Manual of Cardiovascular Diagnosis and Therapy

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CHAPTER 5. Pulmonary Edema

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–Introduction. Patients with either acute or chroni...

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–Summary. Despite the varied underlying etiologies ...

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  1. Introduction. Patients with either acute or chronic cardiac disease may develop pulmonary edema. The recognition and prompt treatment of acute pulmonary edema can be lifesaving. Because both cardiac and noncardiac disease can produce pulmonary edema, the physician must be aware of possible underlying conditions so that treatment can be directed toward the cause and the symptoms of pulmonary edema. The clinical problem is complicated by the fact that patients may have cardiac and pulmonary disease concurrently.

    The pathophysiology for the formation of pulmonary edema is similar to that of edema formation in the subcutaneous tissues. Although much recent work has been performed on the mechanism of pulmonary edema formation, large gaps in our knowledge remain. Elaborate mechanisms function to keep the interstitial tissue of the lung interstitium dry: (i) plasma oncotic pressure is held higher than pulmonary capillary hydrostatic pressure, (ii) connective tissue and cellular barriers are relatively impermeable to plasma proteins, and (iii) an extensive lymphatic system exists in the lung to carry off any interstitial fluid that is generated.

    The basic opposing hemodynamic forces are the pulmonary capillary pressure and the plasma oncotic pressure. In normal individuals, the pulmonary capillary pressure ("wedge" pressure) is between 7 and 12 mm Hg. Because normal plasma oncotic pressure is approximately 25 mm Hg, this force tends to pull fluid back into the capillaries. The hydrostatic pressure operates across connective tissue and cellular barriers, which under normal circumstances are relatively impermeable to plasma proteins. Finally, the lung has an extensive lymphatic system that can increase its flow five or six times when faced with excess water in the interstitial tissue of the lung. When normal mechanisms to keep the lung dry malfunction or are overwhelmed by excess fluid, edema tends to accumulate through a predictable sequence of steps. This process has been divided into three stages. During stage 1, fluid transfer is increased into the interstitial tissue of the lung; because lymphatic flow also increases, no net increase in interstitial volume occurs. During stage 2, the capacity of the lymphatics to drain excess fluid is exceeded, and liquid begins to accumulate in the interstitial spaces that surround the bronchioles and lung vasculature (which yields the roentgenographic pattern of interstitial pulmonary edema). As fluid continues to build up, increased pressure causes it to track into the interstitial space around the alveoli and finally to disrupt the tight junctions of the alveolar membranes. Fluid first builds up in the periphery of the alveolar capillary membranes (stage 3a) and finally floods the alveoli (stage 3b). During stage 3, the roentgenographic picture of alveolar pulmonary edema is generated, and gas exchange becomes impaired.

    In addition to the processes occurring at the level of each alveolus, gravity also exerts an important influence on the fluid mechanics of the lung. Because blood is much denser than air and air-containing tissue, the effect of gravity on it is most pronounced in the lung. Under normal circumstances, more perfusion occurs at the lung bases than at the apices; however, when pulmonary venous pressure rises and when fluid begins to accumulate at the lung bases, the blood flow in the lung is redistributed toward the apices. Apical redistribution of pulmonary blood flow is apparently the result of increased pressure from accumulated fluid within the walls of the basilar pulmonary blood vessels and from hypoxia-mediated vasoconstriction. This process results in the roentgenographic finding of pulmonary vascular redistribution, an important early sign of pulmonary edema.

    When any disease process alters the capillary hydrostatic pressure, plasma oncotic pressure, lung permeability, or lymphatic function, pulmonary edema can occur. Most cardiac causes of pulmonary edema ultimately can be traced to increased capillary hydrostatic pressure. A partial list of conditions causing pulmonary edema is found in Table 5-1.

  2. Diagnosis

    1. History. A careful history of previous cardiac or pulmonary disease should be elicited. Pulmonary edema can result from an exacerbation of previously known cardiac disease. It can also be the presenting symptom in previously undiagnosed cardiac disease. In acute pulmonary edema, the patient may be extremely fearful or agitated. Breathlessness, dizziness, and faintness are common complaints. Because pulmonary edema frequently arises from left ventricular failure, questions concerning underlying causes for heart failure of left ventricular origin should be asked: Has the patient had chest pain? Is there any history of congenital or valvular disease? Has the patient ever been treated for hypertension? All the questions concerning left ventricular failure outlined in Chapter 4 are relevant and should be asked to determine extent and duration of symptoms (e.g., shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea). The possibility of recent infection should be explored, and any history of pulmonary disease should be obtained. Specific questions should be addressed concerning exposure to toxic inhalants, smoke, or possible aspiration.

