eMedicine Specialties > Cardiology > Myocardial Disease and Cardiomyopathies

Pulmonary Edema, Cardiogenic

Ali A Sovari, MD, Research Fellow, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA)
Abraham G Kocheril, MD, FACC, FACP, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago; Arnold S Baas, MD, FACC, FACP, Assistant Professor of Medicine, University of California at Los Angeles; Attending Physician, UCLA Santa Monica Hospital and UCLA Westwood Hospital

Updated: Apr 22, 2008

Introduction

Background

Pulmonary edema refers to extravasation of fluid from the pulmonary vasculature into the interstitium and alveoli of the lung. The formation of pulmonary edema may be caused by 4 major pathophysiologic mechanisms: (1) imbalance of Starling forces (ie, increased pulmonary capillary pressure, decreased plasma oncotic pressure, increased negative interstitial pressure), (2) damage to the alveolar-capillary barrier, (3) lymphatic obstruction, and (4) idiopathic or unknown mechanism.

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, when pulmonary veins and left atrium venous return exceeds left ventricular (LV) output.

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 myxoma), or LV failure secondary to systolic or diastolic dysfunction of the LV. CPE leads to progressive deterioration of alveolar gas exchange and respiratory failure. Without prompt recognition and treatment, a patient's condition can deteriorate rapidly.

Pathophysiology

CPE is caused by elevated pulmonary capillary hydrostatic pressure leading to transudation of fluid into the pulmonary interstitium and alveoli. Increased left atrial 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 (P _cap -P _is) - l(P_cap - P_is),

where Q is net fluid filtration; K is a constant called the filtration coefficient; P _cap is capillary hydrostatic pressure, which tends to force fluid out of the capillary; P _is 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; P_cap is the colloid osmotic pressure of plasma, which tends to pull fluid into the capillary; and P_is is the colloid osmotic pressure in the interstitial fluid, which pulls fluid out of the capillary.

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 left atrial 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.

In stage 1, elevated left atrial 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.

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. J-type receptors are involved in reflexes modulating respiration and heart rates.

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 500 mL 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.

Pathophysiologic considerations

CPE usually occurs secondary to left atrial outflow impairment or LV dysfunction. Left atrial outflow impairment may be acute or chronic. Causes of chronic impairment include mitral stenosis or left atrial tumors. Increased heart rate, which may occur secondary to atrial fibrillation, leads to pulmonary edema because of reduced LV filling. Acute mitral-valve regurgitation secondary to papillary muscle dysfunction or ruptured chordae tendineae increases LV end-diastolic pressure and is another cause of pulmonary edema.

LV dysfunction can be systolic or diastolic or combined. It can also be associated with LV volume overload or LV outflow obstruction. 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, respectively.

Diastolic dysfunction signals a decrease in LV diastolic distensibility (compliance). Therefore, a heightened diastolic pressure is required to achieve the 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 constriction and restriction.

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. The noncardiac condition is volume overload. These conditions cause elevation of LV end-diastolic pressure and left atrial pressure, leading to pulmonary edema. LV outflow obstruction, such as aortic stenosis, produces increased end-diastolic filling pressure, increased left atrial pressure, and increased pulmonary capillary pressures. Cardiac tamponade results in elevation of left atrial (pulmonary capillary pressure), and right atrial pressure resulting in pulmonary and peripheral edema, respectively.

After pulmonary edema begins to develop, a self-perpetuating cycle of events occurs in the cardiopulmonary system. The cycle begins when LV systolic dysfunction decreases myocardial contractility and cardiac output, activating the renin-angiotensin-aldosterone system and stimulating catecholamine production. As a result, systemic vascular resistance increases leading to increased myocardial wall tension, myocardial ischemia, and worsening LV function and cardiac output, all of which perpetuate the cycle. The increase in myocardial wall tension also leads to concurrent diastolic dysfunction, which increases pulmonary artery and pulmonary capillary pressures. When the pulmonary capillary hydrostatic pressure exceeds the pulmonary interstitial pressure, transudation of fluid in the pulmonary interstitium and alveoli occurs. If the cycle is not aborted promptly with appropriate treatment, pulmonary edema rapidly develops.

Mortality/Morbidity

• In-hospital mortality rates are difficult to assign because the causes and the severity vary considerably. In a high-acuity setting, in-hospital death rates are as high as 15-20%.
• 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 orotracheal intubation), and barotrauma.

Clinical

History

Patients with 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 that 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 recurrent laryngeal nerve palsy from mitral stenosis or pulmonary hypertension (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

• 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 S ₃ , accentuation of pulmonic component of S ₂ and jugular venous distension.
  • 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 myocardial infarction (MI) with rupture of mitral valve chordae.
  • Mitral stenosis typically produces a loud S ₁ , 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 may be the result of hypoxia or hypercapnia. Although CPE is usually associated with hypocapnia, hypercapnia with respiratory acidosis may be seen in patients with severe CPE or underlying COPD.

Causes

• 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. Therefore, 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: Chronic LV failure is usually the result of congestive heart failure (CHF) or cardiomyopathy. Causes of acute exacerbations include the following:
  • Acute 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, nonischemic acute mitral regurgitation (ruptured chordae tendineae), and acute aortic insufficiency (endocarditis, aortic dissection): This can cause acute, severe systemic hypertension (diastolic dysfunction), resulting in CPE.
  • Constrictive pericarditis and pericardial tamponade are other etiologies that mainly compromise LV diastolic function.
  • Ischemia and infarction may cause LV diastolic dysfunction in addition to systolic dysfunction. With a similar mechanism, myocardial contusion induces systolic or diastolic dysfunction.
• Dysrhythmias: New-onset rapid atrial fibrillation and ventricular tachycardia can be responsible for CPE.
• LVH and cardiomyopathies: These can increase LV stiffness and end-diastolic pressure, leading to pulmonary edema by increasing capillary hydrostatic pressure.
• LV volume overload
  • Some sodium retention may occur in association with LV systolic dysfunction. However, in some situations, 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 the result of noncompliance with dietary restrictions or noncompliance with hemodialysis sessions.
  • Valvular diseases, especially aortic regurgitation and mitral regurgitation, may be associated with volume overload. 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.
• MI: 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 BP can be considered an etiology of LV outflow obstruction because it increases systemic resistance against the pump function of the LV.

Differential Diagnoses

Other Problems to Be Considered

CPE should be differentiated from pulmonary edema associated with injury to the alveolar-capillary membrane caused by diverse etiologies. Damage to alveolar capillary barrier can be seen in various direct lung injuries (pneumonia, aspiration pneumonitis, toxin inhalation, pulmonary contusion, radiation, drowning and fat emboli) or indirect lung injuries (sepsis, shock and multiple transfusions, acute pancreatitis, anaphylactic shock).

In addition, 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, lymphangitic carcinomatosis, fibrosing lymphangitis, lung transplantation) is another important pathophysiologic 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 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.

Workup

Laboratory Studies

• Blood count: The CBC with differential helps in assessing for severe anemia and may suggest sepsis or infection if a markedly elevated WBC count or bandemia is present.
• Serum electrolyte measurements
  • Patients with chronic CHF often use diuretics. Therefore, they are predisposed to have 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.
• BUN and creatinine determinations: These tests help in assessing 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.

Imaging Studies

• Chest radiography is helpful in distinguishing CPE from other pulmonary causes of severe dyspnea.
• An enlarged heart, inverted blood flow, Kerley lines, basilar edema (vs diffuse edema), absence of air bronchograms, and presence of pleural effusion (particularly bilateral and symmetrical pleural effusions) are features that suggest CPE versus NCPE and other lung pathologies.
• Chest radiography is somewhat limited in patients with CPE of abrupt onset because the classic radiographic abnormalities may not appear for as long as 12 hours after dyspnea begins.
• Echocardiography: A bedside echocardiogram in a patient with decompensated CHF is an important diagnostic tool in determining the etiology of pulmonary edema. Echocardiography can evaluate LV systolic and diastolic function, valvular function, and assess for pericardial disease. It is especially helpful in identifying a mechanical etiology for pulmonary edema (eg, acute papillary muscle rupture, acute ventricular septal defect [VSD], cardiac tamponade, contained LV rupture, valvular vegetation with resulting acute severe mitral, aortic regurgitation).

