Cardiogenic pulmonary edema (CPE)

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(Pcap - Pis),

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; Pcap is the colloid osmotic pressure of plasma, which tends to pull fluid into the capillary; and 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 left atrial 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 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.
o Auscultation of murmurs can help in the diagnosis of acute valvular disorders manifesting with pulmonary edema.
o 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.
o In contrast, acute aortic regurgitation is associated with a short, soft diastolic murmur.
o 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.
o 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:
o Acute MI or ischemia
o Patient noncompliance with dietary restrictions (eg, dietary salt restrictions)
o Patient noncompliance with medications (eg, diuretics)
o Severe anemia
o Sepsis
o Thyrotoxicosis
o Myocarditis
o Myocardial toxins (eg, alcohol, cocaine, chemotherapeutic agents such as doxorubicin [Adriamycin], trastuzumab [Herceptin])
o 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.
o Constrictive pericarditis and pericardial tamponade are other etiologies that mainly compromise LV diastolic function.
o 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
o 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.
o 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
o 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.
o Hypertrophic cardiomyopathy is a cause of dynamic LV outflow obstruction.
o 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
o Patients with chronic CHF often use diuretics. Therefore, they are predisposed to have electrolyte abnormalities, especially hypokalemia and hypomagnesemia.
o 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
o This test is more accurate than pulse oximetry for measuring oxygen saturation.
o The decision to start mechanical ventilation is mainly based on clinical findings and rarely arterial blood gas results.
• Pulse oximetry
o Pulse oximetry is useful in assessing hypoxia and, therefore, the severity of CPE.
o It is also useful for monitoring the patient's response to supplemental oxygenation and other therapies.
• Electrocardiography
o Left atrial enlargement and LV hypertrophy are sensitive, though nonspecific, indicators of chronic LV dysfunction.
o The ECG may suggest an acute tachydysrhythmia or bradydysrhythmia as the cause of CPE.
o 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
o Ventricular myocytes secrete proBNP in response to muscle-wall tension.
o NT-proBNP has a longer half-life (120 min) than that of BNP (20 min)
o NT-proBNP is less studied than BNP, but its levels are well correlated with BNP levels.
o 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
o CHF is the most common form of CPE.
o Several observational studies and clinical trials have shown the important diagnostic value of BNP measurements in differentiating heart failure from pulmonary causes of dyspnea.
o BNP testing decreases the total cost of treatment and the length of hospitalization. This is a cost-effective diagnostic test in this setting.
o 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.
o 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.
o In a recent study, a cutoff point of 250 pg/mL was the most accurate for elderly patients (mean age, 80 y).
o Renal dysfunction may be associated with a significantly increased level of BNP.
o 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.
o 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.
o Values of 100-400 pg/mL may be related to various pulmonary conditions, such as cor pulmonale, COPD, and pulmonary embolism.
o 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.
o 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.
o 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.
o NCPE occurs secondary to injury to the alveolar-capillary membrane rather than to alteration in Starling forces.
o A PCWP exceeding 18 mm Hg in a patient not known to have chronically elevated left atrial pressure indicates CPE.
o 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.
o This condition raises pulmonary venous pressure and causes acute pulmonary edema.
o The pulmonary artery waveform appears falsely elevated because of the large V wave reflected back from the left atrium through the compliant pulmonary vasculature.
o 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.
o 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.
o 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.

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 Mdication.
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:
o Patients with CPE due to acute valvular dysfunction requiring urgent valve replacement.
o 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.)
o Patients with CPE who require inotropic support or hemodialysis beyond the capabilities of the initial hospital.
o 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

Acknowledgments
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.
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.

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.

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.

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.

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.

Nonpseudophakic Cystoid Macular Edema

Introduction

Background

Although the most common cause of cystoid macular edema (CME) is due Ioirvine-Gass syndrome of CMEafter cataract extraction or other intraocular surgery, numerous other conditions are associated with the clinical appearance of fluid-filled, cystoid spaces in the macular region. CME is a final common pathway of many intraocular diseases, usually involving the retinal vasculature. The appearance can differ somewhat, depending on the etiology; however, CME can appear as a nonspecific clinical finding. If the cause of CME is not obvious, detailed ophthalmoscopy and, occasionally, ancillary testing may be necessary to identify the cause.

