Definition

Cardiogenic pulmonary edema (CPE) is defined as pulmonary edema due to increased capillary
hydrostatic pressure secondary to elevated pulmonary venous pressure. CPE reflects the
accumulation of fluid with a low-protein content in the lung interstitium and alveoli as a result of
cardiac dysfunction (see the image below). (See Etiology.)
Radiograph shows acute pulmonary edema in a patient who was admitted with acute anterior
myocardial infarction. Findings are vascular
redistribution, indistinct hila, and alveolar
infiltrates.
Pulmonary edema can be caused by the
following major pathophysiologic
mechanisms:

Imbalance of Starling forces - Ie,

increased pulmonary capillary
pressure, decreased plasma oncotic
pressure, increased negative interstitial
pressure

Damage to the alveolar-capillary

barrier

Lymphatic obstruction

Idiopathic (unknown) mechanism

Increased hydrostatic pressure leading to pulmonary edema may result from many causes,
including excessive intravascular volume administration, pulmonary venous outflow obstruction
(eg, mitral stenosis or left atrial [LA] myxoma), and LV failure secondary to systolic or diastolic
dysfunction of the left ventricle. CPE leads to progressive deterioration of alveolar gas exchange
and respiratory failure. Without prompt recognition and treatment, a patient's condition can
deteriorate rapidly. (See Etiology, Prognosis, Presentation, Workup, Treatment, and Medication.)

Etiology
CPE is caused by elevated pulmonary capillary hydrostatic pressure leading to transudation of
fluid into the pulmonary interstitium and alveoli. Increased LA pressure increases pulmonary
venous pressure and pressure in the lung microvasculature, resulting in pulmonary edema.
Mechanism of CPE

Pulmonary capillary blood and alveolar gas are separated by the alveolar-capillary membrane,
which consists of 3 anatomically different layers: (1) the capillary endothelium; (2) the
interstitial space, which may contain connective tissue, fibroblasts, and macrophages; and (3) the
alveolar epithelium.
Exchange of fluid normally occurs between the vascular bed and the interstitium. Pulmonary
edema occurs when the net flux of fluid from the vasculature into the interstitial space is
increased. The Starling relationship determines the fluid balance between the alveoli and the
vascular bed. Net flow of fluid across a membrane is determined by applying the following
equation:
Q = K(Pcap - Pis) - l(Pcap - Pis),
where Q is net fluid filtration; K is a constant called the filtration coefficient; Pcap is capillary
hydrostatic pressure, which tends to force fluid out of the capillary; Pis is hydrostatic pressure in
the interstitial fluid, which tends to force fluid into the capillary; l is the reflection coefficient,
which indicates the effectiveness of the capillary wall in preventing protein filtration; the second
Pcap is the colloid osmotic pressure of plasma, which tends to pull fluid into the capillary; and the
second Pis is the colloid osmotic pressure in the interstitial fluid, which pulls fluid out of the
capillary.
The net filtration of fluid may increase with changes in different parameters of the Starling
equation. CPE predominantly occurs secondary to LA outflow impairment or LV dysfunction.
For pulmonary edema to develop secondary to increased pulmonary capillary pressure, the
pulmonary capillary pressure must rise to a level higher than the plasma colloid osmotic
pressure. Pulmonary capillary pressure is normally 8-12 mm Hg, and colloid osmotic pressure is
28 mm Hg. High pulmonary capillary wedge pressure (PCWP) may not always be evident in
established CPE, because the capillary pressure may have returned to normal when the
measurement is performed.
Lymphatics

The lymphatics play an important role in maintaining an adequate fluid balance in the lungs by
removing solutes, colloid, and liquid from the interstitial space at a rate of approximately 10-20
mL/h. An acute rise in pulmonary arterial capillary pressure (ie, to >18 mm Hg) may increase
filtration of fluid into the lung interstitium, but the lymphatic removal does not increase
correspondingly. In contrast, in the presence of chronically elevated LA pressure, the rate of
lymphatic removal can be as high as 200 mL/h, which protects the lungs from pulmonary edema.
Stages

The progression of fluid accumulation in CPE can be identified as 3 distinct physiologic stages.

