Pathophysiology of cardiogenic pulmonary edema

INTRODUCTION — Cardiogenic pulmonary edema is a common and potentially fatal cause of acute respiratory failure. Cardiogenic pulmonary edema is most often a result of acute decompensated heart failure (ADHF). The clinical presentation is characterized by the development of dyspnea associated with the rapid accumulation of fluid within the lung's interstitial and/or alveolar spaces, which is the result of acutely elevated cardiac filling pressures [1].

ADHF is most commonly due to left ventricular (LV) systolic and/or diastolic impairment, with or without additional cardiac pathology, such as coronary artery disease or valve abnormalities. However, a variety of conditions or events can cause cardiogenic pulmonary edema in the absence of heart disease, including primary fluid overload (eg, due to blood transfusion), severe hypertension, renal artery stenosis, and severe renal disease.

Noncardiogenic pulmonary edema is a distinct clinical syndrome associated with diffuse filling of the alveolar spaces in the absence of elevated pulmonary capillary wedge pressure [1]. A focused history, physical examination, echocardiography, laboratory analysis and, in some cases, direct measurement of pulmonary capillary wedge pressure can be used to distinguish cardiogenic from noncardiogenic pulmonary edema, as well as from other causes of acute respiratory distress. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults" and "Noncardiogenic pulmonary edema".)

"Flash" pulmonary edema is a term that is used to describe a particularly dramatic form of cardiogenic alveolar pulmonary edema. In "flash" pulmonary edema, the underlying pathophysiologic principles, etiologic triggers, and initial management strategies are similar to those of less severe ADHF, although there is a greater degree of urgency to the implementation of initial therapies and the search for triggering causes. (See 'Precipitating factors' below.) Often, "flash" pulmonary edema is related to a sudden rise in left-sided intracardiac filling pressures in the setting of hypertensive emergency, acute ischemia, new onset tachyarrhythmia, or obstructive valvular disease. In addition to standard therapies for cardiogenic pulmonary edema, this condition responds well to combined venous and arterial vasodilators.

General issues related to the pathophysiology and etiology of cardiogenic pulmonary edema will be reviewed here. The evaluation and treatment of ADHF and the evaluation of the clinically stable patient with suspected HF are presented separately. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults" and "Treatment of acute decompensated heart failure: General considerations" and "Heart failure: Clinical manifestations and diagnosis in adults".)

PATHOPHYSIOLOGY — Cardiogenic pulmonary edema is characterized by increased transudation of protein-poor fluid into the pulmonary interstitium and alveolar spaces. The primary etiologic factor is a rapid and acute increase in left atrial filling pressure, which is most commonly the result of elevated LV filling pressure. This is in contrast to the pathophysiology of noncardiogenic pulmonary edema where the primary etiologic factor is an increase in the permeability of the pulmonary endothelium. (See "Noncardiogenic pulmonary edema".)

Fluid transudation — Fluid transudation is mediated by a rise in pulmonary capillary pressure that results from an increase in pulmonary venous and left atrial pressure. This occurs in the absence of a primary change in the permeability or integrity of the endothelial and epithelial layers of the pulmonary capillaries. The net result is filtration of protein-poor fluid across the pulmonary endothelium into the pulmonary interstitium and alveolar spaces, leading to decreased diffusing capacity, hypoxia, and shortness of breath [2].

The Starling relationship — Fluid balance between the interstitium and vascular bed in the lung, as in other microcirculations, is determined by the Starling relationship, which predicts the net flow of liquid across a membrane [3,4]. This can be expressed in the following equation:

where:

●K_f is the filtration coefficient = L_p  x  S.

●L_p is the hydraulic conductivity.

●S is the surface area available for fluid movement.

●P_c and P_i are the capillary and interstitial fluid hydrostatic pressures.

●∏_c and ∏_i are the capillary and interstitial fluid oncotic pressures; the interstitial oncotic pressure is derived primarily from filtered plasma proteins and to a lesser degree proteoglycans in the interstitium.

●σ represents the reflection coefficient of proteins across the capillary wall (with values ranging from 0 if completely permeable to 1 if completely impermeable).

In normal microvessels, there is ongoing filtration of a small amount of low protein fluid. In cardiogenic pulmonary edema, the increase in transcapillary filtration is generally attributed to elevation in pulmonary capillary pressure, although permeability of the capillary wall may also be affected. (See 'Pulmonary capillary stress failure' below.)