      In some situations, the cause of pulmonary edema will be apparent or suspected (smoke inhalation, near-drowning, excess infusion of intravenous (IV) fluids, heroin or other narcotic overdose), or the history may be brief or not obtainable. When none of the foregoing lines of questioning are fruitful, it is helpful to resort to a detailed differential diagnosis of possible underlying etiologies for pulmonary edema (Table 5-1). Specific questions may then be directed to the possibility of unusual etiologies (e.g., radiation pneumonia, uremia). In acute pulmonary edema, prompt treatment is essential, and it is often not be possible to elicit a detailed history before some form of treatment is undertaken. Once the clinical situation has stabilized, however, a detailed history is required to plan rational long-term therapy. An approach to history taking in pulmonary edema is outlined in Table 5-2.

    2. Physical examination. The patient may be terrified. Frequently, he or she will have difficulty talking because of respiratory distress. The patient is usually sitting, standing, or occasionally pacing in an agitated manner. Respirations are rapid and shallow (often reaching 30 to 40 respirations per minute in the adult, and higher in children). The heart rate is rapid (often more than 100 beats per minute), and the pulse is thready (if the heart rate is slow, heart block must be considered). Both systolic and diastolic blood pressures may be elevated, but this should not be confused with true, chronic, systemic hypertension. An elevated body temperature should raise a suspicion of underlying or concurrent infection (rectal temperatures are preferable because the patient is often breathing rapidly). The skin is often cold and clammy, and peripheral cyanosis may be present. The alae nasi may be dilated or flaring with the increased respiratory effort. Chest examination is likely to reveal retraction of intercostal muscles and extensive use of accessory muscles of respiration. The patient will often grasp the side rails of a hospital bed or stretcher to provide extra mechanical advantage to allow the use of these accessory muscles. Moist rales are present (starting at the lung bases and extending to various levels of the lung, depending on the severity of the edema). Coughing may be present and, in fulminant cases, productive of pink frothy sputum. Wheezing and a prolonged expiratory phase may also be observed. The cardiac examination usually is difficult because of respiratory noise. An third heart sound (S3) gallop is frequently present. Careful auscultation for murmurs is necessary because of possible valvular or congenital etiologies of pulmonary edema. Peripheral edema should be looked for as evidence of right ventricular failure accompanying pulmonary edema. The finding of peripheral edema suggests that chronic heart failure has been present. A neurologic examination helps to rule out neurogenic causes of pulmonary edema (central nervous system [CNS] trauma, epilepsy, subarachnoid hemorrhage). An approach to the physical examination in patients with pulmonary edema is given in Table 5-3.

    3. Laboratory tests. Serum electrolyte values must be obtained in all patients with pulmonary edema. These values assume particular importance in patients who are being treated with diuretics for hypertension or heart failure, or in whom diuretic or digitalis treatment (or both) is contemplated. Blood urea nitrogen and creatinine readings are needed to assess renal function. Serum protein levels should be ascertained because of possible hypoalbuminemia. A urinalysis and microscopic examination of the urine should be performed routinely to assess the patient for possible underlying renal disease. A complete blood cell count with differential should be obtained. This is particularly important in patients in whom pulmonary infection or endocarditis is suspected.

      Room-air arterial blood gas concentrations are essential to assess the patient's level of oxygenation and acid-base status. In the past, it was commonly taught that patients with pulmonary edema were hypocapnic and alkalotic because of hyperventilation. However, approximately 50% of such patients are eucapnic or retain carbon dioxide, whereas 80% of these patients are at least mildly acidemic.

      Pulmonary function tests are difficult or impossible to interpret in the acute setting. They may be obtained after respiratory stabilization to establish baseline pulmonary function. A typical pattern of respiratory mechanics for a patient with residual pulmonary edema includes decreases in vital capacity and total lung capacity. Vital capacity provides a simple bedside parameter that can be followed serially as the patient recovers.