Other Tests

• Arterial blood gas analysis
  • This test is more accurate than pulse oximetry for measuring oxygen saturation.
  • The decision to start mechanical ventilation is mainly based on clinical findings and rarely arterial blood gas results.
• 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.
• Electrocardiography
  • Left atrial enlargement and LV hypertrophy are sensitive, though nonspecific, indicators of chronic LV dysfunction.
  • The ECG may suggest an acute tachydysrhythmia or bradydysrhythmia as the cause of CPE.
  • The ECG may suggest acute myocardial ischemia or infarction as the cause of CPE.

Plasma brain-type natriuretic peptide (BNP) and NT-proBNP testing

Both BNP and NT-proBNP are derived from pre-proBNP, a 134-amino-acid precursor synthesized by cardiac myocytes. A number of triggers including wall stretch, ventricular dilation, and/or increased pressures stimulate a 26-amino-acid signal peptide sequence to be cleaved from the precursor’s N-terminus to produce proBNP (108-amino-acid). This hormone is further cleaved by a membrane-bound serine protease (corin) into the inactive N-terminal fragment (NT-proBNP) and the active BNP (32-amino-acid) fragment. Both NT-proBNP and BNP testing are clinically available and have exhibited parallel changes across broad ranges of age, ejection fraction, diastolic CHF, and renal function. 

• NT-proBNP testing 
  • Ventricular myocytes secrete proBNP in response to muscle-wall tension.
  • NT-proBNP has a longer half-life (120 min) than that of BNP (20 min)
  • NT-proBNP is less studied than BNP, but its levels are well correlated with BNP levels.
  • The cutoff value of NT-proBNP >450 pg/mL in patients younger than 50 years correlates to values of BNP >100 pg/mL. NT-proBNP is less accurate than BNP in patients older than 65 years.
• BNP testing
  • CHF is the most common form of CPE.
  • Several observational studies and clinical trials have shown the important diagnostic value of BNP measurements in differentiating heart failure from pulmonary causes of dyspnea.
  • BNP testing decreases the total cost of treatment and the length of hospitalization. This is a cost-effective diagnostic test in this setting.
  • Although reports differ, a cutoff value of 100 pg/mL is generally accepted. By using this cutoff value, measurement of BNP has a high negative predictive value. That is, in patients with BNP value of <100 pg/mL, heart failure is unlikely.
  • The level of BNP increases with age and is slightly higher in women than men. BNP levels also tend to be lower in obese patients.
  • In a recent study, a cutoff point of 250 pg/mL was the most accurate for elderly patients (mean age, 80 y).
  • Renal dysfunction may be associated with a significantly increased level of BNP.
  • In the Breathing Not Properly Multinational Study, the mean BNP level in patients without heart failure and with a glomerular filtration rate (GFR) below normal was 300 pg/mL.
  • Although the predictive value of BNP measures with cutoff value of 100 pg/mL is high, its positive predictive value is not as high as its negative predictive value. This means that mildly to moderately elevated levels of BNP should be interpreted in accordance to the patient's clinical status and other diagnostic results.
  • Values of 100-400 pg/mL may be related to various pulmonary conditions, such as cor pulmonale, COPD, and pulmonary embolism.
  • Atrial fibrillation is another factor that may mildly increase the cutoff value of BNP in diagnosing heart failure. Important information to know is the patient's baseline heart function. Patients with chronic heart failure and BNP values of £ 400 pg/mL may have pulmonary causes of dyspnea without an exacerbation of their CHF.
  • Until additional studies establish the precise cutoff values for different conditions, the threshold of 100 pg/mL is recommended, with the exceptions noted above. This cutoff value has an accuracy of 80-85%, a sensitivity of 90%, and a specificity of about 75% along with other appropriate clinical and laboratory findings.
  • One study of ICU patients who required invasive hemodynamic monitoring showed that they had markedly elevated BNP values, but the correlation between BNP values and PCWP was weak.

Procedures

• PCWP can be measured by using a pulmonary arterial catheter (Swan-Ganz catheter). This method helps in differentiating CPE from NCPE.
  • NCPE occurs secondary to injury to the alveolar-capillary membrane rather than to alteration in Starling forces.
  • A PCWP exceeding 18 mm Hg in a patient not known to have chronically elevated left atrial pressure indicates CPE.
  • In patients with chronic pulmonary capillary hypertension, capillary wedge pressures exceeding 30 mm Hg are required to overcome the pumping capacity of the lymphatics and produce pulmonary edema.
• Large V waves are sometimes observed in the PCWP tracing with acute mitral regurgitation because large volumes of blood regurgitate into a poorly compliant left atrium.
  • This condition raises pulmonary venous pressure and causes acute pulmonary edema.
  • The pulmonary artery waveform appears falsely elevated because of the large V wave reflected back from the left atrium through the compliant pulmonary vasculature.
  • The Y descent of the waveform is rapid, as the overdistended left atrium quickly empties.
• Cardiogenic shock is the result of a severe depression in myocardial function.
  • Cardiogenic shock is hemodynamically characterized by a systolic BP <80 mm Hg, a cardiac index <1.8 L/min/m², and a PCWP >18 mm Hg.
  • This form of shock can occur from a direct insult to the myocardium (large acute MI, severe cardiomyopathy) or from a mechanical problem that overwhelms the functional capacity of the myocardium (acute severe mitral regurgitation, acute ventricular septal defect). Although the pulmonary artery catheter is commonly used in ICU patients with severe acute decompensated CHF, it is not clear whether this technique improves mortality rate and clinical outcome. The results of the recent ESCAPE trial showed no mortality benefit or decrease in the number of hospitalized days in the group of patients who underwent PAC insertion.¹ This matter needs further investigation.

Treatment

Medical Care

Initial management of patients with CPE should address the ABCs of resuscitation, that is, airway, breathing, and circulation. Oxygen should be administered to all patients to keep oxygen saturation >90%. The method of oxygen delivery varies from use of a face mask to bilevel noninvasive positive-pressure ventilation (NPPV) or continuous positive airway pressure (CPAP) or intubation and mechanical ventilation depending on presence of hypoxemia and acidosis and on the patient's level of consciousness. In case of persistent hypoxemia, acidosis or altered mental status, intubation and mechanical ventilation may become necessary. Any associated arrhythmia or myocardial infarction should be treated appropriately.

Then medical therapy of CPE focuses on 3 main goals: (1) reduction of pulmonary venous return (preload reduction), (2) reduction of systemic vascular resistance (afterload reduction), and (3) inotropic support in some cases. 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, the third goal in this subset of patients is to provide inotropic support to maintain adequate BP.

Patients who remain hypoxic despite supplemental oxygenation and patients who have severe respiratory distress require ventilatory support in addition to maximal medical therapy.

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 the energy 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 recent small clinical trial showed that in patients with CPE defined as having severe dyspnea, oxygen saturation less than 90%, and basal rales, early and prehospital NPSV treatment by paramedics is safe and associated with faster improvement of oxygen saturation.² However, the mortality and the need for intensive care did not differ between the patients who were treated with NPSV versus Venturi face mask in this small study. A recent randomized trial compared CPAP, NIPPV, and standard oxygen therapy in 1069 patients with acute cardiogenic pulmonary edema demonstrating no mortality benefit from noninvasive ventilation, but improvements in symptomatology and oxygenation.⁴⁴  

Two types of NPSV are continuous positive airway pressure (CPAP) and bilevel positive airway pressure (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.