Stage 1
In stage 1, elevated LA pressure causes distention and opening of small pulmonary vessels. At
this stage, blood gas exchange does not deteriorate, or it may even be slightly improved.
Stage 2
In stage 2, fluid and colloid shift into the lung interstitium from the pulmonary capillaries, but an
initial increase in lymphatic outflow efficiently removes the fluid. The continuing filtration of
liquid and solutes may overpower the drainage capacity of the lymphatics. In this case, the fluid
initially collects in the relatively compliant interstitial compartment, which is generally the
perivascular tissue of the large vessels, especially in the dependent zones.
The accumulation of liquid in the interstitium may compromise the small airways, leading to
mild hypoxemia. Hypoxemia at this stage is rarely of sufficient magnitude to stimulate
tachypnea. Tachypnea at this stage is mainly the result of the stimulation of juxtapulmonary
capillary (J-type) receptors, which are nonmyelinated nerve endings located near the alveoli. Jtype receptors are involved in reflexes modulating respiration and heart rates.
Stage 3
In stage 3, as fluid filtration continues to increase and the filling of loose interstitial space occurs,
fluid accumulates in the relatively noncompliant interstitial space. The interstitial space can
contain up to 500mL of fluid. With further accumulations, the fluid crosses the alveolar
epithelium in to the alveoli, leading to alveolar flooding. At this stage, abnormalities in gas
exchange are noticeable, vital capacity and other respiratory volumes are substantially reduced,
and hypoxemia becomes more severe.
Cardiac disorders manifesting as CPE

Atrial outflow obstruction

This can be due to mitral stenosis or, in rare cases, atrial myxoma, thrombosis of a prosthetic
valve, or a congenital membrane in the left atrium (eg, cor triatriatum). Mitral stenosis is usually
a result of rheumatic fever, after which it may gradually cause pulmonary edema. Other causes of
CPE often accompany mitral stenosis in acute CPE; an example is decreased LV filling because
of tachycardia in arrhythmia (eg, atrial fibrillation) or fever.
LV systolic dysfunction
Systolic dysfunction, a common cause of CPE, is defined as decreased myocardial contractility
that reduces cardiac output. The fall in cardiac output stimulates sympathetic activity and blood

volume expansion by activating the renin-angiotensin-aldosterone system, which causes

deterioration by decreasing LV filling time and increasing capillary hydrostatic pressure.
Chronic LV failure is usually the result of congestive heart failure (CHF) or cardiomyopathy.
Causes of acute exacerbations include the following:

Acute myocardial infarction (MI) or ischemia

Patient noncompliance with dietary restrictions (eg, dietary salt restrictions)

Patient noncompliance with medications (eg, diuretics)

Severe anemia

Sepsis

Thyrotoxicosis

Myocarditis

Myocardial toxins (eg, alcohol, cocaine, chemotherapeutic agents such as

doxorubicin [Adriamycin], trastuzumab [Herceptin])

Chronic valvular disease, aortic stenosis, aortic regurgitation, and mitral

regurgitation

LV diastolic dysfunction
Ischemia and infarction may cause LV diastolic dysfunction in addition to systolic dysfunction.
With a similar mechanism, myocardial contusion induces systolic or diastolic dysfunction.
Diastolic dysfunction signals a decrease in LV diastolic distensibility (compliance). Because of
this decreased compliance, a heightened diastolic pressure is required to achieve a similar stroke
volume. Despite normal LV contractility, the reduced cardiac output, in conjunction with
excessive end-diastolic pressure, generates hydrostatic pulmonary edema. Diastolic
abnormalities can also be caused by constrictive pericarditis and tamponade.
Dysrhythmias

New-onset rapid atrial fibrillation and ventricular tachycardia can be responsible for CPE.
LV hypertrophy and cardiomyopathies

These can increase LV stiffness and end-diastolic pressure, with pulmonary edema resulting from
increased capillary hydrostatic pressure.

