Pathophysiology of cardiogenic pulmonary edema

Authors
Duane S Pinto, MD, MPH
Robb D Kociol, MD
Section Editor
Wilson S Colucci, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC
Disclosures: Duane S Pinto, MD, MPH Grant/Research/Clinical Trial Support: Medtronic [Transcatheter aortic
valves (CoreValve)]. Consultant/Advisory Boards: Medtronic [Coronary stents (Resolute DES)]; Medicines
Company [Anticoagulants (Bivalirudin)]; St. Jude [Coronary flow reserve (FFR Pressure Wire)]; Covidien/eV3
[Iliac stents [Visibility Iliac Stent)]; Abbott Vascular [Coronary stents, mitral disease (MitraClip, Xience
DES)]. Robb D Kociol, MD Consultant/Advisory Boards: GE Healthcare [Heart failure (I-131 MIBG
imaging)]. Wilson S Colucci, MD Consultant/Advisory Boards: Merck [Heart failure (Enalapril)]; Novartis [Heart
failure (Enalapril)]; Janssen [Heart failure]; Mast [Heart failure]. Equity Ownership/Stock Options: Cardioxyl [Heart
failure]. Susan B Yeon, MD, JD, FACC Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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Literature review current through: Feb 2015. | This topic last updated: Feb 18, 2014.
INTRODUCTION Cardiogenic pulmonary edema is a common and potentially fatal cause of
acute respiratory distress. 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 systolic or diastolic dysfunction, 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].
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 "Evaluation of acute decompensated heart
failure" 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 urgency, 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 such as
intravenousnitroglycerin.
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 "Evaluation of acute
decompensated heart failure" and "Treatment of acute decompensated heart failure: General
considerations" and "Evaluation of the patient with suspected heart failure".)
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 ventricular filling pressures and left
atrial pressure.
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 liquid 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:
Net filtration = Kf x ( hydrostatic pressure - oncotic pressure)
= Kf x [(Pc - Pi) - (c - i)]
where:
Kf is the filtration coefficient.
S is the surface area available for fluid movement.
Pc and Pi 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.
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 liquid. 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 left
ventricle to fill
An elevated SVR increases left ventricular afterload (wall stress), increasing myocardial
oxygen demand