Compensatory mechanisms, particularly activation of the renin-angiotensin and sympathetic nervous systems, result in tachycardia and an elevation in systemic vascular resistance (SVR) that may be deleterious in this setting:

●Tachycardia, which shortens the duration of diastole, impairs the ability of the LV to fill.

●An elevated SVR with or without an increase in LV chamber dimension increases LV afterload (wall stress), increasing myocardial oxygen demand.

These changes can lead to a further increase in LV end-diastolic pressure and more edema formation. To the degree that pulmonary edema results in hypoxia, there may be a further worsening of myocardial function.

Pulmonary capillary stress failure — Although cardiogenic pulmonary edema is generally attributed to transudation of low protein fluid in response to high pulmonary capillary pressure, experimental studies have demonstrated that severe elevation in pulmonary capillary pressure can lead to increased permeability of the capillary wall and eventually stress failure of the blood-gas barrier at the capillary endothelial and/or alveolar epithelial layer [5]. Stress failure of pulmonary capillaries is manifested as high-permeability edema and/or alveolar hemorrhage. Pulmonary capillary stress failure may occur in some patients with flash pulmonary edema with abrupt severe increases in pulmonary capillary pressure [6]. (See 'Precipitating factors' below.)

Role of lymphatics — The rate of accumulation of lung fluid at a given elevation in pulmonary capillary pressure is related to the functional capacity of the lymphatic vessels to remove the excess fluid, which varies from patient to patient and with the duration of disease [7]. With acute rises in pulmonary capillary pressure, the pulmonary lymphatics cannot rapidly increase the rate of fluid removal; as a result, pulmonary edema occurs at pulmonary capillary pressures as low as 18 mmHg. In contrast, patients with chronic heart failure, in whom the pulmonary capillary wedge pressure is persistently elevated, have increased lymphatic capacity and do not develop pulmonary edema until significantly higher pulmonary capillary pressures are reached.

PREDISPOSING CONDITIONS — When considering the etiologies of cardiogenic pulmonary edema, it is useful to distinguish the chronic cardiac conditions that predispose to episodes of pulmonary edema from the triggers that precipitate pulmonary edema.

The chronic conditions that predispose to heart failure (HF) are presented in detail separately. For the purposes of this discussion, some of the more common conditions leading to HF and cardiogenic pulmonary edema (eg, LV systolic and diastolic dysfunction) are reviewed briefly here. (See "Epidemiology of heart failure", section on 'Risk factors for heart failure'.)

Systolic dysfunction — Impaired LV contractility, resulting in reduced cardiac output, is one of the most common predisposing conditions leading to cardiogenic pulmonary edema. LV systolic dysfunction itself has many causes, including the following (see "Causes of dilated cardiomyopathy"):

●Coronary heart disease

●Hypertension

●Valvular heart disease

●Idiopathic dilated cardiomyopathy.

●Toxins (eg, anthracyclines)

●Metabolic disorders (eg, hypothyroidism)

●Viral myocarditis (eg, Coxsackie B virus or echovirus infection).

The decrease in forward flow caused by systolic dysfunction leads to activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. The compensatory renal sodium and water retention induced by these adaptations ultimately contribute to pulmonary edema.

Diastolic dysfunction — Diastolic dysfunction refers to an increase in ventricular stiffness (reduced compliance) and impaired relaxation that impedes ventricular filling during diastole. It can be induced by chronic disorders, such as LV hypertrophy of any etiology or hypertrophic and restrictive cardiomyopathies, and acutely with myocardial ischemia and acute hypertensive crisis. The net effect of diastolic dysfunction is an increased LV end-diastolic pressure for any given end-diastolic volume. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

In addition to the elevated end-diastolic pressure, factors that may promote the development of pulmonary edema in patients with diastolic dysfunction include concurrent systolic dysfunction, reduced diastolic coronary blood flow (resulting in subendocardial ischemia), and arrhythmia (eg, atrial fibrillation with rapid ventricular response). (See "Pathophysiology of heart failure with preserved ejection fraction".)

Not all cases of cardiogenic pulmonary edema in patients with normal LV ejection fraction are due primarily to intrinsic abnormalities of LV diastolic function. Other causes include volume overload (as in renal failure) and increased afterload (as in hypertensive crisis and LV outflow obstruction) [8]. (See 'Volume overload' below and 'Renovascular hypertension' below.)