LV volume overload

LV volume overload occurs in a variety of cardiac or noncardiac conditions. Cardiac conditions

are ventricular septal rupture, acute or chronic aortic insufficiency, and acute or chronic mitral
regurgitation. Endocarditis, aortic dissection, traumatic rupture, rupture of a congenital valve
fenestration, and iatrogenic causes are the most important etiologies of acute aortic regurgitation
that may lead to pulmonary edema.
Ventricular septal rupture, aortic insufficiency, and mitral regurgitation cause elevation of LV
end-diastolic pressure and LA pressure, leading to pulmonary edema. LV outflow obstruction,
such as that caused by aortic stenosis, produces increased end-diastolic filling pressure, increased
LA pressure, and increased pulmonary capillary pressures.
Some sodium retention may occur in association with LV systolic dysfunction. However, in
certain conditions, such as primary renal disorders, sodium retention and volume overload may
play a primary role. CPE can occur in patients with hemodialysis-dependent renal failure, often
as a result of noncompliance with dietary restrictions or noncompliance with hemodialysis
sessions.
Myocardial infarction

One of the mechanical complications of MI can be the rupture of ventricular septum or papillary
muscle. These mechanical complications substantially increase volume load in the acute setting
and therefore may cause pulmonary edema.
LV outflow obstruction

Acute stenosis of the aortic valve can cause pulmonary edema. However, aortic stenosis due to a
congenital disorder, calcification, prosthetic valve dysfunction, or rheumatic disease usually has
a chronic course and is associated with hemodynamic adaptation of the heart. This adaptation
may include concentric LV hypertrophy, which itself can cause pulmonary edema by way of LV
diastolic dysfunction. Hypertrophic cardiomyopathy is a cause of dynamic LV outflow
obstruction.
Elevated systemic blood pressure can be considered an etiology of LV outflow obstruction
because it increases systemic resistance against the pump function of the left ventricle.

Approach Considerations
Laboratory studies used in the evaluation of patients with cardiogenic pulmonary edema (CPE)
include the following:

Complete blood count - The complete blood count (CBC) with differential
helps in assessing for severe anemia and may suggest sepsis or infection if a
markedly elevated white blood cell (WBC) count or bandemia is present

Serum electrolyte measurements - Patients with chronic CHF often use

diuretics and are therefore predisposed to electrolyte abnormalities,
especially hypokalemia and hypomagnesemia; patients with chronic renal
failure are at high risk for hyperkalemia, especially when they are
noncompliant with hemodialysis sessions

Blood urea nitrogen (BUN) and creatinine determinations - These tests help in
assessing patients for renal failure and the anticipated response to diuretics;
in low-output states, such as systolic dysfunction, decreased BUN and
creatinine levels may be secondary to hypoperfusion of the kidneys

Pulse oximetry - Pulse oximetry is useful in assessing hypoxia and, therefore,

the severity of CPE; it is also useful for monitoring the patient's response to
supplemental oxygenation and other therapies

Arterial blood gas analysis - This test is more accurate than pulse oximetry
for measuring oxygen saturation; the decision to start mechanical ventilation
is based mainly on clinical findings, but in rare instances, arterial blood gas
results are taken into account

Electrocardiography

LA enlargement and LV hypertrophy are sensitive, although nonspecific, indicators of chronic

LV dysfunction. The electrocardiogram (ECG) may suggest acute tachydysrhythmia or
bradydysrhythmia or acute myocardial ischemia or infarction as the cause of CPE.
Computed tomography (CT) scanning

Chest CT scanning may be a useful tool for differentiating CPE from acute respiratory distress
syndrome (ARDS) in the emergency department setting, with an overall 88.5% accuracy of
diagnosis.[1] Chest CT scan features with a high positive predictive value (PPV) and moderate
negative predictive value (NPV) for CPE appear to include the presence of ground glass
attentuation predominantly in the upper lobe or central region as well as central-airspace
consolidation. CT scan characteristics with relatively high PPVs and NPVs for ARDS include
left-dominant pleural effusion and small, ill-defined opacities.[1]

Complications
The major complications associated with CPE are respiratory fatigue and failure. Prompt
diagnosis and treatment usually prevent these complications, but the physician must be prepared
to provide assisted ventilation if the patient begins to show signs of respiratory fatigue (eg,
lethargy, fatigue, diaphoresis, worsening anxiety). (See Prognosis and Treatment.)
Sudden cardiac death secondary to cardiac arrhythmia is another concern, and continuous
monitoring of heart rhythm is helpful in prompt diagnosis of dangerous arrhythmias.