Pathophysiology

Macular edema is excessive fluid within the layers of the retina, distinct from the accumulation of fluid under or between the retinal layers (eg, subsensory fluid, serous retinal detachment). The amount of fluid normally present in the retina is maintained according to osmotic and hydrostatic pressures between the retina and the surrounding vasculature, which are compartmentalized by the blood-retinal barrier. A breakdown in the blood-retinal barrier allows for fluid to accumulate in cystoid spaces within the retina. Pathologic evidence of cell loss and Müller cell abnormalities may contribute to the resulting CME.

Several mechanisms have been proposed to explain how CME develops. The characteristic distribution of vascular leakage and retinal edema may be explained best by the diffusion of mediators (eg, prostaglandins) released in the eye. This theory is supported by evidence that cyclooxygenase inhibitors (eg, indomethacin, other nonsteroidal anti-inflammatory drugs) reduce the incidence of angiographic CME. However, this finding has only been shown conclusively in pseudophakic CME associated with surgical trauma to the anterior segment.

Another mechanism emphasizes the role of mechanical factors, such as tractional forces on the macula from disruption of the normal vitreoretinal interface. Even according to this theory, it is believed that local forces induce a release of mediators that lead to a breakdown of the blood-retinal barrier, resulting in the clinical appearance of CME.

Photic injury has been implicated in the development of pseudophakic CME; however, there is no scientific evidence that light damage to the retina causes CME.

Frequency

United States

Frequency of CME that is unassociated with cataract surgery varies widely, both in the United States and internationally, depending on the etiology or underlying condition leading to CME. The incidence figures vary because of the difficulty of observing subtle CME clinically, the surgeon bias in reporting CME, and the fact that fluorescein angiography (FA) or optical coherence tomography (OCT) that would detect CME is often not performed.

Mortality/Morbidity

CME from any etiology often leads to significant central visual loss, typically in the 20/40 to 20/200 range.

Race

No racial predilection has been associated with CME.

Sex

CME is distributed equally among males and females.

Age

Age of incidence of nonpseudophakic CME varies according to etiology.

Clinical

History

CME typically presents with a complaint of painless visual loss in one eye. It can be bilateral, depending on the etiology. The onset of symptoms is usually gradual; however, patients often only notice it suddenly, when they check one eye separately. Different causes of CME have different clinical presentations. The most common entities are discussed below.