    4. Chest x-ray examination. As outlined in Chapter 4, the chest x-ray film often yields valuable and early information about the presence of excess fluid in the pulmonary interstitium. Assuming normal capillary permeability and normal plasma oncotic pressure, transudation of fluid in the lung begins to occur when capillary hydrostatic pressure approaches the oncotic pressure of plasma proteins (approximately 25 mm Hg). The roentgenographic pattern of pulmonary edema reflects the anatomic location of collected fluid. Initially, interstitial edema is seen as fluid gathers in tissues immediately surrounding the capillary membrane. Early roentgenographic signs of interstitial edema include thickening and loss of definition of the shadows of the pulmonary vasculature. Fluid then accumulates in septal planes and interlobular fissures, resulting in Kerley A and B lines. Subpleural or free pleural fluid (recognized as blunting of the costophrenic angles) also may be seen at this juncture. Finally, as transudated fluid collects in the parenchymal space, roentgenographic signs of alveolar edema become apparent. These roentgenographic changes may be diffuse, may be confined to the lower portion of one or both lungs, or may surround the hilus ("butterfly pattern").

    5. ECG. The ECG in pulmonary edema should be examined to aid in defining the underlying etiology. Evidence of myocardial infarction (MI) and arrhythmias should be sought. ECG evidence of left ventricular hypertrophy suggesting aortic stenosis, systemic hypertension, or cardiomyopathy may be present.

    6. Echocardiography. Echocardiography is not essential to recognize pulmonary edema. It does help identify underlying disease that may lead to pulmonary edema. For example, echocardiography can assist the physician in recognizing established valvular disease, which may lead to pulmonary edema. Echocardiograms are often successful in demonstrating valvular vegetations in patients with endocarditis. Abnormalities of left ventricular wall motion after MI, and poor left ventricular function in patients with cardiomyopathy can easily be documented by echocardiography.

    7. Radionuclide studies. Radionuclide studies can be of value in quantitating left ventricular function in patients with pulmonary edema. Moreover, radionuclide angiocardiography can demonstrate a left-to-right shunt in patients with ventricular septal rupture secondary to MI.

    8. Catheterization and angiography. The use of cardiac catheterization to document underlying etiologies for pulmonary edema is well established and discussed elsewhere in this book under specific disease entities. In addition to the traditional diagnostic use of catheterization, Swan-Ganz (balloon-tipped) catheters, inserted at the patient's bedside, may provide important information, although their use is not mandatory. Measurement of pulmonary capillary wedge (PCW) pressure can distinguish cardiogenic from noncardiogenic pulmonary edema. Other hemodynamic parameters such as cardiac output, oxygen saturation in various cardiac chambers, and the presence of giant V waves in the PCW tracing are also available from right-sided heart catheterization. Recent reports have demonstrated that giant V waves may be present in a variety of conditions other than acute mitral regurgitation, including mitral stenosis, coronary artery disease, mitral valve prosthesis, and ventricular septic defect. Moreover, in long-standing mitral regurgitation (MR) the large, compliant left atrium may prevent generation of V waves. Despite these limitations, mitral regurgitation remains the most common cause of V waves, and this finding in the PCW position tracing during pulmonary artery catheterization provides useful diagnostic information. Finally, the catheter may be left in the pulmonary artery for several days and can continue to provide hemodynamic information while therapy for pulmonary edema is administered. Such serial measurements of pulmonary pressures are particularly important when pulmonary edema and diminished cardiac output occur together. In this situation, left ventricular filling pressures should be monitored to produce maximum cardiac output with minimum elevation in pulmonary pressure.

    9. Protocol for the diagnosis of pulmonary edema

      1. Confirmatory tests. The diagnosis of pulmonary edema is a clinical one. Patients generally present with a history of underlying cardiac or pulmonary disease but sometimes with pulmonary edema as the initial manifestation of underlying disease. The diagnosis is made by a combination of history, physical examination, and chest x-ray studies that reveal excess fluid in the lung. Other confirmatory tests are not needed for diagnosis.

      2. Differential diagnosis. The major differential diagnostic problem in pulmonary edema resides not in establishing the diagnosis but in distinguishing among the possible underlying causes. Table 5-1 lists cardiogenic and noncardiogenic causes of pulmonary edema.

