Pulmonary Edema: A Clinical Overview
Pulmonary edema refers to the accumulation of fluids in the alveolar spaces throughout the lungs that results from a disruption of the normal fluid flux within the lungs. This common condition is often seen in the inpatient and outpatient settings and can lead to respiratory failure if not treated promptly. Rapid intervention is necessary to prevent clinical deterioration and fatal consequences. Common clinical findings include dyspnea and wheezing. More severe symptoms signal greater acuity. The myriad causes of pulmonary edema are generally divided into cardiogenic or noncardiogenic types. This distinction is important for deciding on the type of treatment. Diagnosis is made clinically. This article focuses on recent advances in our understanding of the pathogenesis, diagnosis, and treatment of pulmonary edema.
Pulmonary edema is a common condition that is defined as the transfer of fluid from the intravascular compartment into the interstitium of the lung and alveolus. The multiple causes can generally be divided into cardiac or noncardiac types. The physiologic basis of the high hydrostatic pressures and increased permeability of the alveolar capillary membrane seen in pulmonary edema have been extensively studied, but the exact mechanisms remain uncertain. However, considerable progress has been made in our understanding of pulmonary physiology and the factors influencing lung fluid balance.
The mechanisms regulating the active transport of salt and water into the alveolus and the airway epithelium of the lung, and hence lung fluid balance, have been the subject of intense research recently.1 Vectorial transport of salt (active transport of sodium across the alveolar epithelium through apical channels and the basolateral cell wall sodium-potassium adenosine triphosphatase) and water across the alveolus and distal airway may be key to lung fluid balance.
Alveoli are made up of 2 types of epithelial cells that comprise 99% of the airspace surface area: thin squamous cells (type I cells) and thick cuboidal cells (type II cells). Type I cells cover 95% of the alveolar surface and are also the apposition between the alveolar epithelium and the vascular endothelium. This area facilitates efficient gas exchange and forms a tight barrier to fluid and protein movement from the interstitial and vascular spaces, thereby maintaining relatively dry alveoli. Tight junctions connect adjacent epithelial cells near their apical surfaces and maintain apical and basolateral cell polarity. Tight junctions are critical for the barrier function of the alveolar epithelium (and were once thought to be rigid structures, but this is now deemed unlikely).
The alveolar type II cell, known for surfactant secretion, is thought to contribute to the vectorial transport of sodium.2 Active transport of sodium provides a major driving force for fluid removal from the alveolar space. Amiloride-sensitive sodium channels on the apical surface are also involved in fluid transport, with the driving force on the basolateral surface.1
The regulation of pulmonary edema is complex. Elimination and regulation of fluid transport can be controlled by either catecholamine-dependent or catecholamine-independent mechanisms. The stimulation of beta2-adrenergic receptors by salmeterol xinafoate (Serevent Diskus), terbutaline sulfate (Brethine), or epinephrine (eg, Adrenaline Chloride, EpiPen, Primatene Mist) increases fluid clearance.1 This process is blocked by the beta2-receptor antagonist propranolol HCl (Inderal). Beta2-agonists increase fluid clearance by stimulating amiloride mechanisms, which in turn increases transepithelial sodium transport. The use of an aerosolized beta2-agonist may, therefore, accelerate the resolution of alveolar edema in some patients.
Opposing forces responsible for the transfer of fluid into the interstitium include pulmonary capillary pressure and plasma oncotic pressure. When the normal mechanisms that keep the lung dry malfunction or flood, fluid accumulates. In addition, gravity exerts important influences on lung fluid mechanics. Under normal circumstances, more perfusion occurs at the lung bases than at the apices. When pulmonary venous pressures rise, fluid accumulates at the lung bases, and blood flow is redistributed toward the apices. Pulmonary edema resolves when sodium is transported across the alveolar epithelium by apical amiloride channels and basolateral sodium-potassium adenosine triphosphatase.
The causes of pulmonary edema are many, although the underlying mechanism is not always fully understood (Table 1). The general classification of the etiology of pulmonary edema into cardiac and noncardiac causes is crucial for determining the appropriate type and course of therapy.
Cardiac causes of pulmonary edema are common, and include heart failure, atrial fibrillation/flutter, mitral valve disease, left atrial myxoma/thrombus, and cor triatriatum.
