Pulmonary edema

Background and epidemiology of pulmonary edema

Acute pulmonary edema is a commonly occurring emergency that demands immediate medical attention. ^, It is broadly classified into cardiogenic (increased hydrostatic pressure) or noncardiogenic (increased microvascular permeability) causes; however, it is common for critically ill patients to present with pulmonary edema arising from a combination of cardiogenic and noncardiogenic etiologies. It is a major health problem, accounting for ∼10% of intensive care unit (ICU) admissions, and is associated with an estimated acute hospital mortality of ∼10%–25% and 1-year mortality exceeding 40%. ^{, ,}

Pathophysiology of pulmonary edema

The alveolar-capillary microcirculation regulates the amount of fluid within the lung. Normal pulmonary physiology is governed by Starling forces that favor a small net extravasation of fluid from the alveolar capillaries into the lung interstitial space that is facilitated by hydrostatic forces and by the presence of microscopic gaps between the capillary endothelial cells. The rate of fluid influx is mitigated by a protein osmotic pressure gradient favoring movement of fluid from the interstitial space back into the circulating plasma. The resulting relatively small physiologic fluid movement from the vasculature into the lungs is normally offset by fluid efflux via the pulmonary lymphatic system, which ultimately drains back into the systemic venous circulation. In normal adults, interstitial fluid volume is strictly controlled because the physiologic extravasation is exactly balanced by lymphatic clearance ; as fluid passes through the lung interstitium, it is excluded from the alveolar space (AS) by occlusive tight junctions between alveolar epithelial cells. ^, The Starling equation for filtration mathematically represents the fluid balance between the pulmonary vasculature and interstitium, which “depends on the net difference in hydrostatic and protein osmotic pressures and permeability of the capillary membrane.”

where:

• Q = net transvascular filtration of fluid into the IS

• K= filtration coefficient

• Ppmv = hydrostatic pressure in perimicrovascular IS

• Pmv = hydrostatic pressure within the capillaries (e.g., the pulmonary capillary wedge pressure [PCWP])

• πmv = protein osmotic pressure in the circulation

• πpmv = protein osmotic pressure in the perimicrovascular IS

Although the Starling equation is conceptually useful in understanding the mechanisms favoring pulmonary edema formation, it is impractical to accurately measure most of these parameters clinically. Among the four forces, only the pulmonary artery occlusion pressure (PAOP) can be measured clinically. It is derived from the pulmonary artery catheter balloon wedged into a pulmonary artery segment, is a reflection of left atrial filling pressure, and is thought to be a useful but imperfect estimate of the hydrostatic pressure of the lung microcirculation. In the absence of acute lung injury (e.g., capillary damage), changes in the rate of fluid flux through the lungs are dictated primarily by changes in hydrostatic pressure. Nonetheless, a basic understanding of this equation is needed to understand the mechanisms governing the development of pulmonary edema.

In the presence of factors altering the Starling equation, the surplus fluid in the capillaries results in interstitial edema, which is reflected in chest images as peribronchial and perivascular cuffing. Pathologically, dilation of lymphatics may be noted as the lymphatic capacitance increases and is eventually overwhelmed as it attempts to accommodate the additional interstitial fluid. Ongoing accumulation of excess fluid in the interstitium overcomes the tight junctions in the alveolar epithelium, and subsequent alveolar edema results. Alveolar edema results in marked changes in lung water that are clinically manifested as increased work of breathing and hypoxemia. Lack of ventilation in the flooded alveolar units results in variable degree of right-to-left shunting of the pulmonary arterial blood flow, which contributes to hypoxemia.