• Diabetic maculopathy
• Diabetic maculopathy affects the capillaries in the macular region, leading to macular edema. Occasionally, a CME component of the macular edema develops, with cystoid changes in the foveal region. This is more common in cases of diffuse and chronic diabetic macular edema, and the vision may be reduced to the 20/200 level.
• When eyes with clinically significant macular edema (ie, edema overwhelming the homeostasis of the retina causing noticeable thickening) are treated early, before the onset of diffuse edema, CME possibly can be avoided if the patient maintains excellent control of the underlying medical problems.
• CME, in association with diabetic macular edema, has also been correlated to the presence of an attached posterior hyaloid, whereas patients with a posterior vitreous separation are much less likely to develop a component of CME. This may support a mechanical mechanism of the development of CME, where tractional forces induce the formation of cystoid spaces in the macula. Alternatively, the traction on the macula may lift the retina away from the RPE pump, causing CME. Occasionally, even in the absence of an attached posterior hyaloid, a preretinal membrane can exert tractional forces and lead to CME.
• Age-related macular degeneration
• Age-related macular degeneration (ARMD) can present in 1 of 2 forms: atrophic or exudative (dry or wet). Atrophic macular degeneration without exudative changes does not generally lead to CME. The exudative form of ARMD, with choroidal neovascularization, can cause a serous detachment of the overlying retina and resultant CME.
• CME is more common if the serous detachment of the macula has been present for 3-6 months or if the choroidal neovascular membrane has involved most of the subfoveal region. In such cases, the likelihood of restoring good vision is low.
• Retinal vein occlusions
• Retinal vein occlusion, a branch retinal vein occlusion (BRVO), or a central retinal vein occlusion (CRVO) can cause macular edema resulting from breakdown of the capillary endothelium associated with increased intravascular hydrostatic pressure. The damaged vessels leak fluid into the intercellular spaces, and, eventually, intraretinal cystoid spaces can be seen. This form of CME can be associated with further visual loss and usually results in some permanent visual loss if the situation persists for more than 6 months. However, it can improve with earlier resolution of the macular edema.
• Recovery of the macular edema can occur after laser therapy (even if the edema persists >6 mo) or with development of collateral vessels. Although laser grid photocoagulation has been shown to improve visual outcome in patients with BRVO, patients with CRVO do not appear to benefit from laser photocoagulation to treat macular edema. Although the edema may resolve, the visual outcome is unchanged.
• Newer approaches to treating macular edema associated with retinal vein occlusions include intraocular steroids and vascular endothelial growth factor (VEGF) inhibitors.
• Epiretinal membranes can cause surface wrinkling of the underlying retina resulting from contracture of the membrane. Occasionally, macular edema may develop due to distortion and traction on the surrounding intraretinal vessels. If the edema persists, breakdown of the intraretinal architecture can lead to cystoid spaces. This breakdown may be related to mechanical traction leading to edema, or it may be caused by the loss of apposition between the retina and the RPE pump. Ideally, surgical removal of a significant epiretinal membrane causing surface wrinkling retinopathy and macular edema reducing vision to the 20/60 to 20/80 level should be performed before irreversible CME develops.
• Choroidal tumors, such as malignant melanoma, choroidal nevus, or capillary hemangioma, have been associated with CME. These cystoid changes can occur overlying the tumor and in the macula, even when the tumor is located some distance from the macula, a phenomenon known as the Wise theory of macular accentuation. The source of CME at the level of the retinal capillary network results from intraretinal microvascular abnormalities resembling endothelial cell proliferation.
• Chronic uveitis, especially pars planitis, is associated with CME, most likely because of a breakdown in the blood-retinal barrier. The chronic inflammation disrupts the competence of the perimacular blood vessels, allowing for the development of the cystoid spaces. A clinical entity distinct from pars planitis has been described, characterized by CME, retinal periphlebitis, and vitreous inflammation. This condition typically is bilateral, affecting middle-aged women. Most patients maintain good vision over a prolonged time period.
• Radiation retinopathy, a condition of vascular damage from prior radiation treatment to the eye or orbit, can mimic diabetic retinopathy in its appearance. A form of macular edema often develops that is quite similar to diabetic macular edema and may manifest as CME.
• Perifoveal retinal telangiectasis or Coats disease typically presents with irregularly dilated and incompetent retinal vessels. These telangiectatic changes can occur at the level of the arterioles, venules, or capillaries. The closer the findings are to the macula, the earlier symptoms present. A clinical picture of CME may occur due to leakage from incompetent retinal vessels. Idiopathic juxtafoveal telangiectasis is a milder form of retinal telangiectasis, typically involving the temporal macula. CME is less common in this condition.
• CME without leakage on FA has been reported in middle-aged men on high doses of niacin for treatment of hypercholesterolemia.
• The presence of CME after successful retinal reattachment surgery has been reported to range from 30-43% during the first 4-6 weeks postoperatively. In aphakic eyes, incidence may be as high as 64%. Older patients are at a higher risk to develop CME after retinal detachment repair.
• CME has been reported after corneal relaxing incisions for astigmatism.
• CME after penetrating keratoplasty ranges from 20-43%. Aphakic eyes are at a much higher risk to develop postoperative CME. If an anterior vitrectomy was performed at the time of surgery, the risk of CME is 8-9 times more likely to occur.
• Retinitis pigmentosa (RP) is associated with CME. Studies have found an increased permeability of the retinal pigment epithelium (RPE) and perifoveal capillaries to fluorescein in eyes with RP. A study found an increased presence of circulating antiretinal antibodies in patients who presented with RP and CME. This suggests a possibility of an autoimmune process mediating the development of CME in patients with RP.
• Birdshot retinochoroidopathy presents with multiple, small, round or oval hypopigmented spots at the level of the choroid or RPE. Vitreous cells, disc edema, and leakage of fluorescein from retinal vessels are common features. CME can occur in conjunction with this condition.
• CME has been reported in association with orbital pseudotumor. The edema resolved after treatment of the orbital condition.
• Glaucoma treatment with latanoprost has been associated with the development of CME. The prostaglandin-like effect of latanoprost is believed to cause CME. CME typically resolves after discontinuation of the drug. In a study by Moroi et al of 7 patients with CME, after starting latanoprost therapy, all 7 patients had coexisting ocular conditions that may have placed these eyes at risk for prostaglandin-mediated blood-retinal barrier vascular insufficiency.
• CME has been associated with cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS) and immunocompetent patients. In some patients, CME develops specifically while the CMV retinitis resolves. A separate entity of CME has been described in patients with inactive CMV retinitis after immune recovery and improvement of their CD4 counts because of highly active antiretroviral therapy (HAART).
• CME inducing visual loss has been reported after the use of topical echothiophate iodide therapy.
• Retinal neovascularization and CME have been reported in patients with punctata albescens retinopathy.
• Dominantly inherited CME has been described as a macular dystrophy with an onset at middle age and a slow progression over ensuing decades. Pathologic studies of eyes with this condition suggest that the predominant changes occur in the inner nuclear layer and that this entity may present as a primary disease of the Müller cell.
• Foveal X-linked retinoschisis has been mistakenly described as CME.