In 1 small study, researchers compared the 2 types of NPSV and found that BiPAP was associated with more rapid improvement in vital signs but an increased rate of MIs.³ However, patients who received BiPAP initially had more chest pain than patients who received CPAP. Other randomized clinical trials did not show any 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 CPAP. Therefore, the authors suggest that CPAP is the preferred method 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 the patient is hemodynamically unstable (eg, hypotensive, severely tachycardic).

Mechanical ventilation maximizes myocardial oxygen delivery and ventilation.

Positive end-expiratory pressure is generally recommended to increase alveolar patency and to enhance oxygen delivery and carbon dioxide exchange (see Noninvasive pressure-support ventilation).

Medical therapy

Preload reduction

• Nitroglycerin
  • Nitroglycerin (NTG) is the most effective, predictable, and rapid-acting medication available for preload reduction.
  • Several studies demonstrated greater efficacy and safety and a faster onset of action with NTG than with furosemide or morphine sulfate.
  • Use of sublingual NTG is associated with preload reduction within 5 minutes and some afterload reduction.
  • Topical NTG may be as effective as sublingual NTG in most patients with CPE, but it should be avoided in patients with severe LV failure because of poor skin perfusion (manifesting as skin pallor or mottling) and resultant poor absorption.
  • Intravenous (IV) NTG at high dosages provides rapid and titratable preload and afterload reduction and is excellent mono therapy for patients with severe CPE.
  • IV NTG can be started with 10 mcg/min and then rapidly uptitrated to >100 mcg/min.
  • The other alternative is NTG given as 3-mg IV boluses every 5 minutes.
  • The antianginal dose of NTG of 0.4 mg every 5 minutes has the bioequivalence of an NTG IV infusion of <80 mcg/min. Therefore, the dosage of NTG for patients with CPE is higher than the standard antianginal dosage.
  • Physicians should be comfortable with the high dosage for CPE, especially in most patients with CPE, who present with a hyperadrenergic state and moderately elevated BP, considering short half-life of nitrates. However, nitrates should not be used in hypotensive patients, and they should be used with extreme caution in patients with aortic stenosis and pulmonary hypertension.
• Loop diuretics
  • Loop diuretics have been considered the cornerstone of CPE treatment for many years. Furosemide is used most commonly.
  • Loop diuretics are presumed to decrease preload through 2 mechanisms: diuresis and direct vasoactivity (venodilation).
  • In most patients, diuresis does not occur for at least 20-90 minutes; therefore, the effect is delayed. Loop diuretics affect the ascending loop of Henle; therefore, the diminished renal perfusion in CPE may delay the onset of effects of loop diuretics.
  • Many patients with CPE do not have fluid overload. Continued use of diuretics in these patients after their acute symptoms resolved may be associated with adverse outcomes, including electrolyte derangements, hypotension, and worsening renal function (GFR) as a result of tubuloglomerular feedback.
  • The presumption that these medications have a direct vasoactive (venodilating) effect has been questioned. Some studies demonstrated initial adverse hemodynamic consequences (eg, elevations of PCWP, LV filling pressure, heart rate, and systemic vascular resistance) after the administration of IV furosemide.
  • Premedication with drugs that decrease preload (eg, NTG) and afterload (eg, angiotensin-converting enzyme [ACE] inhibitors) before the administration of loop diuretics can prevent potential adverse hemodynamic changes.
• Morphine sulfate
  • Use of morphine sulfate in CPE for preload reduction has been commonplace for many years.
  • Good evidence supporting a beneficial hemodynamic effect is lacking.
  • Data suggest that morphine sulfate may contribute to a decrease in cardiac output and that it may be associated with an increased need for ICU admission and endotracheal intubation.
  • Adverse effects (eg, nausea and vomiting, local or systemic allergic reactions, respiratory depression) may outweigh any potential benefit, especially given the availability of medications that are more effective than morphine in reducing preload (eg, NTG).
  • Any beneficial hemodynamic effect is probably due to anxiolysis, with a resulting decrease in catecholamine production and decrease in systemic vascular resistance. An alternative can be low-dose benzodiazepines (eg, lorazepam 0.5 mg IV) in patients who are extremely anxious. This alternative reduces the risk of respiratory depression in patients whose condition responded to initial therapy.
• Nesiritide
  • Nesiritide is recombinant human BNP, which decreases PCWP, pulmonary artery pressure, right atrial 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.
  • Most of the beneficial effects of nesiritide was shown in the landmark Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study. Investigators compared IV nesiritide with IV NTG. IV nesiritide was associated with some hypotension but was otherwise well tolerated. The VMAC study also showed a trend for increased mortality with IV nesiritide group compared with IV NTG, though the difference was not statically significant (90-day mortality, 19% for nesiritide vs 13% for NTG; P = 0.8). The most important limitation of this study was the use of suboptimal dosages of IV NTG (mean 30-40 mcg/min) because the dosage was based on physician's decision and not on a protocol.
  • A later meta-analysis of 3 randomized trials of 485 patients receiving nesiritide and 377 patients not receiving nesiritide showed a 7.2% 30-day mortality with nesiritide versus 4% without nesiritide.
  • Another analysis included 5 randomized trials showed that patients who received nesiritide were more likely than others to have significant renal failure.
  • Finally, length of hospitalization, rate of readmission because of heart failure, and cost-effectiveness of nesiritide compared with NTG therapy is not clear.
  • The evidence is not conclusive whether an increased risk of death or renal failure is present when using nesiritide, and a large (7000 patients) randomized, double-blind, placebo-controlled trial (ASCEND-HF) will provide more precise information in this regard. When NTG is contraindicated (eg, in a patient who has taken sildenafil), nesiritide can be an alternative in the treatment of CPE.