Prognosis
In-hospital mortality rates for patients with CPE are difficult to assign because the causes and
severity of the disease vary considerably. In a high-acuity setting, in-hospital death rates are as
high as 15-20%.
Myocardial infarction, associated hypotension, and a history of frequent hospitalizations for CPE
generally increase the mortality risk.
Severe hypoxia may result in myocardial ischemia or infarction. Mechanical ventilation may be
required if medical therapy is delayed or unsuccessful. Endotracheal intubation and mechanical
ventilation are associated with their own risks, including aspiration (during intubation), mucosal
trauma (more common with nasotracheal intubation than with orotracheal intubation), and
barotrauma.

Patient education
To help prevent recurrence of CPE, counsel and educate patients in whom pulmonary edema is
due to dietary causes or medication noncompliance.

Clinical Persentation
Patients with cardiogenic pulmonary edema (CPE) present with the dramatic clinical features of
left heart failure. Patients develop a sudden onset of extreme breathlessness, anxiety, and feelings
of drowning. Clinical manifestations of acute CPE reflect evidence of hypoxia and increased
sympathetic tone (increased catecholamine outflow).
Patients most commonly complain of shortness of breath and profuse diaphoresis. Patients with
symptoms of gradual onset (eg, over 24 h) often report dyspnea on exertion, orthopnea, and
paroxysmal nocturnal dyspnea.
Cough is a frequent complaint and may provide an early clue to worsening pulmonary edema in
patients with chronic LV dysfunction. Pink, frothy sputum may be present in patients with severe
disease. Occasionally, hoarseness may be present as a result of compression of the recurrent
laryngeal nerve palsy from an enlarged left atrium, such as in mitral stenosis (Ortner sign).
Chest pain should alert the physician to the possibility of acute myocardial ischemia/infarction or
aortic dissection with acute aortic regurgitation, as the precipitant of pulmonary edema.

Physical Examination
Physical findings in patients with CPE are notable for tachypnea and tachycardia. Patients may
be sitting upright, they may demonstrate air hunger, and they may become agitated and confused.
Patients usually appear anxious and diaphoretic.
Hypertension is often present, because of the hyperadrenergic state. Hypotension indicates severe
LV systolic dysfunction and the possibility of cardiogenic shock. Cool extremities may indicate
low cardiac output and poor perfusion.
Auscultation of the lungs usually reveals fine, crepitant rales, but rhonchi or wheezes may also
be present. Rales are usually heard at the bases first; as the condition worsens, they progress to
the apices.
Cardiovascular findings are usually notable for S3, accentuation of the pulmonic component of
S2, and jugular venous distention. Auscultation of murmurs can help in the diagnosis of acute
valvular disorders manifesting with pulmonary edema.
Aortic stenosis is associated with a harsh crescendo-decrescendo systolic murmur, which is heard
best at the upper sternal border and radiating to the carotid arteries. In contrast, acute aortic
regurgitation is associated with a short, soft diastolic murmur.

Acute mitral regurgitation produces a loud systolic murmur heard best at the apex or lower
sternal border. In the setting of ischemic heart disease, this may be a sign of acute MI with
rupture of mitral valve chordae. (See the image below.)

Radiograph shows acute

pulmonary edema in a patient who was admitted with acute anterior myocardial
infarction. Findings are vascular redistribution, indistinct hila, and alveolar
infiltrates.

Mitral stenosis typically produces a loud S1, opening snap, and diastolic rumble at the cardiac
apex.
Another notable physical finding is skin pallor or mottling resulting from peripheral
vasoconstriction, low cardiac output, and shunting of blood to the central circulation in patients
with poor LV function and substantially increased sympathetic tone. Skin mottling at
presentation is an independent predictor of an increased risk of in-hospital mortality.
Patients with concurrent right ventricular (RV) failure may present with hepatomegaly,
hepatojugular reflux, and peripheral edema.
Severe CPE may be associated with a change in mental status, which can be caused by hypoxia
or hypercapnia. Although CPE is usually associated with hypocapnia, hypercapnia with
respiratory acidosis may be seen in patients with severe CPE or underlying chronic obstructive
pulmonary disease (COPD).