Left ventricular outflow obstruction — LV outflow obstruction can be the result of critical aortic stenosis (including supravalvular and subvalvular stenosis), hypertrophic cardiomyopathy, and/or severe systemic hypertension. Chronic LV outflow obstruction is associated with LV hypertrophy, which reduces ventricular compliance and can produce diastolic and, over time, systolic dysfunction. (See "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

Mitral stenosis — Mitral stenosis is most frequently the result of rheumatic heart disease. Rheumatic disease is less often seen in the United States, but is still a major cardiac problem in developing areas of the world. The chronic obstruction to atrial outflow leads to elevated left atrial pressures even in the presence of normal or low LV filling pressures. (See "Rheumatic mitral stenosis: Clinical manifestations and diagnosis".)

Mitral annular calcification and bioprosthetic valve dysfunction are other causes of symptomatic mitral stenosis. (See "Clinical manifestations and diagnosis of mitral annular calcification".)

The typically slow progression of mitral stenosis allows gradual adaptation to the increased pressures, and patients with mild to moderate degrees of stenosis are not typically symptomatic. (See 'Role of lymphatics' above.) However, conditions that cause an elevated heart rate and decreased diastolic filling time, such as exercise or atrial fibrillation with rapid ventricular response, can lead to abrupt elevations of left atrial pressures, and pulmonary edema. (See "Pathophysiology and natural history of mitral stenosis".)

Renovascular hypertension — Renovascular disease, particularly chronic hypertension due to renal artery stenosis, is associated with predisposing conditions as well as precipitating factors for pulmonary edema [8-12]. Patients with renovascular disease may be predisposed to the development of pulmonary edema because of chronic hypertension and secondary diastolic dysfunction and also from excess sodium and water retention due to activation of the renin-angiotensin system and associated renal dysfunction, resulting in chronically elevated cardiac filling pressures [8,13]. (See "Establishing the diagnosis of renovascular hypertension".)

An association between recurrent pulmonary edema and renovascular hypertension was first described by Pickering et al, who reported pulmonary edema in 13 of 55 patients with renovascular hypertension and azotemia [9]. "Flash" pulmonary edema appears to be more common in patients with bilateral renal artery stenosis as compared to those with unilateral disease (eg, 41 versus 12 percent) [9,14]. The combination of bilateral renal artery stenosis and "flash" pulmonary edema has been named the Pickering syndrome [15,16]. Limited evidence is available on the efficacy of renal artery intervention for this condition. (See "Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney" and "Treatment of acute decompensated heart failure: Specific therapies".)

PRECIPITATING FACTORS — In the presence of pre-existing systolic or diastolic dysfunction, other disease entities or physiologic conditions may precipitate hemodynamic decompensation and promote the development of pulmonary edema (table 1) [17]. These can be grouped according to the primary pathophysiologic etiology which includes an acute increase in preload, a decrease in contractility, or an increase in afterload.

Several precipitating factors can coexist and interact with one another, exacerbating the episode of pulmonary edema. For example, hypertensive crisis can provoke myocardial ischemia which in turn may lead to diastolic dysfunction. There may be further activation of the adrenergic system, increasing blood pressure and afterload further. (See "Treatment of acute decompensated heart failure in acute coronary syndromes" and "Acute mitral regurgitation in adults" and "Acute aortic regurgitation in adults" and "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy" and "Evaluation and treatment of hypertensive emergencies in adults", section on 'Cardiac emergencies'.)

Increased preload

Volume overload — LV filling pressure can be induced by any cause of intravascular volume expansion (eg, primary sodium retention due to dietary sodium load, iatrogenic intravenous fluid infusion, blood transfusion).

Acute aortic regurgitation — The abrupt onset of acute aortic regurgitation leads to a rapid rise in cardiac filling pressures due to the inability of the LV to quickly adapt to the rapid increase in end-diastolic volume caused by the regurgitant blood. Acute valvular dysfunction can be seen in cases of endocarditis, aortic dissection, complications associated with prosthetic valves and surgical technique, and spontaneous or traumatic rupture of the aortic leaflets. (See "Acute aortic regurgitation in adults".)