Differential Diagnoses & Workup

Laboratory Studies

• Laboratory studies for CME vary depending on the presumed etiology of the edema.
• If findings suggestive of diabetes are present, the patient should have blood glucose testing or a glucose tolerance test.
• In the presence of uveitis, an appropriate evaluation for chronic uveitis should be initiated. See Uveitis, Evaluation Treatment for details.

Imaging Studies

• OCT is the criterion standard in the identification of CME. OCT is a noninvasive imaging modality that can determine the presence of CME by visualizing the fluid-filled spaces in the retina. The amount of CME can be monitored over time by quantifying the area of cystoid spaces on a cross-sectional image through the macula.
• Studies have reported OCT to be comparable to FA in the evaluation of CME, especially with newer, high-resolution OCT scanners. OCT is beneficial by quantifying the thickness of the retina and by allowing quantitative measurements of macular edema over time. This noninvasive method is especially useful in monitoring the response to treatment.
• Newer software for OCT has increased the resolution of this imaging modality and has led to the identification of specific patterns of CME.
• FA is an alternative imaging study to evaluate CME. Fluid accumulation may be delayed in certain conditions; thus, late phase fluorescein photos, sometimes as long as 20 minutes or more, may be required to properly evaluate the CME. Associated findings on FA may help determine the etiology of CME.
• If leaking microaneurysms are present in the setting of diabetic retinopathy, then diabetes likely is the cause.
• Vascular collaterals crossing the horizontal raphe on FA can help determine that the etiology of the edema (and retinal hemorrhages if present) is likely due to a vascular occlusion.
• The absence of leakage from CME on FA suggests a diagnosis of nicotinic acid retinopathy, Goldmann-Favre disease, or X-linked juvenile retinoschisis.
• FA also is helpful to verify the presence of CME when it is difficult to establish clinically.

Other Tests

• In the appropriate clinical setting, an electroretinogram may be indicated to confirm a diagnosis of RP with associated CME.

Procedures

• Occasionally, in cases of uveitis with associated CME, a diagnostic vitreous biopsy or vitrectomy can aid in determining the correct diagnosis. The vitreous fluid can be sent for the appropriate laboratory tests based upon the clinical picture. It is beyond the scope of this article to discuss the full laboratory workup for uveitis.
• In cases of orbital pseudotumor, an incisional biopsy for the purpose of confirming a diagnosis is indicated; however, CME rarely is associated with this condition.

Treatment

Medical Care

The treatment of nonpseudophakic CME varies greatly, depending on the etiology causing the edema.