Afterload reduction

• ACE inhibitors
  • These are generally considered the cornerstones for treating chronic CHF, and recent studies have demonstrated excellent results with ACE inhibitors for the treatment of acute decompensated CHF and CPE.
  • Use of ACE inhibitors in CPE is associated with reduced admission rates to ICUs and decreased endotracheal intubation rates and length of ICU stay.
  • Hemodynamic effects of ACE inhibitors include reduced afterload, improved stroke volume and cardiac output, and a slight reduction in preload. The last effects happen when renal perfusion improves after cardiac output improves and diuresis occurs.
  • Enalapril 1.25 mg IV or captopril 25 mg given sublingually result in hemodynamic and subjective improvements within 10 minutes. Improvements occur much more slowly with the oral route.
  • Angiotensin II receptor blockers (ARBs) have comparable beneficial effects in heart failure.
  • Recent studies have proposed a role for ACE inhibitors and ARBs in preventing structural and electrical remodeling of the heart resulting in reducing the incidence of arrhythmias. The Valsartan Heart Failure Trial (Val-HeFT) showed that valsartan reduces the incidence of AF by 37%; BNP level and advanced age were the strongest independent predictors for AF occurrence.⁴ Similarly the Candesartan in Heart Failure: Assessment in Reduction of Mortality and Morbidity (CHARM) trial showed a reduction in the onset of AF in patients who were treated with Candesartan compared with placebo with a median follow-up of 37.7 months.⁵
• Nitroprusside
  • Nitroprusside results in simultaneous preload and afterload reduction by causing direct smooth-muscle relaxation, with an increased effect on afterload.
  • Afterload reduction is associated with increased cardiac output.
  • The potency and rapidity of onset and offset of effect make this an ideal medication for patients who are critically ill.
  • It may induce precipitous falls and labile fluctuations in BP; intra-arterial BP monitoring is often recommended.
  • Nitroprusside should generally be avoided in the setting of acute MI. Its use is associated with shunting of blood away from ischemic myocardium toward healthy myocardium (ie, coronary steal syndrome), which potentiates ischemia.
  • If nitroprusside is used, convert therapy to oral or alternative IV vasodilator therapy as soon as possible because prolonged use is associated with thiocyanate toxicity.
  • Use in pregnancy is associated with fetal thiocyanate toxicity.
  • Prolonged infusion can induce tolerance, and reflex tachycardia may occur.
• Inotropics: Inotropic support is usually used when preload- and afterload-reduction strategies are not successful or when hypotension precludes use of these strategies. Two main classes of inotropic agents are available: catecholamine agents and phosphodiesterase inhibitors (PDIs). Calcium-sensitizer agents are a new class of medications that have notably beneficial effects in acute decompensated heart failure; these drugs are under investigation.  
  • Dobutamine
    • Dobutamine, a catecholamine agent, mainly serves as a beta1-receptor agonist, though it has some beta2-receptor and minimal alpha-receptor activity.
    • IV dobutamine induces significant positive inotropic effects with mild chronotropic effects. It also induces mild peripheral vasodilation (decrease in afterload).
    • The combination effect of increased inotropy with decreased afterload significantly increases cardiac output.
    • Combination use with IV NTG may be ideal for patients with MI and CPE and mild hypotension to simultaneously reduce preload and increase cardiac output.
    • In general, avoid dobutamine in patients with moderate or severe hypotension (eg, systolic BP <80 mm Hg) because of the peripheral vasodilation.
• Dopamine
  • The vascular and myocardial receptor effects of dopamine, a catecholamine agent, are dose dependent.
  • Low dosages of 0.5-5 mcg/kg/min stimulate dopaminergic receptors in the renal and splanchnic vascular beds, causing vasodilation and increasing diuresis.
  • Moderate dosages of 5-10 mcg/kg/min stimulate beta-receptors in the myocardium, increasing cardiac contractility and heart rate.
  • High dosages of 15-20 mcg/kg/min stimulate alpha-receptors, resulting in peripheral vasoconstriction (increased afterload), increased BP, and no further improvement in cardiac output.
  • Moderate and high dosages are arrhythmogenic and increase myocardial oxygen demand (with the potential for myocardial ischemia). Therefore, use these dosages only in patients with CPE who cannot tolerate dobutamine because of severe hypotension (eg, systolic BP 60-80 mm Hg)
• Norepinephrine
  • Norepinephrine, a catecholamine agent, primarily stimulates alpha-receptors, significantly increasing afterload (and the potential for myocardial ischemia) and reducing cardiac output.
  • Norepinephrine is generally reserved for patients with profound hypotension (eg, systolic BP <60 mm Hg). After BP is restored, add other medications to maintain cardiac output.
• Phosphodiesterase inhibitors (PDIs)
  • PDIs increase the level of intracellular cyclic adenosine monophosphate by preventing the breakdown of cAMP to 5'AMP and result in a positive inotropic effect on the myocardium, in peripheral vasodilation (decreased afterload) and in a reduction in pulmonary vascular resistance (decreased preload).
  • Unlike the catecholamine inotropes, PDIs do not depend on adrenoreceptor activity. Therefore, patients are less likely to develop tolerance to PDIs than to other medications. Tolerance to catecholamine inotropes can rapidly develop by means of a downregulation of adrenoreceptors.
  • PDIs are less likely than catecholamine inotropes to cause adverse effects that are typically associated with adrenoreceptor activity (eg, increased myocardial oxygen demand, myocardial ischemia).
  • Several direct comparisons of PDIs (milrinone) to dobutamine in patients with CPE demonstrated that milrinone produced equal or greater improvements in stroke volume, cardiac output, PCWPs (preload), and systemic vascular resistance (afterload). However, milrinone was associated with the same or more tachycardia and with an increased incidence of tachyarrhythmias. Furthermore, use of milrinone, in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF), did not reduce hospital length of stay and was associated with a significant increase in adverse events compared with placebo.
• All known IV inotropic agents are associated with an increased long-term mortality compared with placebo and therefore should be reserved for patients with heart failure and a markedly depressed cardiac index and stroke volume.
• Calcium sensitizer
  • Levosimendan is a calcium sensitizer that is used in several European countries to manage moderate-to-severe heart failure. It has inotropic, metabolic, and vasodilatory effects.
  • Levosimendan increases contractility by binding to troponin C. It does not increase myocardial oxygen demand, and it is not a proarrhythmogenic agent.
  • Levosimendan opens potassium channels sensitive to adenosine triphosphate (ATP), causing peripheral arterial and venous dilatation. It also increases coronary flow reserve. Recent studies have shown an anti-inflammatory effect of levosimendan.
  • Overall, levosimendan has been an effective and safe alternative to dobutamine. The most common adverse effects of levosimendan treatment are hypotension and headache. A recent randomized clinical trial (SURVIVE trial) demonstrated no mortality benefit of levosimendan as compared with dobutamine in patients with acute decompensated CHF.⁶
• Tolvaptan
  • Tolvaptan is an oral vasopressin V2 receptor antagonist recently evaluated in a large (4133 patients) randomized, double-blind, placebo controlled trial (EVEREST) in patients with acute clinically decompensated CHF. This trial demonstrated no mortality or CHF hospitalization benefit at a median follow-up of 9.9 months. However, patients randomized to tolvaptan demonstrated early (1-7 d) improvements in body weight, dyspnea, serum sodium, and edema as compared with placebo.⁷

Surgical Care

Intra-aortic balloon pumping

Kantrowitz initially described intra-aortic balloon pumping (IABP) in 1953, but IABP was first used clinically in 1969 in a patient with cardiogenic shock. Since the 1980s, IABP has been increasingly applied in various clinical situations as a life-saving intervention to achieve hemodynamic stabilization before definitive therapy. The IABP decreases afterload as the pump deflates, and it inflates during diastole to improve coronary blood flow.

• Procedure  
  • The intra-aortic balloon pump is inserted percutaneously through the femoral artery by using a modified Seldinger technique. The distal end of the pump is placed just distal to the aortic knob and the origin of the left subclavian artery.
  • Fluoroscopy may be used for correct positioning of the balloon, and a subsequent radiograph should be obtained to document satisfactory placement of the balloon.
  • Helium, a low-density gas with minimal water solubility, is used to inflate the balloon.
• Proper timing of IABP for optimal hemodynamic support  
  • Proper timing of counterpulsation is necessary for maximum hemodynamic support. The timing of balloon inflation and deflation are best evaluated and adjusted at a pump ratio of 1:2.
  • Inflation of the balloon should occur in early diastole, just after the aortic valve closes, and it should correspond to the dicrotic notch of the aortic pressure waveform. Balloon deflation should occur in early systole, just before the aortic valve opens.
  • Proper inflation leads to an assisted peak diastolic pressure higher than the unassisted peak systolic arterial pressure. Proper deflation results in assisted aortic end-diastolic pressure of approximately 10 mm Hg lower than the unassisted end-diastolic pressure.
  • Diastolic augmentation enhances perfusion of the coronary circulation and carotid arteries. The reduction in end-diastolic pressure decreases aortic impedance (afterload) and augments systole.
  • IABP reduces aortic impedance and systolic pressure, leading to a 15-25% reduction in LV wall stress. This level of afterload reduction improves LV volume, LV emptying, and myocardial oxygen consumption.
  • Diastolic aortic pressure augmentation improves myocardial perfusion and coronary blood flow. The effects on coronary blood flow may be variable but generally consist of a boost of 10-20% in the ischemic territories.
  • IABP decreases LV filling pressures by 20-25% and improves cardiac output by 20% in patients with cardiogenic shock. Therefore, IABP substantially reduces myocardial oxygen demand, though increased oxygen supply to the myocardium may also be a beneficial effect in some clinical situations.
• Indications for IABP  
  • IABP is effective in providing temporary support to patients in cardiogenic shock and end-stage cardiomyopathy while definite therapies, such as angioplasty or cardiac bypass surgery or cardiac transplantation, are undertaken. In this case, the use of IABP is considered a bridge to a definitive revascularization procedure or implementation of an LV-assist device.
  • IABP is effective in stabilizing patients with unstable angina refractory to medical therapy before a definitive revascularization procedure.
  • IABP may be a life-saving intervention in patients with acute mitral regurgitation secondary to papillary muscle rupture or in patients with ventricular septal defect as a complication of MI. IABP reduces afterload and thereby reduces the severity of mitral regurgitation. It enhances forward cardiac output, reduces left atrial pressure, and improves pulmonary edema. Furthermore, IABP decreases LV afterload and improves cardiac output.
  • IAPB is used to stabilize patients, which allows time to plan definitive surgery in hemodynamically unstable patients.
  • IABP can also provide hemodynamic support in the perioperative and postoperative period in high-risk patients, such as those with severe coronary disease, severe LV dysfunction, or recent MI.
• Contraindications  
  • Absolute contraindications for IABP counterpulsation are a dissecting aortic aneurysm, severe aortic regurgitation, a large arteriovenous shunt, and severe coagulopathy.
  • Relative contraindications are severe peripheral vascular disease, recent thrombolytic therapy, bleeding diathesis, and descending aortic and peripheral vascular grafts.
• Complications
  • IABP can cause several complications, which should be monitored while the patient is receiving IABP support. In general, the platelet counts are mildly reduced; however, the counts usually do not fall below 100 X 10⁹/L.
  • Complications also may occur during cannulation of the femoral artery. These include perforation, laceration, or dissection of the artery (1-6%). Thrombosis of the iliofemoral artery and distal emboli may also occur (1-7%), and limb ischemia is reported in up to 40% of patients. Limb ischemia is reversible by removing the intra-aortic balloon pump unless thrombosis develops; if so, embolectomy is required to save the limb. 
• The other complications are localized bleeding (3-5%), infection (2-4%), thrombocytopenia (<1%), and intestinal ischemia (<1%).