Cardiogenic pulmonary edema (increased capillary hydrostatic pressure)

Increased hydrostatic pressure in the pulmonary capillaries increases transvascular fluid filtration and is most often caused by volume overload or impaired left ventricular function (elevated filling pressures) that elevates pulmonary vascular pressures. Mild elevations of left atrial pressure, reflected by a PAOP of 18–25 mm Hg, cause edema formation and engorgement of the perimicrovascular and peribronchovascular interstitial spaces. As left atrial pressure rises further (PAOP >25 mm Hg), the capacitance of the lymphatics and lung interstitium (estimated at ∼500 mL fluid) is exceeded and fluid overwhelms the lung epithelial barrier, flooding the alveoli with protein-poor fluid. ^, The development of edema with increases in the hydrostatic pressure is also a function of the acuity of pressure elevation. In the setting of gradual pressure changes associated with valvular deformities, the gradually proliferating collaterals of the lymphatic system prevent rapid edema formation and prevent overt symptoms of pulmonary edema at even high PAOP. On the other hand, sudden impairment of left ventricular function or massive fluid overload may lead to rapid development of the pathophysiologic changes described earlier.

Light and electron microscopic changes in animal lung tissue with hydrostatic lung edema indicate statistically significant increase in nonparenchymal interstitium: that is, the interlobular septa and the connective tissue sleeves that surround conducting portions of the respiratory tree and extraalveolar pulmonary blood vessels. The thickness of the air–blood barrier, which consists primarily of matrix or ground substance in the interstitium, is significantly greater in the edematous lungs. Interestingly in high-pressure edema, barrier lesions have also been noted in both endothelial and alveolar epithelial regions. Frank disruptions of the thin and thick sides of the blood-gas barrier suggest capillary stress fractures. In moderate-pressure edema, epithelial blebs may be noted. These findings imply that barrier leaks may result from hydrostatic pulmonary edema, based on the severity and chronicity of the disease. Thus interstitial edema from capillary injury is an alternative mechanism, in addition to the hydrostatic and osmotic pressure variations, which may explain or contribute to edema formation in some cases of cardiogenic pulmonary edema.

Hypoxemia results clinically from the development of alveolar and interstitial fluid accumulation, destabilization of alveolar units (impaired surfactant function), and consequent ventilation–perfusion (V/Q) mismatching. Gas exchange is severely impaired as a result of alveolar flooding, and intrapulmonary shunting ensues. The presence of edema fluid reduces pulmonary distensibility and moves the lung’s pressure–volume curve rightward. The loss of surfactant plays an important role in the reduction of the total lung volume and related alveolar ventilation because of the instability and collapse of alveoli. Airway resistance is associated with the development of hydrostatic pulmonary edema caused by peribronchiolar fluid accumulation. Consequently, patients developing pulmonary edema have to breathe more rapidly and have to work harder to expand their lungs, leading to increased work of breathing.

Occasionally noncardiogenic causes, such as rapid resuscitation with fluids or administered blood products (specifically in the setting of renal failure), cardiac valvular diseases, or rarely, pulmonary veno-occlusive diseases may cause pulmonary edema by similar mechanisms; however, given that cardiac etiology is by far the most common, we broadly refer to high capillary pressure pulmonary edema as cardiogenic pulmonary edema.

Noncardiogenic pulmonary edema (increased vascular permeability)

This mechanism of pulmonary edema features an abnormal increase in the microvascular permeability of the lung, as opposed to elevated capillary pressures, thereby promoting greater fluid and protein flux into the interstitial and alveolar spaces. In terms of the Starling equation, pulmonary vascular damage results in an increase in the filtration coefficient and the leakage of larger solutes (proteins). This decompartmentalization increases the interstitial osmotic pressure, helping to favor lung edema formation. During permeability pulmonary edema, increasing interstitial hydrostatic pressures associated with proteinaceous fluid eventually disrupt tight junctions in the alveolar epithelial barrier. However, increased interstitial hydrostatic pressure is not the only proponent of increasing extravascular lung water. Important synergy exists between increased vascular permeability and hydrostatic pressure in the lungs. In the presence of increased barrier permeability and absence of oncotic forces that resist transvascular fluid transfer, hydrostatic capillary pressure is relatively unopposed. This tendency for seepage at normal hydrostatic vascular pressure is further exacerbated by decreases in colloidal oncotic pressure (COP) that result from low albumin levels. ^,