In patients with pulmonary edema who have heart failure caused by diastolic dysfunction, therapy is aimed predominantly at decreasing filling pressures, reducing tachycardia, and improving myocardial relaxation. Nonpharmacologic interventions to restore sinus rhythm in patients with atrial tachyarrhythmias include direct cardioversion, atrial overdrive pacing, and catheter ablation with permanent pacing. However, pulmonary edema has been reported following cardioversion.3 The incidence is low and does not appear to be related to gender or age. One half of all cases occur within 3 hours of cardioversion, but delayed onset has been described.3
Ischemic mitral regurgitation plays a role in the pathogenesis of acute pulmonary edema.4 Mitral valve disease resulting from chordal rupture, infarction, papillary muscle dysfunction, or endocarditis can also lead to pulmonary edema. Myocardial ischemia leading to systolic dysfunction can also result in pulmonary edema.
Noncardiogenic causes of pulmonary edema include aspiration pneumonia, sepsis, pancreatitis, burns, severe liver disease, nephrotic syndrome, protein-losing enteropathy, lymphatic blockage, near drowning, transfusion-related lung injury, fever, anemia, thyroid disease, upper airway occlusion, lung transplantation, and the use of certain drugs.
Drug-induced edema. Pulmonary edema associated with opiate overdose occurs almost exclusively with heroin. Noncardiac pulmonary edema is involved in many fatal cases of drug overdose,5 which is associated with depression of the medullary respiratory center, hypoxia, acidosis, and subsequent permeability edema. Pulmonary edema has also been reported with the use of cocaine and ?crack,? methadone, propoxyphene (Darvon), codeine, buprenorphine HCl (Subutex), nalbuphine HCl (Nubain), naloxone HCl (Narcan), and nalmefene HCl (Revex).5
A review of 125 patients presenting with heroin overdose showed that 10% had noncardiogenic pulmonary edema.6 (Earlier studies have shown even higher rates.)
Signs and symptoms of pulmonary edema in drug overdose include persistent hypoxia (after resolution of opiate depression); pink, frothy secretions; and diffuse, fluffy infiltrates on radiography. Treatment consists of mechanical ventilation with supportive care. The edema usually resolves within 2 days with appropriate treatment.
Chemotherapeutic agents associated with pulmonary edema include interleukin-2 (IL-2), which is used for treatment of melanoma and metastatic renal-cell adenocarcinoma. Three fourths of patients treated with intravenous (IV) IL-2 will demonstrate radiologic signs of pulmonary edema within 5 days of chemotherapy initiation, but few require respiratory assistance.7 Radiologic signs resolve after drug cessation.
High altitude. Elevated altitude is one of the most studied noncardiogenic causes of pulmonary edema. High-altitude pulmonary edema is a potentially fatal condition. Usually occurring 24 to 48 hours after a rapid ascent to altitudes of more than 3000 m (9842 ft), the condition is more common in men than in women. The exact mechanism is controversial, but experts agree that acute persistent hypoxia induces vasoconstriction that leads to pulmonary hypertension, capillary leak, and subsequent pulmonary edema. Symptoms include exertional dyspnea, cough, and reduced exercise performance; signs include cyanosis, tachypnea, tachycardia, and fever not exceeding 38.5?C. On examination, rales are discrete, typically located over the middle lung fields. High-altitude pulmonary edema rarely occurs after one week of acclimatization.
Arterial oxygen saturation levels correspond directly to the severity of high-altitude pulmonary edema. In advanced cases there can be signs of cerebral edema, such as ataxia and decreased level of consciousness. Radiologic findings include an enlarged heart and pulmonary trunk dilatation.
Necroscopy reveals distended pulmonary arteries and diffuse pulmonary edema with bloody fluid throughout the airways. Hyaline membranes, arteriolar thrombus, and pulmonary hemorrhages are often present. The mechanism accounting for increased capillary pressure is regional hypoxic vasoconstriction causing overperfusion of capillaries in areas without vasoconstriction. This leads to irregularly distributed pulmonary edema rich in protein and red blood cells. Rapid remodeling resulting in homogenous perfusion could explain why high-altitude pulmonary edema only occurs during the first few days of acute altitude exposure. Inflammation also plays a role in the pathogenesis, as evidenced by increased levels of proinflammatory cytokines, leukotriene B4, and urinary leukotriene E4 in patients with advanced disease.8,9
High-altitude pulmonary edema can be prevented with slow ascent. In healthy individuals, daily ascent at altitudes above 2000 m (6561 ft) should not exceed 350 to 400 m (1148-1312 ft). Since susceptibility increases during and shortly after infections, prophylaxis with nifedipine (eg, Adalat CC, Afeditab CR, Procardia) can be given, starting with the ascent and ending on the day after arriving at the final altitude.10,11 Oxygen treatment should maintain saturations above 90%.