• In drug-induced cases, such as CME associated with latanoprost, echothiophate iodide, or nicotinic acid, discontinuation of the drug usually causes reversal of CME.
• Topical steroids and nonsteroidal anti-inflammatory agents have been used in the treatment of CME, especially when associated with uveitis. Most studies have evaluated the efficacy of these drugs in the presence of pseudophakic CME after cataract surgery. However, the effect of these medications in stabilizing the blood-retinal barrier may aid in the treatment of other forms of CME.
• Injections of long-acting depot steroids (eg, triamcinolone) into the sub-Tenon space usually are more effective and commonly are used in the treatment of noninfectious uveitis. Peribulbar injections have a greater risk of intraocular injection than a subconjunctival approach; however, the drug delivery to the retina is superior when administered into the posterior sub-Tenon space.
• Intraocular triamcinolone acetonide has been found to effectively reverse CME in eyes with many conditions, including pseudophakic CME, retinal vein occlusions, diabetic macular edema, uveitis, and juxtafoveal telangiectasis. Clinical trials are underway to study the long-term benefit and safety of this treatment approach.
• Research implicates VEGF as an important mediator of vascular permeability and CME. Therefore, clinical trials are being conducted to evaluate the benefit of VEGF inhibitors in treating CME associated with different conditions, such as diabetic macular edema and retinal vein occlusions.
• Oral steroids also are a commonly used modality of stabilizing the blood-retinal barrier for the treatment of inflammation and CME in patients with intermediate or posterior uveitis. Oral steroids should be avoided unless necessary because of the associated complications of systemic use (eg, aseptic necrosis of the femoral head).
• When CME is associated with diabetic macular edema, focal laser photocoagulation according to the guidelines of the Early Treatment of Diabetic Retinopathy Study (ETDRS) should be followed (seeMacular Edema,Diabetic). However, CME in the setting of diabetic macular edema often suggests chronicity of the condition and will not respond adequately to laser treatment. Some physicians advocate the use of posterior sub-Tenon or intraocular injection of triamcinolone with or without macular laser photocoagulation to treat diabetic macular edema associated with CME.
• CME associated with choroidal neovascularization in ARMD is a secondary response to the presence of subretinal neovascularization. It is present most commonly in eyes with significant subsensory fluid in the macula and a poor prognosis for central vision. Fortunately, current treatments of exudative ARMD reduce the incidence of disciform scarring and associated CME.
• Macular edema is a common cause of visual loss in eyes with BRVO or CRVO. CME also can be associated with this form of macular edema. Macular laser photocoagulation has been shown to be effective in improving vision in patients with BRVO for greater than 4 months duration and a visual acuity of 20/40 or worse. However, the Central Vein Occlusion Study (CVOS) did not show any visual benefit from laser photocoagulation in eyes with CRVO and macular edema.
• Intravitreal triamcinolone has been reported to be effective in reversing CME in BRVO and nonischemic CRVO. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study, a clinical trial sponsored by the National Institutes of Health (NIH), is evaluating the benefit of intraocular triamcinolone acetonide in retinal vein occlusions.
• Concurrently, the Posurdex Study is evaluating the benefit of an injectable dexamethasone implant for the treatment of macular edema in retinal vein occlusions.
• Many other causes of CME are treated by addressing the underlying condition. CME associated with CMV retinitis is treated by managing the retinitis with antiviral agents (eg, ganciclovir, foscarnet, cidofovir).
• CME associated with immune recovery in patients with inactive CMV retinitis and a stronger immune system are treated with steroids, either oral or posterior sub-Tenon injection of long-acting depot steroids.
• When malignant intraocular tumors are associated with CME, the priority is to treat the tumor. Systemic malignancies, such as multiple myeloma, have been observed to be associated with CME. Systemic treatment of the myeloma is the priority and usually addresses the CME. However, sub-Tenon injection of steroid may enhance resolution of the CME in such cases. Depending on the nature of the disease, CME associated with intraocular tumors requires treatment of the tumor (eg, laser photocoagulation, cryotherapy, radiation, thermotherapy, enucleation).
• CME secondary to juxtafoveal telangiectasis in Coats disease has been shown to respond to laser photocoagulation, with resolution of the edema and improvement in visual acuity.
• Orbital pseudotumor is treated effectively with oral steroids, and, in the case reported to be associated with CME, the macular edema resolved with treatment of the orbital pseudotumor.
• Other forms of CME have been reported to respond to treatment with acetazolamide. CME after scleral buckling procedures, CME in some forms of uveitis, and CME associated with RP may respond to acetazolamide therapy.