      3. How to distinguish among underlying causes

        1. Pulmonary edema caused by altered permeability of endothelial barriers. The group of disorders that alter either alveolar or pulmonary capillary membrane permeability comprises the largest group of causes of noncardiogenic pulmonary edema. Distinction among these entities (Table 5-1) and cardiogenic causes of pulmonary edema may be very difficult. The problem is complicated by the fact that elevated pulmonary capillary pressure itself can increase capillary permeability. Furthermore, increased lung fluid from any cause makes the lung more susceptible to secondary infection, and patients with pulmonary edema of cardiac origin may have intercurrent bacterial pneumonia. It is important to consider altered permeability as a cause of pulmonary edema in any patient who has an underlying disease capable of damaging pulmonary capillary or alveolar endothelium. In this category are patients with bacterial or viral pneumonia, patients exposed to toxins (including the administration of high concentrations of oxygen), patients with smoke inhalation, and patients with radiation pneumonitis (generally secondary to radiation therapy for chest tumors). A more complete listing is found in Table 5-1. Even with this list in mind, the picture may be confusing. The most direct diagnostic procedure in this case is the insertion of a balloon-tipped catheter to measure PCWP, which is normal or low in patients with noncardiogenic pulmonary edema.

        2. Pulmonary edema caused by decreased oncotic pressure. Lowered oncotic pressure should be considered in all patients with hepatic or renal disease who present in pulmonary edema. Nutritional deficits and protein-losing enteropathy are the more two unusual causes of decreased oncotic pressure pulmonary edema.

        3. Pulmonary edema caused by increased pulmonary capillary pressure

          1. Cardiac causes. Any cardiac disease that causes (or simulates, e.g., mitral stenosis) left ventricular dysfunction can lead to pulmonary edema. Although this category encompasses almost every major form of cardiac disease, the most common cardiac etiologies of pulmonary edema are systemic hypertension and MI. The diagnosis of specific underlying cardiac disorders is covered in depth in other chapters in this manual. The level of PCW pressure does not always correlate with the degree of pulmonary edema. Furthermore, it is important to understand that the roentgenographic picture of pulmonary edema may lag behind the clinical syndrome. The oncotic pressure, status of the pulmonary lymphatics, presence of intercurrent diseases that alter capillary and alveolar endothelial permeabilities, and individual patient differences all influence the pressures at which transudation of fluid begins.

          2. Noncardiac causes. A number of rare conditions that involve abnormalities of the pulmonary vasculature may give rise to increased pulmonary capillary pressure. Included in this category are pulmonary venoocclusive disease, congenital stenosis of the origin of the pulmonary veins, and pulmonary venous fibrosis. Although these conditions are rare, they should be considered in young patients with chronic pulmonary edema.

        4. Miscellaneous and unusual causes of pulmonary edema. A variety of rare conditions that involve either direct damage to the lung or indirect alterations in pulmonary function may cause pulmonary edema: disorders of the pulmonary lymphatics (silicosis, lymphangitic carcinomatosis), CNS disturbances (CNS trauma, subarachnoid hemorrhage), cardioversion, eclampsia, heroin overdose, and high-altitude pulmonary edema. The diagnosis of these conditions usually rests on a careful history.

  3. Summary. Despite the varied underlying etiologies of pulmonary edema, it is possible to develop an overall diagnostic approach to the clinical problem. Such an approach is outlined in Table 5-4.

  4. Therapy

    1. Medical treatment. The treatment of pulmonary edema involves two types of action: (i) general measures for the acute symptoms and (ii) measures to correct specific underlying abnormalities.

      1. General measures and drugs

        1. Oxygen and other measures designed to improve respiratory gas exchange. Oxygen should be a first priority in the patient with respiratory distress. If possible, a room-air arterial blood gas level should be obtained before institution of therapy. For most patients, adequate oxygenation is achieved with a nasal catheter or face mask; however, patients with severe hypoxia often require further measures. Endotracheal intubation with controlled, mechanical ventilation will be required in such patients. At times, intermittent positive pressure breathing (IPPB) through a specially adapted mask will be sufficient to correct hypoxia in such patients. If, however, arterial Po2 levels cannot be maintained above 80 mm Hg with either IPPB alone or after endotracheal intubation, or if an Fio2 of 60% or more is required to maintain Po2 above this level, positive end-expiratory pressure (PEEP) should be used.

          Various criteria have been developed for determining when a patient requires intubation and controlled ventilation. Controlled ventilation via an endotracheal tube should usually be instituted when high flows of approximately 100% oxygen through a rebreathing apparatus are unsuccessful in maintaining arterial Po2 levels at or above 80 mm Hg. Important exceptions to this rule are patients with chronic obstructive pulmonary disease, who often have a baseline Po2 of around 50 mm Hg. Intubation of such patients should be attempted only in critical situations, because it can be difficult to wean them from the respirator.