Ultrafiltration

A recent randomized trial of ultrafiltration versus diuresis in patients with acute decompensated systolic heart failure (UNLOAD trial) demonstrated that ultrafiltration was superior in controlling net fluid loss and rehospitalization.⁸  As a result of this trial, UF should be considered in patients with volume overload and acute CHF who have not responded well to moderate to large doses of diuretic treatment or in whom the adverse effects of such treatment (eg, renal dysfunction) did not allow initiation or continuation of the treatment. Broader application of UF needs further investigation with larger clinical trials to determine the efficacy and safety of this method.

Consultations

Consultations with subspecialists depends on the underlying cause of the episode of CPE.

• If the acute episode is attributed to an acute MI, acute cardiac ischemia, or an acute dysrhythmia, consultation with a cardiologist is often warranted.
• If the episode is attributed to fluid overload in patients with renal failure, consultation with a nephrologist is indicated for emergency or urgent hemodialysis.
• If CPE results from acute valvular dysfunction, consultation with a cardiothoracic surgeon (including a cardiologist) for urgent valve replacement may be indicated depending on the integrity of the valve.
• In patients who develop cardiogenic shock, consultation with a cardiologist and/or critical care specialist is generally indicated to assist with titrating inotropic medication and, in some cases, to place an intraaortic balloon pump as a temporizing measure before surgery (eg, valve replacement or coronary revascularization).

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.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Preload reducers

Reduced pulmonary venous return decreases pulmonary capillary hydrostatic pressure and reduces fluid transudation into the pulmonary interstitium and alveoli. Preload reducers include nitroglycerin (eg, Deponit, Minitran, Nitro-Bid IV, Nitro-Bid ointment, Nitrodisc, Nitro-Dur, Nitrogard, Nitroglyn, Nitrol, Nitrolingual, Nitrong, Nitrostat, Transdermal-NTG, Transderm-Nitro, Tridil) and furosemide (eg, Lasix).

Nitroglycerin (Nitro-Bid, Deponit, Nitrol)

Drug of choice (DOC) for patients who are not hypotensive. Provides excellent and reliable preload reduction. High dosages provide mild afterload reduction. Rapid onset and offset (both within min), allowing for rapid clinical effects and rapid discontinuation of effects in adverse reactions.

Dosing

Adult

Mild-to-moderate respiratory distress: 1-2 applied topically if skin perfusion good; not effective in peripheral vessel vasoconstriction resulting from shock
Moderate-to-severe respiratory distress: 0.3-0.4 mg SL q3-5min
Severe distress: 10-20 mcg/min IV, titrate up by 5-10 mcg q5min as BP tolerates

Pediatric

Not established

Interactions

Sildenafil (Viagra) taken within 24 h, tadalafil (Cialis) taken within 48 h, and vardenefil (Levitra) taken within 48 h may induce precipitous decreases in BP; aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (may need to adjust dosage of either)

Contraindications

Documented sensitivity; hypotension; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in RV infarction and constrictive pericarditis because of importance of adequate preload in maintaining cardiac output; caution in severe aortic stenosis because of adequate preload needed to maintain cardiac output

Furosemide (Lasix)

Most commonly used loop diuretic. Increases excretion of water by interfering with chloride-binding cotransport system, inhibiting sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Reduces preload by diuresis in 20-60 min. May contribute to hastened preload reduction with direct vasoactive mechanism, but controversial. As many as 50% of patients with CPE have total-body euvolemia. Generally administered to all patients with CPE but probably most useful in patients with total-body fluid overload.
PO form has relatively slow onset of action and therefore, generally not appropriate in CPE.

Dosing

Adult

1 mg/kg or 60-80 mg IV push

Pediatric

Not established

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity may be increased with coadministration of aminoglycosides; hearing loss of various degrees may occur; may enhance anticoagulant activity of warfarin when taken concurrently; may increase plasma levels and toxicity of lithium when taken concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Patients who are anuric do not produce urine in response to furosemide; some believe acute use in these patients is appropriate because of direct vasoactive effect; frequently monitor serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN levels during first few mo of therapy and periodically thereafter

Afterload reducers

Reduced systemic vascular resistance increases cardiac output and improves renal perfusion, allowing for diuresis.

Captopril (Capoten)

Prevents conversion of angiotensin I to angiotensin II. Potent vasodilator that lowers aldosterone secretion. Option in patients unable to tolerate NTG (eg, concurrent use of sildenafil). Hemodynamic (improved afterload and cardiac output) and subjective (decreased dyspnea) improvements in 10-15 min. Although not specifically formulated for SL use, can wet tab before placing under patient's tongue to achieve desired effect.

Dosing

Adult

12.5-25 mg SL if BP is 90-110 mm Hg

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects may be enhanced when administered concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Avoid when BP <90 mm Hg; CPE unlikely to cause hyperkalemia, but some avoid in known preexisting hyperkalemia; caution in renal impairment, valvular stenosis, or severe CHF

Enalapril (Vasotec)

Competitive ACE inhibitor. Reduces angiotensin II levels, decreasing aldosterone secretion. Use of IV to treat decompensated heart failure and pulmonary edema not been studied as well as SL captopril. In 1993, Varriale evaluated patients with severe CHF and mitral regurgitation; observed improved preload, afterload, cardiac output, and magnitude of regurgitation. In 1996, Annane evaluated patients with acute CPE; found improvements in preload and afterload. No demonstrated effect on cardiac output. Both studies showed excellent safety profile.

Dosing

Adult

1.25 mg IV bolus in studies (awaiting definitive recommendation); alternatively 1-mg infusion over 2 h

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects may be enhanced when administered concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Avoid when BP <90 mm Hg; acute administration unlikely to cause hyperkalemia; some avoid use in known preexisting hyperkalemia; caution in renal impairment, valvular stenosis, or severe CHF

Nitroprusside (Nitropress)

Potent direct smooth-muscle–relaxing agent that primarily reduces afterload but can mildly reduce preload. Improves cardiac output but can precipitously decrease BP. Intra-arterial BP monitoring strongly recommended. Excellent in critically ill patients because of rapid onset and offset of action (within 1-2 min). Excellent in pulmonary edema associated with severe hypertension unresponsive to other agents.