Acute respiratory distress syndrome: A prototypical manifestation of noncardiogenic pulmonary edema

Permeability pulmonary edema resulting from injury to the lung capillary endothelium and/or alveolar epithelium is a classical feature of the acute lung injury that characterizes acute respiratory distress syndrome (ARDS). The very first description of ARDS depicted areas of alveolar atelectasis, hyperemia, and alveolar and interstitial hemorrhage, with a striking presence of alveolar neutrophils along with hyaline membranes. Consequences of disruption of the alveolar epithelial barrier include loss of surfactant and impairment of the endothelial lining, favoring alveolar collapse during normal tidal breathing.

Causes of direct injury to the alveolar epithelium include gastric aspiration, bacterial pneumonia, and the neutrophilic alveolitis that is characteristic of ARDS. Other conditions that promote acute lung capillary endothelial injury include systemic infections (sepsis), severe burns, polytrauma, and other systemic inflammatory conditions. Varied etiologic insults, individually or in combination, lead to represent a spectrum of progressive noncardiogenic lung injury associated with impaired gas exchange (shunting, V/Q mismatching) and reduced lung compliance (increased work of breathing). ^,

High-permeability pulmonary edema markedly affects gas exchange and lung mechanics. Decrease in static respiratory compliance is notable and may be attributable to loss of aerated units (alveolar atelectasis) and, to some extent, to surfactant reduction. Both interstitial lung parenchymal and chest wall edema contribute to reduced thoracic compliance. As noted previously, ventilation–perfusion mismatch with variable degrees of shunting and increased dead space is conspicuous and directly proportionate to the severity of lung injury.

Certain causes of noncardiogenic pulmonary edema deserve special consideration because of their unique clinical presentations.

Transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is an adverse response to transfusion of blood products containing plasma that is characterized by the acute (within 6 hours) onset of dyspnea, hypoxemia, and bilateral pulmonary infiltrates. Injury is mediated mechanistically by anti–human leukocyte antigen (HLA) antibodies, neutrophil activation, and related endothelial barrier damage. ^, The diagnosis of TRALI is supported clinically and by the exclusion of cardiogenic edema or fluid overload. Thus a low brain natriuretic peptide (BNP) (<250 pg/mL) supports the diagnosis. Treatment includes immediate discontinuation of any transfusing blood products, followed by supportive care, which often requires intubation and mechanical ventilation. Duration of symptoms is typically limited (48–96 hours).

Vaping-associated lung injury

Use of vaping devices (electronic cigarettes) containing nicotine, cannabis, and other products rapidly increased after their introduction in 2007. By 2018 vaping had affected more than 3.6 million US youths, with a majority of these being school-age adolescents and children. As of February 18, 2020, a total of 2807 hospitalized vaping-associated lung injury (VALI) cases or deaths have been reported to the Centers for Disease Control and Prevention (CDC), with 68 confirmed deaths. Lung tissue of patients with respiratory failure reveals diffuse alveolar damage, acute fibrinous pneumonitis, or organizing pneumonia. Foamy macrophages and pneumocystis-like vacuolization have been seen consistently. The exact pathology of acute lung injury is yet to be determined. It has been speculated, however, that noncardiogenic edema results from alveolar epithelial injury by inhaled toxic nanoparticles of diluents such as propylene glycol and vegetable glycerin. These may eventually decompose at the parenchymal level, generating potentially harmful carbonyl compounds. Taking a thorough history of any use of vaping products in the 90 days before presentation is key. Hypoxemia is consistently present, with constitutional symptoms, cough, and dyspnea preceding it. Imaging findings on high-resolution computed tomography include ground-glass opacities and fluffy nodules centered on terminal airways. Ruling out other differential diagnoses and providing supportive respiratory assistance is the recommended management approach, followed by absolute abstinence.