Acute mitral regurgitation — The most common cause of isolated, severe acute mitral regurgitation in adults is chordal rupture with or without associated myxomatous disease. Other causes of acute mitral valve incompetence include myocardial ischemia or infarction, resulting in papillary muscle rupture or papillary muscle displacement (previously known as papillary muscle dysfunction); endocarditis, which can lead to chordal rupture; and prosthetic valve dysfunction. (See "Acute mitral regurgitation in adults".)

In patients who do not have chronic mitral regurgitation, the left atrium is usually relatively noncompliant. Regurgitant flow into a noncompliant left atrium leads to an abrupt increase in pressure that is conducted to the pulmonary circulation.

Some patients with ischemic heart disease and LV systolic dysfunction develop acute pulmonary edema without apparent cause. Some of these patients have mitral regurgitation, which may be mild at rest but is made substantially worse with exercise, often leading to dyspnea that requires cessation of exercise [18]. This change can occur in the absence of detectable ischemia. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation", section on 'Stress testing'.)

Decrease in contractility

Myocardial ischemia/infarction — Patients with ADHF commonly have coronary artery disease with or without an acute coronary syndrome [19]. The acute onset of severe myocardial ischemia can lead to a sudden impairment in systolic and diastolic function, resulting in a decreased cardiac output, elevated filling pressures and the development of pulmonary edema. Such patients may or may not have chronic volume overload and may be free of peripheral edema. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".)

●With systolic dysfunction, cardiac output can be diminished, leading to increases in diastolic volume and diastolic pressure.

●With diastolic dysfunction, the enhanced stiffness of the myocardium raises diastolic pressure at any given diastolic volume. Even transient ischemia can exacerbate pre-existing diastolic dysfunction, which is a common finding in patients with coronary artery disease. (See "Pathophysiology of heart failure with preserved ejection fraction".)

Myocardial ischemia may also precipitate acute valvular pathology, particularly mitral regurgitation. (See 'Acute mitral regurgitation' above.)

Increase in afterload

Hypertensive crisis — Patients presenting with cardiogenic pulmonary edema commonly present with systemic hypertension, which may be severe [20]. Many of these patients have a preserved (normal or near normal) LV ejection fraction. Excess afterload, with or without increased preload, may precipitate the development of cardiogenic pulmonary edema and decompensation in these patients. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults".)

Other causes — Other causes of cardiogenic pulmonary edema include obstruction of the left atrial outflow which may result from left atrial tumor (eg, myxoma), or thrombosis of a prosthetic mitral prosthesis. In chronic left atrial outflow impairment (eg, mitral stenosis or cor triatriatum), pulmonary edema is often precipitated when an elevated heart rate decreases the time for LV filling. Pulmonary edema may also be precipitated by an increased intravascular volume, as occurs with pregnancy or an increase in salt intake.

SUMMARY

●Cardiogenic pulmonary edema is characterized by the development of dyspnea associated with the rapid accumulation of fluid within the lung's interstitial and alveolar spaces, which is the result of acutely elevated left atrial pressure. (See 'Pathophysiology' above.)

●Cardiogenic pulmonary edema is characterized by increased transudation of protein-poor fluid into the pulmonary interstitium and alveolar spaces. The primary etiologic factor is a rapid and acute increase in left atrial and, typically, left ventricular (LV) filling pressure, usually associated with a reduction in cardiac output. Fluid exchange between the interstitium and vascular bed in the lung, as in other microcirculations, is determined by Starling forces, which govern the net flow of liquid across a membrane. (See 'Pathophysiology' above.)

●Chronic conditions that predispose to acute decompensated heart failure (ADHF) and resultant pulmonary edema include disorders causing systolic dysfunction, those causing diastolic dysfunction, causes of LV outflow obstruction, and causes of left atrial outflow obstruction. (See 'Predisposing conditions' above.)

●Precipitating factors that promote development of cardiogenic pulmonary edema include increase in preload, increase in afterload, or decrease in contractility (eg, intravascular volume expansion, acute aortic or mitral valvular regurgitation, myocardial ischemia or infarction, and hypertensive crisis). (See 'Precipitating factors' above.)

●"Flash" pulmonary edema is a term that is used to describe a dramatic form of ADHF, caused by an acute increase in LV end-diastolic pressure as may occur with myocardial ischemia with or without myocardial infarction, acute severe mitral regurgitation, hypertensive crisis, and acute aortic regurgitation. (See 'Precipitating factors' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robb Kociol, MD, and Duane Pinto, MD, MPH, who contributed to earlier versions of this topic review.