Dosing

Adult

0.1-0.3 mcg/kg/min continuous IV infusion initially, titrate q5-10min; not to exceed 5-10 mcg/kg/min

Pediatric

Not established

Interactions

Not established for short-term ( <12-24 h) stabilization; combined use with other vasodilators may significantly decrease BP (continuous hemodynamic monitoring imperative)

Contraindications

Documented hypersensitivity; subaortic stenosis; idiopathic hypertrophic subaortic stenosis; atrial fibrillation or flutter

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Precipitous decreases in BP (continuous intra-arterial hemodynamic monitoring strongly recommended); coat drug reservoir and tubing with opaque material (eg, aluminum foil) to protect against light sensitivity; adverse effects include headache, nausea, and vomiting; monitor thiocyanate levels in prolonged use (24 h or 6-12 h in renal failure); fetal cyanide toxicity is concern in prolonged use during pregnancy (convert to oral vasodilator are stabilization)

Catecholamines

These agents produce vasodilation and increase inotropic state. At high dosages, they may increase the patient's heart rate, exacerbating myocardial ischemia.

Dobutamine (Dobutrex)

Synthetic catecholamine with mainly beta1-receptor activity but some beta2- and alpha-receptor activity. Commonly used in CPE and mild hypotension (systolic BP 90-100 mm Hg). Combination of beneficial hemodynamic effects (eg, positive inotropism, decreased afterload due to mild vasodilation, increased cardiac output).

Dosing

Adult

2-5 mcg/kg/min IV infusion initially, titrate to effect; not to exceed 20 mcg/kg/min

Pediatric

Not established

Interactions

Beta-adrenergic blockers antagonize effects; general anesthetics may increase toxicity

Contraindications

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis; atrial fibrillation or flutter

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitoring hemodynamics recommended; ventricular ectopy and tachydysrhythmia (eg, sinus tachycardia) may result from positive inotropic effects and increase myocardial oxygen consumption and cardiac ischemia (not considered as common or as severe as with dopamine); some recommend discontinuing titration if heart rate increases >10% of baseline; vasodilating effect may mildly decrease systolic BP (close hemodynamic monitoring recommended); defer use in moderate or severe hypotension (eg, systolic BP <90 mm Hg)

Dopamine (Intropin)

Naturally occurring catecholamine that acts as precursor to norepinephrine. Stimulates adrenergic and dopaminergic receptors. Hemodynamic effect dose dependent. Low-dose associated with dilation in renal and splanchnic vasculature, enhancing diuresis. Moderate doses enhance cardiac contractility and heart rate. High doses increase afterload due to peripheral vasoconstriction. Use in CPE generally reserved for patients with moderate hypotension (eg, systolic BP 70-90 mm Hg). Moderate-to-high doses usually used.

Dosing

Adult

5 mcg/kg/min continuous IV infusion initially, titrate to stabilize BP; not to exceed 20 mcg/kg/min

Pediatric

Not established

Interactions

Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and monoamine oxidase inhibitor (MAOIs) increase and prolong effects of dopamine

Contraindications

Documented hypersensitivity; pheochromocytoma; ventricular fibrillation; idiopathic hypertrophic subaortic stenosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Closely monitor urine flow, cardiac output, pulmonary wedge pressure, and BP closely infusion; before infusion, correct hypovolemia with whole blood or plasma as indicated; monitoring of central venous pressure or LV filling pressure may help in detecting and treating hypovolemia; 10-20 mcg/kg/min increases peripheral vasoconstriction and afterload; may increase tachydysrhythmias and increase myocardial oxygen consumption and cardiac ischemia; alkaline solutions may inactivate if administered through same IV line

Norepinephrine (Levophed)

Naturally occurring catecholamine with potent alpha-receptor and mild beta-receptor activity. Stimulates beta1- and alpha-adrenergic receptors, increasing myocardial contractility, heart rate, and vasoconstriction. Increases BP and afterload; may decrease cardiac output, increase myocardial oxygen demand, and cardiac ischemia. Generally reserved for patients with severe hypotension (eg, systolic BP <70 mm Hg) or hypotension unresponsive to other medication.

Dosing

Adult

0.5-1 mcg/min IV infusion initially; titrate to effect; not to exceed 30 mcg/min

Pediatric

Not established

Interactions

Atropine may block reflex tachycardia caused by norepinephrine and enhance pressor response

Contraindications

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause tachydysrhythmia (especially sinus tachycardia) and increase myocardial oxygen demand and cardiac ischemia; alkaline solutions may inactivate drug if administered in same IV line; extravasation may cause severe tissue necrosis, (administer into large vein); if extravasation occurs, immediately infiltrate phentolamine 5-10 mg (diluted in 10-15 mL normal sodium chloride solution) to prevent necrosis; caution in occlusive vascular disease; if possible, correct blood-volume depletion before administration

Phosphodiesterase enzyme inhibitors

These bipyridine-positive inotropic agents and vasodilators have little chronotropic activity. They differ from both digitalis glycosides and catecholamines in their mechanism of action.

Milrinone (Primacor)

Positive inotropic agent and vasodilator. Reduces afterload and preload and increases cardiac output. In several comparisons, improved preload, afterload, cardiac output more than dobutamine, without significantly increased myocardial oxygen consumption.

Dosing

Adult

50 mcg/kg IV loading dose over 10 min, then continuous infusion of 0.375-0.75 mcg/kg/min; titrate to maintain adequate systolic BP and cardiac output

Pediatric

Not established

Interactions

Precipitates in presence of furosemide

Contraindications

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor fluids, electrolyte changes, and renal function during therapy; excessive diuresis may increase potassium loss and predispose patients receiving digitalis to arrhythmias (correct hypokalemia with potassium supplementation before treatment); slow or stop infusion if BP excessively decreases; previous vigorous diuretic therapy may significantly decrease cardiac filling pressure; administer cautiously and monitor BP, heart rate, and clinical symptoms

Follow-up

Further Inpatient Care

• When the patient's condition is initially stabilized, further inpatient care depends on the underlying cause of the episode of CPE.
• Admit patients to a telemetry unit to monitor for acute dysrhythmias. Pay strict attention to the patient's fluid balance and closely monitor fluid input and output. Maintain a negative fluid balance in patients who are fluid-overloaded by using diuretics or hemodialysis (in patients with renal failure).
• Check cardiac enzyme levels to evaluate for MI. Stress testing can also be performed during hospitalization to evaluate for reversible ischemia as the cause of pulmonary edema.
• Consider ECG to evaluate for evidence of acute valvular dysfunction and wall-motion abnormalities and to assess the patient's ejection fraction. Patients with poor ejection fractions or severe dilated cardiomyopathies are often given digoxin.
• In general, begin with oral vasodilator therapy, most commonly ACE inhibitors. If the patient was initially treated with inotropic medications, wean the patient off of these as soon as his or her condition is stable to minimize adverse effects.
• Patients in whom pulmonary edema is due to dietary factors or medication noncompliance need strict counseling and education to help prevent recurrences.

Inpatient & Outpatient Medications

• See Treatment and Medication.

Transfer

• Transfer of patients to a tertiary receiving hospital is generally indicated if the initial hospital lacks adequate resources to care for the patient. Most patients with CPE can be treated well at community hospitals. However, if definitive surgery is required to stabilize the cause of CPE, transfer is often indicated.
• Examples of patients who may require transfer include the following:  
  • Patients with CPE due to acute valvular dysfunction requiring urgent valve replacement.
  • Patients with acute MI that results in cardiogenic shock manifesting as CPE with hypotension (thrombolysis may be attempted at the initial hospital, but outcomes are generally poor without percutaneous coronary intervention or coronary artery bypass surgery.)
  • Patients with CPE who require inotropic support or hemodialysis beyond the capabilities of the initial hospital.
  • In severe cases of refractory cardiogenic shock, consider early transfer of appropriate patients to a tertiary medical center where, if clinically indicated, more advanced treatments such as left ventricular assist device and or cardiac transplantation may be performed.