Surgical Care

Surgical treatment is not available for CME. However, situations exist in which an ocular condition associated with CME can be treated with surgery.

• An epiretinal membrane can induce a surface wrinkling retinopathy with CME. Surgical removal of the epiretinal membrane often can result in resolution of the CME and improved visual acuity.
• The vitreomacular traction syndrome is caused by traction of the vitreous on the macula. It can manifest with CME, and relieving the traction with vitrectomy surgery often can lead to resolution of the macular edema. Some authors advocate performing a vitrectomy for the treatment of CME without evidence of obvious vitreomacular traction (usually in patients after cataract surgery). This approach may be beneficial in select patients.
• In cases of CME associated with Coats disease or peripheral lesions of pars planitis, cryotherapy to these peripheral areas of exudation can induce the cystoid macular changes to dry up.

Medication

The most common drugs used to treat CME include steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetazolamide.

Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli. Used to stabilize the blood-retinal barrier and to induce resolution of macular edema.

Prednisone (Deltasone, Orasone, Meticorten)

Used rarely for severe inflammatory conditions with associated CME. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity

Follow-up

Further Outpatient Care

• Typically, patients with CME are evaluated 1-3 months after intervention to evaluate the efficacy of treatment.

Complications

• Complications associated with the treatment of CME are infrequent. When a posterior sub-Tenon injection of triamcinolone is given, patients can occasionally experience a transient ptosis or subconjunctival hemorrhage. Retinal arterial occlusion after sub-Tenon steroid injections has been reported due to intravascular injection of the drug.
• Intravitreal triamcinolone has been associated with ocular hypertension, cataract progression, retinal tear or detachment, infectious and noninfectious endophthalmitis, and lens damage.

Prognosis

• Visual prognosis in eyes with CME depends on the etiology of the CME. If the CME resolves with treatment, visual acuity of 20/40 or better is common. However, in long-standing CME, vision is often 20/100 to 20/200.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize CME can lead to failure to diagnose an associated disease. This can severely limit the visual prognosis if the condition is treatable. Usually, a characteristic fundus appearance allows the ophthalmologist to recognize conditions associated with CME, such as diabetic retinopathy, branch vein occlusion, or an epiretinal membrane. However, in the absence of an obvious associated condition, especially in a phakic eye, care should be taken to rule out such pathology as uveitis or a tumor. Missing such a diagnosis can have devastating consequences.
• The use of commercially available triamcinolone acetonide is not approved for intraocular injection; however, triamcinolone acetonide is commonly used at the discretion of the treating physician as an off-label use. This use has become accepted clinical practice and has an acceptably low-risk profile. Nevertheless, specific ophthalmic preparations of triamcinolone and other long-acting steroid implants are being developed.

Multimedia

Media file 1: Fundus photograph of left eye with branch retinal vein occlusion and cystoid macular edema. Visual acuity was 20/50, and the patient was treated with a modified grid laser photocoagulation and posterior sub-Tenon injection of triamcinolone.

Fundus photograph of left eye with branch retinal vein occlusion and cystoid macular edema. Visual acuity was 20/50, and the patient was treated with a modified grid laser photocoagulation and posterior sub-Tenon injection of triamcinolone.

Media file 2: Fundus photograph of nonproliferative diabetic retinopathy with clinically significant macular edema and cystoid macular edema.

Fundus photograph of nonproliferative diabetic retinopathy with clinically significant macular edema and cystoid macular edema.

Media file 3: Fluorescein angiogram of same eye as in Media file 2, revealing both cystoid macular edema and leakage from microaneurysms associated with diabetic retinopathy.

Fluorescein angiogram of same eye as in Media file 2, revealing both cystoid macular edema and leakage from microaneurysms associated with diabetic retinopathy.

Media file 4: Ocular coherence tomographic image of cystoid macular edema in a patient with uveitis.

Ocular coherence tomographic image of cystoid macular edema in a patient with uveitis.

Media file 5: Cystoid macular edema in patient with diabetic retinopathy.

Cystoid macular edema in patient with diabetic retinopathy.

Media file 6: Eye in previous image with diabetic CME after injection with 4 mg of intravitreal triamcinolone.