Recently, portable hyperbaric chambers have been used for treatment. Evacuation to lower altitudes and the use of beta2-agonists are helpful.12 Results of a recent small study suggested that off-label prophylaxis with both dexamethasone (Decadron) and tadalafil (Cialis) reduces the incidence of high-altitude pulmonary edema in climbers who have a history of developing the condition. The efficacy of both agents was attributed to their role in decreasing systolic pulmonary artery pressure.13 Acetazolamide (Diamox) is another medication used to prevent high-altitude pulmonary edema.
Neurogenic pulmonary edema. Neurogenic pulmonary edema occurs in 50% of patients who have suffered a severe brain injury, such as trauma, subarachnoid hemorrhage, stroke, or status epilepticus.14 It is a diagnosis of exclusion, since the mechanism is still controversial. Radiologic findings are distinctive, showing bilateral airspace consolidations, which are primarily at the apices in about 50% of all cases.15 Radiologic findings typically disappear within 1 to 2 days.16
Reexpansion. Reexpansion pulmonary edema is an uncommon iatrogenic complication after rapid reexpansion of a collapsed lung, thoracentesis, thromboendarterectomy, lung transplantation, or pneumonectomy.15 It often occurs within 1 hour after the lung is reexpanded,17 and typically only one lung is involved, although both may be involved. A high index of clinical suspicion is required to make the diagnosis. The typical presentation includes cough, dyspnea, tachypnea, and tachycardia.15
Pulmonary edema is a clinical diagnosis, and a chest radiograph showing unilateral pulmonary edema confirms the diagnosis.
Signs and symptoms
The survival of patients with pulmonary edema depends on the physician?s ability to identify and promptly treat the underlying cause. A thorough history can be very valuable in providing clues to the cause. The rate at which dyspnea develops is an important clue to the etiology?sudden onset suggests pneumothorax or pulmonary embolism; slowly progressing shortness of breath is more likely to be caused by infection, asthma, pulmonary edema, or diaphragm paralysis.
Cough and dyspnea are common presenting complaints in patients with pulmonary edema. Other signs and symptoms include tachypnea, orthopnea, tachycardia, hypotension, cold extremities with cyanosis, frothy or pink sputum, use of accessory muscles, moist rales, wheezing, and chest discomfort.
Airflow obstruction may be manifested by wheezing. The mechanism of wheezing in pulmonary edema is thought to be narrowing of the small airways because of bronchial wall edema and intraluminal fluid.
Orthopnea is a late manifestation of pulmonary edema, resulting from the redistribution of fluid from the abdomen and lower extremities, which elevates the diaphragm and increases pulmonary capillary pressures. Paroxysmal nocturnal dyspnea is caused by depression of respiratory centers during sleep, which reduces arterial oxygen tension. The effect is pronounced in patients with interstitial edema and reduced pulmonary compliance. Fatigue and weakness are nonspecific, common complaints. Anorexia and nausea associated with abdominal pain and fullness occurring with pulmonary edema are related to passive congestion of the liver and portal veins.
Clinical signs of pulmonary edema start as a manifestation of certain pathology (eg, heroin overdose, acute papillary muscle rupture) or as evolution of an already established disease, such as mitral valve regurgitation. Typically, tachypnea and use of accessory muscles of respiration are noted on examination of patients presenting with pulmonary edema. Elevated jugular venous pressures reflect high right-sided filling pressures. Cardiac auscultation may reveal an S3, S4, or summation gallop, or a new or changed cardiac murmur. An examination of the lower extremities may reveal peripheral edema and possible venous stasis changes. Lung auscultation is critical to the diagnosis. Fine crackles over both lung bases suggest pulmonary edema, whereas course, localized crackles suggest pneumonia. Expiratory wheezes indicate airway obstruction in severe cases.