Complications

• The major complication associated with CPE is respiratory fatigue and failure.
• Prompt diagnosis and treatment usually prevent this complication, 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).
• Sudden cardiac death secondary to cardiac arrhythmia is another concern and continues monitoring of heart rhythm is helpful in prompt diagnosis of dangerous arrhythmias.

Prognosis

• In general, the inpatient mortality rate for patients with CPE is 15-20%.
• CPE associated with acute MI is associated with a mortality rate of at least 40%. The mortality rate approaches 80% if the patient is also hypotensive.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Failure to rapidly recognize CPE and distinguish this entity from other pulmonary diseases
• Failure to rapidly initiate medical therapy for CPE
• Failure to obtain an early ECG and failure to rapidly diagnose and treat MI and ischemia
• Failure to rapidly and aggressively treat intractable hypoxia with mechanical ventilation

Multimedia

Media file 1: 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.

Media file 2: Radiograph shows acute pulmonary edema in a patient known to have ischemic cardiomyopathy. Findings are Kerley B lines (1 mm thick and 1 cm long) in lower lobes and Kerley A lines in the upper lobes.

Media file 3: Radiograph demonstrates cardiomegaly, bilateral pleural effusions, and alveolar opacities in a patient with pulmonary edema.

Media file 4: Radiograph shows interstitial pulmonary edema, cardiomegaly, and left pleural effusion presenting at an earlier stage of pulmonary edema.

Media file 5: Lateral chest radiograph shows prominent interstitial edema and pleural effusions.

References

1. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. Oct., 2005;294(5):1625-33. [Medline].

2. Weitz G, Struck J, Zonak A, Balnus S, Perras B, Dodt C. Prehospital noninvasive pressure support ventilation for acute cardiogenic pulmonary edema. Eur J Emerg Med. Oct 2007;14(5):276-9. [Medline].

3. Mehta S, Jay GD, Woolard RH. Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med. Apr 1997;25(4):620-8. [Medline].

4. Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J. Mar, 2005;149(3):548-57. [Medline].

5. Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J. Jul, 2006;152(1):86-92. [Medline].

6. [Best Evidence] Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. May, 2007;297(17):1883-91. [Medline].

7. [Best Evidence] Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. Mar, 2007;297(12):1332-43. [Medline].

8. [Best Evidence] Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. Feb, 2007;49(6):675-83. [Medline].

9. Annane D, Bellissant E, Pussard E. Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation. Sep 15 1996;94(6):1316-24. [Medline].

10. Barnett JC, Zinc KM, Touchon RC. Sublingual captopril in the treatment of acute heart failure. Curr Ther Res. 1991;49:274-81.

11. Bauer JB, Randazzo MA. Nesiritide for outpatient treatment of heart failure. Am J Health Syst Pharm. 2005;15;62(24):2639-2642.

12. Bersten AD, Holt AW, Vedig AE. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med. Dec 26 1991;325(26):1825-30. [Medline].

13. Cheng JW, Merl MY, Nguyen HM. Effect of nesiritide on renal function: a retrospective review. Curr Med Res Opin. Nov 2005;21(11):1857-63. [Medline].

14. Dupuis J. Nitrates in congestive heart failure. Cardiovasc Drugs Ther. Jun 1994;8(3):501-7. [Medline].

15. Earl GL, Fitzpatrick JT. Levosimendan: a novel inotropic agent for treatment of acute, decompensated heart failure. Ann Pharmacother. Nov 2005;39(11):1888-96. [Medline].

16. Figueras J, Weil MH. Blood volume prior to and following treatment of acute cardiogenic pulmonary edema. Circulation. Feb 1978;57(2):349-55. [Medline].

17. Figueras J, Weil MH. Hypovolemia and hypotension complicating management of acute cardiogenic pulmonary edema. Am J Cardiol. Dec 1979;44(7):1349-55. [Medline].

18. Follath F, Franco F, Cardoso JS. European experience on the practical use of levosimendan in patients with acute heart failure syndromes. Am J Cardiol. Sep 19 2005;96(6A):80G-5G. [Medline].

19. Franciosa JA, Silverstein SR. Hemodynamic effects of nitroprusside and furosemide in left ventricular failure. Clin Pharmacol Ther. Jul 1982;32(1):62-9. [Medline].

20. Francis GS, Siegel RM, Goldsmith SR. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med. Jul 1985;103(1):1-6. [Medline].

21. Fromm RE Jr, Varon J, Gibbs LR. Congestive heart failure and pulmonary edema for the emergency physician. J Emerg Med. Jan-Feb 1995;13(1):71-87. [Medline].

22. Gagnon RM, Fortin L, Boucher R. Combined hemodynamic effects of dobutamine and IV nitroglycerin in congestive heart failure. Chest. Nov 1980;78(5):694-8. [Medline].

23. Gammage M. Treatment of acute pulmonary edema: diuresis or vasodilatation?. Lancet. Feb 7 1998;351(9100):382-3. [Medline].

24. Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol. Sep 19 2005;96(6A):68G-73G. [Medline].

25. Gropper MA, Wiener-Kronish JP, Hashimoto S. Acute cardiogenic pulmonary edema. Clin Chest Med. Sep 1994;15(3):501-15. [Medline].

26. Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad Emerg Med. Mar 1996;3(3):205-12. [Medline].

27. Hoffman JR, Reynolds S. Comparison of nitroglycerin, morphine and furosemide in treatment of presumed pre-hospital pulmonary edema. Chest. Oct 1987;92(4):586-93. [Medline].

28. Holt AW, Bersten AD, Fuller S. Intensive care costing methodology: cost benefit analysis of mask continuous positive airway pressure for severe cardiogenic pulmonary edema. Anaesth Intensive Care. Apr 1994;22(2):170-4. [Medline].

29. Karlsberg RP, DeWood MA, DeMaria AN. Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group. Clin Cardiol. Jan 1996;19(1):21-30. [Medline].

30. Keung EC, Siskind SJ, Sonneblick EH. Dobutamine therapy in acute myocardial infarction. JAMA. Jan 9 1981;245(2):144-6. [Medline].

31. Klinger JR, Houtchens J, Thaker S. Acute cardiopulmonary hemodynamic effects of brain natriuretic Peptide in patients with pulmonary arterial hypertension. Chest. 2005;128(6 Suppl):618S-9S. [Medline].

32. [Best Evidence] Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. Mar, 2007;297(12):1319-31. [Medline].

33. Kostuk W, Barr JW, Simon AL. Correlations between the chest film and hemodynamics in acute myocardial infarction. Circulation. Sep 1973;48(3):624-32. [Medline].

34. Kraus PA, Lipman J, Becker PJ. Acute preload effects of furosemide. Chest. 1990;98:124-8. [Medline].

35. LHer E, Duquesne F, Girou E, de Rosiere XD, Le Conte P, Renault S, et al. Noninvasive continuous positive airway pressure in elderly cardiogenic pulmonary edema patients. Intensive Care Med. May 2004;30(5):882-8. [Medline].

36. Langes K, Siebels J, Kuck KH. Efficacy and safety of intravenous captopril in congestive heart failure. Curr Ther Res. 1993;53:167-76.

37. Le Conte P, Coutant V, NGuyen JM, Baron D, Touze MD, Potel G. Prognostic factors in acute cardiogenic pulmonary edema. Am J Emerg Med. Jul 1999;17(4):329-32. [Medline].

38. Lin M, Yang YF, Chiang HT. Reappraisal of continuous positive airway pressure therapy in acute cardiogenic pulmonary edema. Short-term results and long-term follow-up. Chest. May 1995;107(5):1379-86. [Medline].