Diagnostic Considerations
Cardiogenic pulmonary edema (CPE) should be differentiated from pulmonary edema associated
with injury to the alveolar-capillary membrane, caused by diverse etiologies. Damage to the
alveolar-capillary barrier can be seen in various direct lung injuries (from pneumonia, aspiration
pneumonitis, toxin inhalation, pulmonary contusion, radiation, drowning, or fat emboli) and
indirect lung injuries (from sepsis, shock and multiple transfusions, acute pancreatitis, or
anaphylactic shock).
Several conditions related to noncardiogenic pulmonary edema (NCPE) primarily affect Starling
forces rather than the alveolar-capillary barrier. These conditions include decreased oncotic
pressure of the plasma due to various etiologies and increased negativity of interstitial pressure
due to rapid removal of pneumothorax. Lymphatic insufficiency (eg, from lymphangitic
carcinomatosis, fibrosing lymphangitis, or lung transplantation) is another important etiologic
mechanism of NCPE.
Several features may differentiate CPE from NCPE. In CPE, a history of an acute cardiac event
is usually present. Physical examination shows a low-flow state, an S3 gallop, jugular venous
distention, and crackles on auscultation. Patients with NCPE have a warm periphery, a bounding
pulse, and no S3 gallop or jugular venous distention. Definite differentiation is based on
pulmonary capillary wedge pressure (PCWP) measurements. The PCWP is generally >18 mm
Hg in CPE and < 18 mm Hg in NCPE, but superimposition of chronic pulmonary vascular
disease can make this distinction difficult to assess.
Conditions to consider in the differential diagnosis of CPE include the following:

Myocardial ischemia

Pneumothorax

High-altitude pulmonary edema

Neurogenic pulmonary edema

Pulmonary embolism

Respiratory failure

Approach Considerations
The initial management of patients with cardiogenic pulmonary edema (CPE) should address the
ABCs of resuscitation, that is, airway, breathing, and circulation. Oxygen should be administered
to all patients to keep oxygen saturation at greater than 90%. Any associated arrhythmia or MI
should be treated appropriately.
Methods of oxygen delivery include the use of a face mask, noninvasive pressure-support
ventilation (which includes bilevel positive airway pressure [BiPAP] and continuous positive
airway pressure [CPAP]), and intubation and mechanical ventilation. Which method is used
depends on the presence of hypoxemia and acidosis and on the patient's level of consciousness.
For example, intubation and mechanical ventilation may become necessary in cases of persistent
hypoxemia, acidosis, or altered mental status.[10, 11] The use of noninvasive pressure support
ventilation in acidotic patients with severe acute cardiogenic pulmonary edema does not appear
to be associated with adverse outcomes (early mortality and intubation rates) in these patients.[12]
Following initial management, medical treatment of CPE focuses on 3 main goals: (1) reduction
of pulmonary venous return (preload reduction), (2) reduction of systemic vascular resistance
(afterload reduction), and, in some cases, (3) inotropic support. Preload reduction decreases
pulmonary capillary hydrostatic pressure and reduces fluid transudation into the pulmonary
interstitium and alveoli. Afterload reduction increases cardiac output and improves renal
perfusion, which allows for diuresis in the patient with fluid overload.
Patients with severe LV dysfunction or acute valvular disorders may present with hypotension.
These patients may not tolerate medications to reduce their preload and afterload. Therefore,
inotropic support is necessary in this subset of patients to maintain adequate blood pressure.
Patients who remain hypoxic despite supplemental oxygenation and patients who have severe
respiratory distress require ventilatory support in addition to maximal medical therapy.
Ultrafiltration

Ultrafiltration is a fluid removal procedure that is particularly useful in patients with renal
dysfunction and expected diuretic resistance.
Intra-aortic balloon pumping

Intra-aortic balloon pumping (IABP) can be employed to achieve hemodynamic stabilization in

the patient before definitive therapy. The IABP decreases afterload as the pump deflates; during
diastole, the pump inflates to improve coronary blood flow.
Diet

Patients admitted with heart failure or pulmonary edema should be given a low-salt diet to
minimize fluid retention. Closely monitor their fluid balance.