          As noted earlier, when controlled ventilation does not provide adequate oxygenation, PEEP may be added. End-expiratory pressures from 5 to 20 mm Hg generally are used. In severe degrees of pulmonary edema, the respiratory management is identical to ventilatory management of the adult respiratory distress syndrome. The primary effect of PEEP seems to be that of increasing functional residual capacity, thereby preventing premature closure of small airways during expiration.

          It should be remembered that the amount of oxygen delivered to the tissues is a function of both cardiac output and the level of arterial oxygen. Controlled ventilation with and without PEEP may have the adverse side effect of decreasing cardiac output through restriction of venous return. The most accurate way of determining the effect of mechanical ventilation on cardiac output is by monitoring the cardiac output with a thermodilution balloon-tipped catheter or by measuring the mixed venous oxygen content in the pulmonary artery by means of a right-heart catheterization. The lower the cardiac output, the lower will be the mixed venous oxygen content.

        2. Other general measures. Measures to ensure patient comfort should be instituted; for example, the head of the bed should be elevated to at least 30 degrees.

          Fluid management will be dictated by clinical condition and blood pressure. If the patient is hypotensive, diuresis should be done with great caution to prevent worsening hypotension secondary to dehydration. In this event, the clinician walks the fine line between inadequate fluid depletion and exacerbation of pulmonary edema. Measurement of PCW pressure is often important in this setting to make this distinction. Central venous pressure does not adequately reflect filling of the left side of the heart. Treatment of hypotension is discussed together with shock in Chapter 6. If the patient is hypertensive, measures should be taken to lower arterial pressure, as outlined in Chapter 12.

        3. Drugs

          1. Furosemide and other diuretics. Parenteral furosemide (Lasix) has become standard in the management of acute pulmonary edema, although patients can, at times, be managed adequately without this drug. The initial dose is generally 10 to 20 mg IV for patients who have never been treated with furosemide before, although doses of 40 to 80 mg by slow IV bolus (over 1 to 2 minutes) are common in patients who have been treated with diuretics as outpatients. Continuous IV infusion of furosemide may produce a diuresis in patients who have been previously refractory to bolus infusions of furosemide. The dosage here ranges from 10 to 40 mg per hour, depending on the level of renal function. Patients with decreased renal function require higher dosage of IV furosemide. Ethacrynic acid (Edecrin) is an alternative loop diuretic to furosemide. Initial doses of 20 to 60 mg IV bolus are typically used. Occasionally, a diuresis can be achieved by combination of furosemide (100 mg IV slow bolus) and chlorothiazide(500 mg IV slow bolus) when neither furosemide nor ethacrynic acid alone is successful. There are at least three mechanisms of action of furosemide: (i) rapid peripheral, vasodilative effect; (ii) diuretic effect; and (iii) mild afterload reduction.

          2. Digitalis. The use of digitalis glycosides has virtually disappeared in recent years as a therapeutic intervention for patients with acute pulmonary edema. Digitalis is still used in the management of chronic heart failure (Chapter 4).

            Digitalis may be used in patients whose pulmonary edema is secondary to a supraventricular arrhythmia. For example, digitalis may be used to control ventricular response in atrial fibrillation. However, there are drugs that are more effective for this indication (Chapter 3). A control ECG and serum potassium level should be obtained before digitalis preparations are administered.

          3. Morphine. Morphine is an important drug in the treatment of acute pulmonary edema. It is thought to have both a direct venodilating effect and a CNS effect (allaying anxiety). Morphine may be administered either intramuscularly (5 to 10 mg repeated in 2 to 4 hours) or intravenously (1 to 4 mg).

            In patients in whom MI is a possibility, the IV route is preferred, because intramuscular injections increase serum creatine phosphokinase levels. Caution must be exercised in the administration of morphine to patients with obstructive pulmonary disease, because morphine blunts respiratory drive and may result in respiratory arrest.

          4. Aminophylline. If bronchospasm is present, aminophylline may be beneficial. In addition, aminophylline provides inotropic stimulation to the heart. Standard dosage is a loading dose of 6 mg/kg followed by a constant infusion of 0.5 to 1.0 mg/kg per hour. Aminophylline also exerts a mild diuretic effect.