39. Mager G, Klocke RK, Kux A. Phosphodiesterase III inhibition or adrenoreceptor stimulation: milrinone as an alternative to dobutamine in the treatment of severe heart failure. Am Heart J. Jun 1991;121(6 Pt 2):1974-83. [Medline].

40. Mattu A. Cardiogenic Pulmonary Edema. Curr Opin Cardiovascular, Pulmonary, and Renal Investigational Drugs. 2000;2:9-16.

41. Mattu A, Martinez JP, Kelly BS. Modern management of cardiogenic pulmonary edema. Emerg Med Clin North Am. Nov 2005;23(4):1105-25. [Medline].

42. Mehta S, Nava S. Mask ventilation and cardiogenic pulmonary edema: another brick in the wall. Intensive Care Med. Jun 2005;31(6):757-9. [Medline].

43. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. Jan 16 2002;39(2):202-9. [Medline].

44. Newby D. Efficacy of non-invasive ventilation in patients with acute cardiogenic pulmonary oedema: The 3CPO trial. Presented at the ESC meeting. Sept 2007;[Full Text].

45. Pang D, Keenan SP, Cook DJ. The effect of positive pressure airway support on mortality and the need for intubation in cardiogenic pulmonary edema: a systematic review. Chest. Oct 1998;114(4):1185-92. [Medline].

46. Parissis JT, Filippatos G, Farmakis D, Adamopoulos S, Paraskevaidis I, Kremastinos D. Levosimendan for the treatment of acute heart failure syndromes. Expert Opin Pharmacother. Dec 2005;6(15):2741-51. [Medline].

47. Ray P, Arthaud M, Birolleau S, Isnard R, Lefort Y, Boddaert J. Comparison of brain natriuretic peptide and probrain natriuretic peptide in the diagnosis of cardiogenic pulmonary edema in patients aged 65 and older. J Am Geriatr Soc. Apr 2005;53(4):643-8. [Medline].

48. Ray P, Arthaud M, Lefort Y, Birolleau S, Beigelman C, Riou B. Usefulness of B-type natriuretic peptide in elderly patients with acute dyspnea. Intensive Care Med. Dec 2004;30(12):2230-6. [Medline].

49. Rihal CS, Davis KB, Kennedy JW. The utility of clinical, electrocardiographic, and roentgenographic variables in the prediction of left ventricular function. Am J Cardiol. Feb 1 1995;75(4):220-3. [Medline].

50. Sacchetti A, McCabe J, Torres M. ED management of acute congestive heart failure in renal dialysis patients. Am J Emerg Med. Nov 1993;11(6):644-7. [Medline].

51. Sacchetti A, Ramoska E, Moakes ME. Effect of ED management on ICU use in acute pulmonary edema. Am J Emerg Med. Oct 1999;17(6):571-4. [Medline].

52. Sacchetti AD, Harris RH, Paston C. Bi-level positive airway pressure support system use in acute congestive heart failure: preliminary case series. Acad Emerg Med. Aug 1995;2(8):714-8. [Medline].

53. Scroggins N, Edwards M, Delgado R 3rd. Increased cost effectiveness with nesiritide vs. milrinone or dobutamine in the treatment of acute decompensated heart failure. Congest Heart Fail. Nov-Dec 2005;11(6):311-4. [Medline].

54. Shipley JB, Tolman D, Hastillo A. Milrinone: basic and clinical pharmacology and acute and chronic management. Am J Med Sci. Jun 1996;311(6):286-91. [Medline].

55. Silver MA. The natriuretic peptide system: kidney and cardiovascular effects. Curr Opin Nephrol Hypertens. Jan 2006;15(1):14-21. [Medline].

56. Teerlink JR. Overview of randomized clinical trials in acute heart failure syndromes. Am J Cardiol. Sep 19 2005;96(6A):59G-67G. [Medline].

57. Timmis AD, Rothman MT, Henderson MA. Haemodynamic effects of intravenous morphine in patients with acute myocardial infarction complicated by severe left ventricular failure. Br Med J. Apr 5 1980;280(6219):980-2. [Medline].

58. Travill CM, Pugh S, Noble MI. The inotropic and hemodynamic effects of intravenous milrinone when reflex adrenergic stimulation is suppressed by beta-adrenergic blockade. Clin Ther. Sep-Oct 1994;16(5):783-92. [Medline].

59. Varriale P, David W, Chryssos BE. Hemodynamic response to intravenous enalaprilat in patients with severe congestive heart failure and mitral regurgitation. Clin Cardiol. Mar 1993;16(3):235-8. [Medline].

60. Verma SP, Silke B, Hussain M. First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomized evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. J Cardiovasc Pharmacol. Jul 1987;10(1):38-46. [Medline].

61. Verma SP, Silke B, Nelson GI. Haemodynamic advantages of a combined inotropic/venodilator regimen over inotropic monotherapy in acute heart failure. J Cardiovasc Pharmacol. Sep-Oct 1985;7(5):943-7. [Medline].

62. Verma SP, Silke B, Reynolds GW. Haemodynamic dose-response effects of a transdermal nitrate delivery system in acute myocardial infarction with and without left heart failure. J Cardiovasc Pharmacol. Feb 1988;11(2):151-7. [Medline].

63. Vismara LA, Leaman DM, Zelis R. The effects of morphine on venous tone in patients with acute pulmonary edema. Circulation. Aug 1976;54(2):335-7. [Medline].

64. Zelis R, Mansour EJ, Capone RJ. The cardiovascular effects of morphine. The peripheral capacitance and resistance vessels in human subjects. J Clin Invest. Dec 1974;54(6):1247-58. [Medline].

Keywords

PE, pulmonary edema, cardiogenic pulmonary edema, pulmonary edema cardiogenic, CPE, congestive heart failure, CHF, decompensated heart failure, heart failure, increased capillary hydrostatic pressure, increased capillary permeability, decreased plasma oncotic pressure, lymphatic obstruction, noncardiogenic pulmonary edema, NCPE

Contributor Information and Disclosures

Author

Ali A Sovari, MD, Research Fellow, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles (UCLA)
Ali A Sovari, MD is a member of the following medical societies: American College of Physicians, American Heart Association, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Abraham G Kocheril, MD, FACC, FACP, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago
Abraham G Kocheril, MD, FACC, FACP is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, Cardiac Electrophysiology Society, Central Society for Clinical Research, Heart Failure Society of America, Heart Rhythm Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

Arnold S Baas, MD, FACC, FACP, Assistant Professor of Medicine, University of California at Los Angeles; Attending Physician, UCLA Santa Monica Hospital and UCLA Westwood Hospital
Arnold S Baas, MD, FACC, FACP is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, and American Society of Echocardiography
Disclosure: Pfizer Honoraria Speaking and teaching

Medical Editor

George A Stouffer III, MD, Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Managing Editor

Marschall S Runge, MD, PhD, Charles and Anne Sanders Distinguished Professor of Medicine, Chairman, Department of Medicine, Vice Dean for Clinical Affairs, University of North Carolina at Chapel Hill School of Medicine
Marschall S Runge, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society for Investigative Pathology, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Southern Society for Clinical Investigation, and Texas Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Orthoclinica Diagnostica Consulting fee Consulting

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC, Sidney W and Marilyn S Lassen Professor of Cardiovascular Medicine, Chief, Section of Cardiology, Director, Cardiovascular Center of Excellence, Tulane University; Professor of Physiology, Chair, Department of Medicine, Tulane University School of Medicine
Patrice Delafontaine, MD, FACC, FAHA, FACP, FESC is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American College of Cardiology, American College of Physicians, American Diabetes Association, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Medical Association, American Society for Clinical Investigation, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Endocrine Society, European Society of Cardiology, Louisiana State Medical Society, and Southern Society for Clinical Investigation
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The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Ari M Perkins, MD, Michael E Zevitz, MD, Sat Sharma, MD, and Amal Mattu, MD, to the development and writing of this article.

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