Laboratory tests and imaging studies help establish the diagnosis. Relevant laboratory studies include assessment of cardiac, respiratory, and renal functioning with a complete blood cell count; measurements of electrolytes, blood urea nitrogen, creatinine, serum protein, and B-type natriuretic peptide (BNP) concentration; urinalysis; and arterial blood gas measurements while breathing room air.
Chest radiography may help distinguish features of cardiogenic and noncardiogenic pulmonary edema but are not sensitive enough to distinguish between these etiologies (Table 2). Unilateral pulmonary edema on chest radiograph, an uncommon occurrence, can help narrow the differential diagnosis (Table 3). In general, the most helpful radiologic findings are the number and caliber of pulmonary vessels, the distribution of edema, and the presence or absence of cardiomegaly (Figure 1).
Much of the superior mediastinal opacity seen on chest radiographs is caused by the great vessels; this mediastinal silhouette has been called the ?vascular pedicle.? Measuring the width of the vascular pedicle may help in pointing toward a cardiogenic or noncardiogenic cause, but trends or changes in vascular pedicle width may be more reliable than any specific measurement unit.
Computed tomography (CT) is another tool that can help the diagnosis of pulmonary congestion edema. Kerley B or septal lines (short horizontal lines seen at the periphery of the lower zones of the lungs) are characteristic findings seen on CT scans in early pulmonary edema. In contrast to blood vessels, these lines reach the lung?s edge. Later-stage pulmonary edema appears as a ?bat wing? pattern, with a central predominance of shadows and a clear zone at the peripheral area of the ?wings? (Figures 2, 3). Bat wing pattern is a classic imaging finding in pulmonary edema.
Septal lines may be one of the most useful findings in the diagnosis of pulmonary edema.18 In one study of 33 patients with pulmonary edema, septal lines were seen on chest radiography in 21% of those with a cardiogenic cause and in 11% of those with a noncardiogenic cause.19
One helpful feature for distinguishing pulmonary edema from the widespread exudates seen in pneumonia is the rate of the development and resolution of the edema. Improvement within 24 hours is virtually diagnostic of cardiac pulmonary edema.
Electrocardiography helps identify conditions that predispose to pulmonary edema, such as left ventricular (LV) hypertrophy, left atrial abnormalities, myocardial ischemia, and atrial fibrillation.
Right heart catheterization can be used to measure pulmonary capillary wedge pressures, which are universally elevated (>25 mm Hg) in cardiogenic pulmonary edema and are normal or low in noncardiac pulmonary edema.
Echocardiography is considered the ?gold standard? for the diagnosis of LV dysfunction. It reveals LV hypertrophy and diastolic dysfunction, provides an indirect measurement of right ventricular pressures, and identifies valvular lesions or reduced LV function. Echocardiography is not, however, always readily available and is a costly intervention.
Measurements of plasma BNP and its precursor, pro-BNP, are frequently used to evaluate patients with pulmonary edema. They can be used as a rapid test to determine whether heart failure or lung disease is the cause of the patient?s dyspnea. Compared with other neurohormones, plasma BNP concentration correlates directly with pulmonary capillary wedge pressure, LV end diastolic pressure, and LV ejection fraction in patients with heart failure.20 Using a pro-BNP cutoff value of 1500 pg/mL has been shown to be an accurate predictor of heart failure in patients with pleural effusions, with a sensitivity of 91% and a specificity of 93%.21 In a recent small study, BNP was found to be more sensitive (100%) but much less specific (62%) for predicting heart failure in a study of patients with pleural effusions that used a BNP cutoff value of 258 ng/L.22
BNP measurements may be especially valuable in the evaluation of elderly individuals with pulmonary edema who may have a history of chronic obstructive pulmonary disease or other conditions that can obscure the diagnosis. In a recent study of 202 patients aged 65 years and older who presented to an emergency department with acute dyspnea, 75% of those with cardiogenic pulmonary edema had pro-BNP levels of >1500 pg/mL compared with 24% of those without cardiogenic pulmonary edema.23 Similarly, 72% of the patients with cardiogenic pulmonary edema had a BNP level of >250 pg/mL compared with 9% of those without cardiogenic pulmonary edema. However, in critically ill patients with pulmonary edema, BNP values may be elevated in the absence of underlying cardiac dysfunction.24
Although thoracentesis is an appropriate diagnostic technique in most patients with pleural effusion, it is not needed in those with established heart failure; the procedure itself carries a small risk of reexpansion pulmonary edema.25
Cardiac pulmonary edema
Pulmonary edema is a dynamic medical condition, and treatment must begin as soon as the diagnosis is suspected. Initial therapy is directed at ensuring adequate oxygenation and maintaining hemodynamic stability, while reducing myocardial stress. IV morphine (2-5 mg) will lessen anxiety, decrease sympathetic outflow, and cause vasodilation (thus decreasing preload)?all of which help relieve pulmonary edema. However, caution is needed in patients with a decreased sensorium or respiratory drive to prevent respiratory arrest.