          5. Vasodilators. A variety of vasodilators are available that reduce left ventricular work. The dosages and clinical characteristics of these medications are summarized in Chapter 4. Both nitroglycerin (IV, sublingual, or oral) and IV nitroprusside have been used for this purpose. When nitroprusside is used, a common starting dose is 20 to 40 mcg per minute, with increments of 5 mcg per minute every 5 to 10 minutes until the desired effects (lowering pulmonary artery pressure or initiating a diuresis) are achieved. Therapy with nitroprusside should be monitored carefully to prevent hypotension.

            Vasodilators are used most commonly for pulmonary edema secondary to chronic, intractable left ventricular failure, or for acute pulmonary edema secondary to MI (see Chapter 15).

          6. IV inotropic agents. IV inotropes such as dobutamine or dopamine are occasionally used in patients with severe and/or refractory pulmonary edema, particularly if hypotension is present (see Chapter 6).

          7. Miscellaneous medicines used to treat pulmonary edema. IV albumin may be indicated when hypoproteinemia contributes to pulmonary edema.

      2. Activity. The activity recommendations outlined in Chapter 4 also apply to patients with pulmonary edema. Initially, patients should be kept at bed rest until they stabilize and much of their pulmonary edema has resolved. At this point, they may be rapidly and progressively mobilized.

      3. Diet. The dietary recommendations outlined for patients with moderate to severe heart failure also apply to patients with pulmonary edema. Salt restriction is advised.

    2. Surgery. Surgical intervention for patients with pulmonary edema may be helpful in a number of different situations, including correction of surgically remediable causes such as acute mitral regurgitation. Surgery may also be used for and insertion of an intraaortic balloon pump (IABP).

      Surgically remediable causes of pulmonary edema include valvular lesions and ventricular septal rupture after MI. The IABP may be lifesaving in severe left ventricular failure. The use of the IABP is discussed in greater detail in Chapter 15. A general protocol for the treatment of pulmonary edema is found in Table 5-5.

Selected Readings

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Bersten AD, Holt AW, Vedig AE, et al. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. N Engl J Med 1991;325:1825–1830.

Continuous positive airway pressure therapy reduces the need for intubation in patients with pulmonary edema.

Brater DC. Diuretic therapy. N Engl J Med 1998;339:387–395.

An extensive review of the indications for and correct usage of diuretics.

Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 1998;97:1411–1420.

An authoritative review of angiotensin-converting enzyme inhibitors and their use in acute and chronic heart failure.

Fedullo AJ, Swinburne AJ, Wahl GW, et al. Acute cardiogenic pulmonary edema treated with mechanical ventilation: factors determining in-hospital mortality. Chest 1991;99:1220–1226.

Mortality in patients with pulmonary edema depends on the severity of left ventricular dysfunction. Variables related to the degree of respiratory failure were not predictive of mortality.

Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996;334:1649–1654.

A review of the underlying mechanisms for the efficacy of angiotensin receptor blocking agents.

Lin M, Yang YF, Chiang HT, et al. Reappraisal of continuous positive airway pressure therapy in acute cardiogenic pulmonary edema: short-term results and long-term follow-up. Chest 1995;107:1379–1386.

Continuous positive airway pressure therapy results in physiologic cardiovascular and pulmonary function improvement in patients with pulmonary edema.

Pang D, Keenan SP, Cook DJ, et al. The effect of positive pressure airway support on mortality and the need for intubation in cardiogenic pulmonary edema: a systematic review. Chest 1998;114:1185–1192.

Positive pressure airway support decreases the need for intubation and may decrease mortality in patients with pulmonary edema.

Robin ED, Cross CE, Felix R. Pulmonary edema. N Engl J Med 1973;288:239–246.

The classic paper on pulmonary edema; an excellent review, particularly of pathophysiology of pulmonary edema formation.

Schuster DP. Pulmonary edema: etiology and pathogenesis. In: Rippe JM, Irwin RS, Fink MP, et al., eds. Intensive care medicine. Boston: Little, Brown and Company, 1995.

A good recent summary with particular emphasis on the underlying pathophysiology of pulmonary edema.

Sharon A, Shpirer I, Kaluski E, et al. High dose intravenous isosorbide dinitrate is safer and better than bilevel positive airway ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol 2000;36:832–837.

Long-acting nitrate therapy is safe and highly effective therapy for patients with severe pulmonary edema.