These changes can lead to a further increase in left ventricular 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 bloodgas barrier at the capillary endothelial and/or alveolar epithelial layer [5]. Stress failure of
pulmonary capillaries is manifest 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 liquid 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, left ventricular [LV] systolic and diastolic dysfunction) are
reviewed briefly here. (See "Epidemiology and causes of heart failure", section on 'Predisposing
conditions for HF'.)
Systolic dysfunction Impaired LV contractility, resulting in reduced cardiac output, is the
most common predisposing condition 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 reninangiotensin-aldosterone and sympathetic nervous systems. The compensatory renal sodium
and water retention induced by these adaptations ultimately result in pulmonary edema.
(See "Pathophysiology of heart failure: Neurohumoral adaptations".)
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 left ventricular hypertrophy of any etiology or
hypertrophic and restrictive cardiomyopathies, and acutely with ischemia and acute
hypertensive crisis. The net effect of diastolic dysfunction is an increased end-diastolic pressure
for any given end-diastolic volume. (See"Clinical manifestations and diagnosis of diastolic heart
failure".)
In addition to the elevated end-diastolic pressure, additional 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 tachycardia (eg, atrial fibrillation with rapid ventricular response).
(See "Pathophysiology of diastolic heart failure".)
Not all cases of cardiogenic pulmonary edema in patients with normal 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) [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 a hypertrophied LV wall, which can produce diastolic and, over time, systolic
dysfunction. (See "Clinical features, diagnosis, and evaluation of aortic stenosis in
adults" and "Overview of hypertrophic cardiomyopathy management including treatment of
special problems".)
Mitral stenosis Mitral stenosis is generally the result of rheumatic heart disease. It is now
less often seen in the United States, but is still a major cardiac problem in the third world. The
chronic obstruction to atrial outflow leads to elevated left atrial pressures. (See "Clinical
manifestations and diagnosis of mitral stenosis".) Mitral annular calcification is a rare cause of
symptomatic mitral stenosis. (See "Mitral annular calcification".)
The typically slow progression of the disease 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 poorly rate-controlled atrial fibrillation or exercise, can
lead to acute elevations of left atrial pressures, and pulmonary edema. (See "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
pulmonary edema because of chronic hypertension and secondary diastolic dysfunction and
also from excess sodium and water retention secondary to activation of the renin-angiotensin
system and associated renal dysfunction, resulting in chronically elevated 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 revascularization 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: Components of therapy".)
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].
Flash pulmonary edema is a term that is used to describe a particularly dramatic form of acute
decompensated heart failure (ADHF) caused by acute increases in left ventricular (LV) diastolic
pressure with rapid fluid accumulation in the pulmonary interstitial and alveolar spaces [6]. This
may occur in some patients with myocardial ischemia with or without myocardial infarction,
acute severe mitral regurgitation, hypertensive crisis, acute aortic regurgitation, and stressinduced (takotsubo) cardiomyopathy. (See "Treatment of acute decompensated heart failure in
acute coronary syndromes" and "Acute mitral regurgitation in adults" and "Acute aortic
regurgitation in adults" and "Stress (takotsubo) cardiomyopathy" and "Evaluation and treatment
of hypertensive emergencies in adults", section on 'Cardiac emergencies'.)
Bilateral renal artery stenosis is a risk factor for flash pulmonary edema. (See 'Renovascular
hypertension' above.)
Hypertensive crisis Patients presenting with cardiogenic pulmonary edema commonly
present with systemic hypertension, which may be severe [18]. Many of these patients have a
preserved (normal or near normal) LV ejection fraction. Excess afterload, instead of or in
addition to fluid overload, may precipitate decompensation in these patients. (See "Moderate to
severe hypertensive retinopathy and hypertensive encephalopathy in adults".)
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.
(See "Overview of the acute management of unstable angina and non-ST elevation myocardial
infarction" and "Overview of the acute management of ST elevation myocardial infarction".)
With systolic dysfunction, there is less forward ejection, 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 preexisting diastolic dysfunction, which is a common finding in patients with coronary artery
disease. (See "Pathophysiology of diastolic heart failure".)
Myocardial ischemia may also precipitate acute valvular pathology, particularly mitral
regurgitation. (See 'Acute mitral regurgitation' below.)
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 left ventricle 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 root 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 not compliant.
Regurgitant flow into a noncompliant left atrium leads to an 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 [20]. This change can occur in the absence of
detectable ischemia. (See "Ischemic mitral regurgitation", section on 'Exercise
echocardiography'.)
Acute left atrial outflow obstruction Acute impairment of outflow from the left atrium to the
LV can cause increased pulmonary pressures. Although uncommon, this can precipitate
pulmonary edema. Causes of acute left atrial outflow impairment include the following:
Left atrial tumors (eg, myxoma) (see "Cardiac tumors", section on 'Left atrial tumors')
Thrombosis of a prosthetic valve (see "Complications of prosthetic heart valves", section
on 'Valve obstruction')
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.
Volume overload Volume overload of the LV can be induced by any cause of increased
intravascular volume (eg, primary sodium retention), and also by ventricular septal rupture or
aortic insufficiency. Acute ventricular septal rupture is a complication of acute myocardial
infarction (both anterior and inferior). Rupture occurs within five to seven days after the infarct.
(See "Mechanical complications of acute myocardial infarction", section on 'Rupture of the
interventricular septum'.)
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 cardiac filling pressures (cardiogenic
pulmonary edema). (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 ventricular filling pressures and left atrial 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 left ventricular outflow obstruction, and causes of mitral
stenosis. (See 'Predisposing conditions' above.)

Precipitating factors that promote development of cardiogenic pulmonary edema include

myocardial ischemia or infarction, acute aortic regurgitation, acute mitral regurgitation,
renovascular hypertension, acute left atrial outflow impairment, and other causes of
volume overload. (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 left ventricular diastolic pressure as may occur with
myocardial ischemia with or without myocardial infarction, acute severe mitral
regurgitation, hypertensive crisis, acute aortic regurgitation, and stress-induced
(takotsubo) cardiomyopathy. (See 'Precipitating factors' above.)
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