Furosemide (40-100 mg IV bolus) produces instant vasodilation and diuresis, mobilizing fluid from the lungs into the circulation and reducing venous return.
Nitroglycerin, which can be administered sublingually or by IV drip, also causes vasodilation and helps relieve pulmonary edema. Sublingual nitroglycerin (0.3 mg) may be given twice at 5-minute intervals, as long as there is no significant fall in blood pressure.
Inhaled beta2-adrenergic agonists or aminophylline can be used to treat bronchospasms. Aminophylline increases renal plasma flow, the excretion of sodium, and cardiac contraction and provokes vasodilation, thus decreasing peripheral vascular resistance. Aminophylline and beta2-adrenergic agonists, however, can induce tachycardia and supraventricular arrhythmias. Phlebotomy (removing 500 mL of blood) and dialysis are measures used to help reduce ventricular preload.
Noncardiac pulmonary edema
Treatment for noncardiac pulmonary edema focuses on respiratory support. Noninvasive positive-pressure ventilation with a tightly fitting nasal or full facial mask improves gas exchange and minimizes the work of breathing. Positive pressure increases intrathoracic pressure, reducing preload by diminishing venous return. The increased intrathoracic pressure also decreases afterload by elevating intracardiac pressure relative to the systemic vascular resistance, leading to enhanced LV performance. Positive airway pressure also keeps the airways open, increasing the time for gas exchange.
Two forms of noninvasive positive-pressure ventilation are available: continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP). The latter alternates between a higher pressure during inspiration and a lower pressure during exhalation. A recent meta-analysis of 15 randomized, controlled trials found that treatment with noninvasive ventilation reduced the risk of death by almost 45% compared with conventional oxygen therapy in patients with acute cardiogenic pulmonary edema.26 Noninvasive ventilation also reduced the need for intubation by 57%.
Despite concerns raised in an early study about an increased risk for myocardial infarction (MI) in patients treated with BiPAP,27 results from subsequent studies showed no differences in the incidence of MI between the 2 techniques or compared with conventional oxygen therapy. BiPAP and CPAP were found to be equally effective in this meta-analysis and in a second meta-analysis published in 2006.28 The second study also determined that the 2 modalities were comparably cost-effective, leading the authors to conclude that the choice of CPAP or BiPAP for the treatment of patients with pulmonary edema will likely be based on the availability of either equipment.
Early recognition and an understanding the spectrum of findings in pulmonary edema are crucial for effective patient management. The multiple etiologies may pose a diagnostic challenge, but a careful history and physical examination, combined with laboratory tests and imaging studies, can help determine the likely cause.
1. Which statement about pulmonary edema is NOT true?
A. It may occur after cardioversion
B. 75% of patients treated with IV IL-2 have radiographic signs of pulmonary edema within 5 days of starting treatment
C. Reexpansion pulmonary edema typically occurs >2 hours after the lung is reexpanded
D. High-altitude pulmonary edema can be prevented with a slow ascent
2. Which sign/symptom is NOT generally associated with pulmonary edema?
C. Moist rales on auscultation
D. Course, localized crackles on auscultation
3. All these radiographic findings are typical of cardiogenic pulmonary edema, except:
A. Air bronchograms
B. Kerley B lines
D. Thickened interlobular fissures
4. Which condition is NOT associated with unilateral pulmonary edema?
A. Head trauma
B. Pulmonary vein thrombosis
C. Coarctation of the aorta
D. LV failure secondary to mitral regurgitation
5. All these drugs are appropriate initial treatment, except:
A. Morphine, 2 mg IV
B. Furosemide, 100 mg IV bolus
C. Digoxin, 1 mg IV
D. Sublingual nitroglycerin, two 0.3-mg tablets at 5-minute intervals
(Answers at end of references list)
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Answers: 1. C; 2. D; 3. A; 4. A; 5. C.