Ventilatory Support
Noninvasive pressure-support ventilation

Consider noninvasive pressure-support ventilation (NPSV) early when treating patients with
severe CPE.
In NPSV, the patient breathes through a face mask against a continuous flow of positive airway
pressure. NPSV maintains the patency of the fluid-filled alveoli and prevents them from
collapsing during exhalation. As a result, the patient saves energy that would have been spent
trying to reopen collapsed alveoli. NPSV improves pulmonary air exchange, and it increases
intrathoracic pressure with reduction in preload and afterload.
Several studies suggest that NPSV is associated with decreased length of stay in the ICU,
decreased need for mechanical ventilation, and decreased hospital costs. A few clinical trials
showed that in patients with CPEmainly defined as having severe dyspnea, oxygen saturation
of less than 90%, and basal ralesearly and prehospital NPSV treatment by paramedics is safe
and associated with faster improvement of oxygen saturation.[13, 14] However, the mortality and
the need for intensive care did not differ between the patients who were treated with NPSV and
those who were treated with a Venturi face mask in most of those studies. Indeed, a more recent
study that evaluated the safety and efficacy of implementing prehospital CPAP
for the treatment of acute (CPE) and acute exacerbations of chronic obstructive
pulmonary disease (AECOPD) found no benefit in morbidity, mortality, and length of hospital
stay.[15]
CPAP and BiPAP
Two types of NPSV are CPAP and BiPAP. In CPAP, a single airway pressure is maintained
throughout all phases of the respiratory cycle. In BiPAP, high pressures can be applied during
inspiration and low pressures, during expiration, increasing the patient's comfort.[10]
A randomized trial comparing CPAP, noninvasive intermittent positive pressure ventilation
(NIPPV), and standard oxygen therapy in 1069 patients with acute cardiogenic pulmonary edema
demonstrated no mortality benefit from noninvasive ventilation, but improvements were seen in
symptomatology and oxygenation.[16]
Although CPAP improves the condition of patients with cardiogenic pulmonary edema and has
been associated with a reduced need for tracheal intubation, its use fails to reduce short-term
mortality in this setting.[17]

In one small study, researchers compared CPAP with BiPAP and found that BiPAP was
associated with more rapid improvement in vital signs but also with an increased rate of MIs.[18]
Moreover, patients who received BiPAP initially had more chest pain than did patients who
received CPAP. Other randomized clinical trials, however, did not show an increased rate of MI
in patients who received CPAP or BiPAP compared with those who received oxygen by means of
a face mask.
As of now, the data are insufficient to compare the efficacy and safety of BiPAP with those of
CPAP. Therefore, the authors suggest that CPAP be the preferred method employed when NPSV
is used unless the patient has obstructive airway disease.
Mechanical ventilation

In general, use endotracheal intubation and mechanical ventilation when patients with CPE
remain hypoxic despite maximal noninvasive supplemental oxygenation, when patients have
evidence of impending respiratory failure (eg, lethargy, fatigue, diaphoresis, worsening anxiety),
or when patients are hemodynamically unstable (eg, hypotensive, severely tachycardic).
Mechanical ventilation maximizes myocardial oxygen delivery and ventilation. Positive endexpiratory pressure is generally recommended to increase alveolar patency and to enhance
oxygen delivery and carbon dioxide exchange.

Medication Summary
Loop diuretics have long been the cornerstone of cardiogenic pulmonary edema (CPE) treatment,
with furosemide being the most commonly used of these drugs. Premedication with drugs that
decrease preload (eg, nitroglycerin [NTG]) and afterload (eg, angiotensin-converting enzyme
[ACE] inhibitors) before the administration of loop diuretics can prevent adverse hemodynamic
changes.
Nesiritide is recombinant human brain-type natriuretic peptide (BNP); it reduces pulmonary
capillary wedge pressure (PCWP), pulmonary artery pressure, RA pressure, and systemic
vascular resistance while increasing the cardiac index and stroke volume index. Therapy with
nesiritide has decreased plasma renin, aldosterone, norepinephrine, and endothelin-1 levels and
reduced ventricular ectopy and ventricular tachycardia. Heart-rate variability also improves with
nesiritide. However, owing to the lack of positive outcomes data (ASCEND-HF) from the use of
nesiritide, nesiritide cannot be recommended for routine use in the broad population of patients
with acute heart failure.
Inotropic support is usually used following unsuccessful attempts at preload and afterload
reduction or when hypotension precludes the use of these strategies. The 2 main classes of
inotropic agents that are available are catecholamine agents and phosphodiesterase inhibitors
(PDIs).

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