endothelial cells are relatively impermeable to protein but remain permeable
to water and solutes, the tight intercellular junctions of the alveolar epithelium remain nearly impermeable to water and solutes, thereby constituting an effective barrier that is a major factor in preventing the development of pulmonary edema. Lymphatic drainage (Q_lymph) represents another way of eliminating excess lung water. A manyfold increase in lymphatic flow has been observed with chronically increased hydrostatic pressure. This increase in lymphatic flow is very efficient in eliminating excess water, especially when there is diminished oncotic pressure due to hypoalbuminemia.⁷ However, its impact requires time, and therefore, it may not be as effective in acute settings.

Cardiogenic pulmonary edema (CPE) arises when HP_ev or the capillary pressure increases secondary to left atrial hypertension, causing transudation of fluid across the interstitium into the alveoli. Noncardiogenic edema most commonly arises when the reflection coefficient (t) is decreased because of endothelial injury. The variable t varies in value from 0 to 1, depending on the restriction of plasma protein by the endothelium. This injury allows the passage of normally restricted plasma proteins from the vascular space into the interstitium and alveoli, creating an exudative edema.

Pulmonary edema can be divided into four main categories on the basis of its pathophysiology:

This classification scheme is helpful because pulmonary edema is often seen perioperatively in the ICU and emergency department.

The formation and morphology of hydrostatic pulmonary edema appear to be complex, and fluid and protein movement from the microvasculature into the interstitial and alveolar spaces cannot be explained solely by uniform membrane models of fluid exchange. Barrier leaks and, in particular, epithelial cell layer leaks play a role not only in permeability edema, but also in hydrostatic edema. The differences between these two types of edema reflect the type and extent of injury to the cellular layers of the blood-gas barrier, whether there is a causative, associated, or ensuing inflammatory process.

Pulmonary surfactant is a complex lipoprotein structure. Its primary physiologic function is to maintain flow, and reduce surface tension in the alveoli and small airways. The low surface tensions stabilize the lung at low transpulmonary pressures and decrease the work of breathing. Surfactant will improve lung compliance, arterial PO₂, and minimum surface tension in animal models. Once edema is present, surfactant concentration falls, and its production can be inhibited by soluble proteins, lipids, or other substances.

Increased alveolar surface tension due to surfactant deficiency is thought to result in negative pressure surrounding the pulmonary capillaries, which promotes fluid filtration. Therefore, if pericapillary liquid pressure in the interstitium approximates P_liquid, surfactant deficiency will facilitate the formation of pulmonary edema.

Microvascular injury, manifested as an increase in microvascular permeability to fluid and protein, occurs in tissues subjected to periods of ischemia followed by reperfusion. The factors that promote, limit, and prevent ischemia-reperfusion microvascular injury to the lung are multiple and complex. The knowledge of how lung injury affects the microvascular barrier has been
considerably extended in the last 10 years. Several important discoveries, such as the reversal effects of cyclic adenosine 3′, 5′-monophosphate (cAMP) and the protective effect of nitric oxide, may eventually influence the clinical therapy.

Two pathophysiologic and radiologic phases are recognized in the development of pressure edema: interstitial edema and alveolar flooding or edema. These phases are virtually identical for left-sided heart failure and fluid overload, and are the two most frequently observed causes of pressure edema in operating room, intensive care, and emergency patients. The intensity and duration of both phases are clearly related to the degree of increased pressure, which is determined by the hydrostatic-oncotic pressure ratio.

Interstitial edema occurs when mean transmural arterial pressure increases 15 to 25 mm Hg. This results in early loss of definition of subsegmental and segmental vessels, mild enlargement of the peribronchovascular spaces, appearance of Kerley lines, and subpleural effusions.¹⁸ If the quantity of extravascular fluid continues to increase, the edema will migrate centrally, with progressive blurring of vessels, first at the lobar level and later at the level of the hilum. At this point, lung radiolucency decreases markedly, making identification of the small peripheral vessels difficult. Peribronchial cuffing becomes apparent, particularly in the perihilar areas.

When transmural pressure exceeds 25 mm Hg, fluid drainage from the extravascular compartment is at maximum capacity. The second phase (alveolar flooding) then commences, leading to a sudden extension of edema into the alveolar spaces, and thereby creating tiny nodular or acinar areas of increased opacity that mature into frank consolidations (see Fig. 12.2).

Pulmonary artery catheters are frequently used to assess hydrostatic pressure in intensive care patients. The pulmonary capillary wedge pressure has been shown to reflect left atrial pressure and correlates well with the radiologic features of congestive heart failure and pulmonary venous hypertension (see Table 12.1). However, in acute heart failure, a time lag is often observed between the increased pulmonary capillary wedge pressure and the radiologic manifestation of pulmonary edema due to the relatively slow movement of water through the widened capillary endothelial cell junctions.⁸ Similarly, as pulmonary edema resolves, the radiologic findings will persist, with decreasing, or even normal, pulmonary capillary wedge pressure (see Fig. 12.3). In addition, pressure edema may show an asymmetric distribution on chest radiographs. The most frequent cause is an abnormal lung parenchyma, as seen in chronic obstructive pulmonary
disease (COPD). In cardiac failure, extensive lung emphysema of the apices (seen in heavy smokers) or marked destruction and fibrosis of the upper and middle portions of the lungs (seen in end-stage tuberculosis, sarcoidosis, or asbestosis) will result in pulmonary edema that predominates in the regions less affected by these disease processes.

Hemodynamic factors can also produce asymmetric distribution of pulmonary edema. Edema associated with severe mitral regurgitation has been shown to favor one particular lung, a result of flow impairment provoked by the reflux stream directed toward a particular upper pulmonary vein.¹⁹ Such asymmetric distribution occurs in 9% of adults and 22% of children with grade 3 or 4 mitral regurgitation.²⁰

Finally, the position of the patient also influences intravascular and extravascular fluid distribution. In supine patients, axial computed tomography scan usually demonstrates an anteroposterior gradient, whereas more asymmetric distribution of edema secondary to prolonged surgery or immobilization is frequently observed in the lung fields of recumbent patients. This distribution is typically seen in congestive heart failure but is also observed in overhydration.