Acute pulmonary edema can be divided into two categories: edema caused by increased capillary pressure (hydrostatic, or cardiogenic, edema) and edema caused by increased capillary permeability (noncardiogenic pulmonary edema, or acute respiratory distress syndrome [ARDS]). In some cases of pulmonary edema, both pressure and permeability are increased.
Pathogenesis
Pulmonary edema is an abnormal, diffuse, extravascular accumulation of liquid in the pulmonary tissues and air spaces. It is the most common noninfectious, diffuse parenchymal lung disease. The pathogenesis of pulmonary edema can be best understood by examination of the Starling equation, which defines the determinants of liquid flux across the pulmonary capillary membrane:
where Q is liquid flux; K, the filtration coefficient, which is directly proportional to the endothelial surface area and inversely proportional to alveolar capillary wall thickness; Pcap, the in-travascular (capillary) hydrostatic pressure; Pint, the interstitial hydrostatic pressure; a, the reflection coefficient for protein (i.e., the degree of permeability to macromolecules); ncap, the plasma oncotic pressure; and nint, the interstitial oncotic pressure. In this equation, Pcap – Pint represents the hydrostatic force, and ncap -nint represents the colloid osmotic force.
An alteration in any of the factors in the Starling equation could conceivably lead to an increase in transvascular liquid flux. However, in clinical practice, only two of these factors commonly lead to pulmonary edema: (1) an increase in capillary pressure, which leads to cardiogenic, or hydrostatic, pulmonary edema, and (2) a decrease in the reflection coefficient, which leads to noncardiogenic, or permeability, pulmonary edema.
The primary defense against pulmonary edema is provided by the lymphatic system. Normally, liquid that is filtered across the capillary membrane is removed by the lymphatic vessels. The lymphatic reserve is such that even a fourfold to sixfold increase in transcapillary liquid flux can be tolerated without an increase in lung water. A secondary defense mechanism and pathway for the removal of edema liquid is the active transport of Na+ with passive osmotic water reabsorption in type II alveolar lining cells.1
Once the liquid removal reserve is overwhelmed, lung water increases, first in the interstitium around the airways, then in the interstitium around the alveoli, and finally within the alveoli. Clinical or radiographic evidence of pulmonary edema therefore implies a large increase in transcapillary liquid flux.
Approach to the Patient with Suspected Pulmonary Edema
Because of the different therapeutic approaches in cardio-genic and noncardiogenic pulmonary edema, it is important to differentiate between these conditions, though this is sometimes difficult, and some patients have components of both. The patient’s history provides some important clues [see Table 1]. Patients with cardiogenic pulmonary edema often have a history of cardiac disease or hypertension, whereas patients with non-cardiogenic edema may have a history of alcoholism or other problems that increase the risk of infection. The patient with cardiogenic pulmonary edema may have symptoms of a new cardiac event (ischemic chest pain) or a hypertensive emergency. The patient with noncardiogenic pulmonary edema will almost always have a clear precipitating event, such as sepsis, trauma, aspiration of gastric contents, multiple transfusions, or pneumonia.
The symptoms and signs are similar in the two forms of pulmonary edema, with some important exceptions [see Table 1]. Although both groups of patients experience dyspnea, patients with cardiogenic pulmonary edema have cool, diaphoretic skin with evidence of left ventricular (LV) dysfunction (LV heave, gallop); by contrast, most patients with noncardiogenic pulmonary edema have warm skin and show evidence of a hyper-dynamic circulation.
Table 1 Cardiogenic versus Noncardiogenic Pulmonary Edema
|
Clinical Features |
Cardiogenic Pulmonary Edema |
Noncardiogenic Pulmonary Edema |
|
Clinical setting |
Prior MI, hypertension, cardiomyopathy, MI, hypertensive emergency, dietary indiscretion, others |
Alcoholism, immunosuppression, sepsis, trauma, aspiration, pneumonia, others |
|
Symptoms |
Dyspnea, cough productive of pink sputum |
Dyspnea, cough |
|
Signs |
Tachypnea, tachycardia, weak pulse, hypertension, cool skin, diaphoresis, central or peripheral cyanosis, wheezing, rales, LV heave, gallop |
Tachypnea, fever, hypothermia, bounding pulse, warm skin, central cyanosis, hyperdynamic precordium |
|
Findings on chest radiography |
Venous cephalization, wide vascular pedicle, increased cardiothoracic ratio, perihilar infiltrates, Kerley B lines |
Diffuse infiltrates, air bronchograms |
|
Findings on echocardiography |
Decreased LV ejection fraction, diastolic dysfunction, valvular disease, segmental wall motion abnormalities |
Hyperdynamic LV, RV dilatation, pulmonary hypertension |
|
Findings on pulmonary artery catheterization |
Increased PCWP, normal or decreased CO, increased pulmonary arterial pressure with normal PVR, increased SVR |
Normal or low PCWP; when sepsis is present: increased CO, increased pulmonary arterial pressure with increased PVR, decreased SVR |
CO—cardiac output
LV—left ventricular
MI—myocardial infarction
PCWP—pulmonary capillary wedge pressure
PVR—pulmonary vascular resistance
RV—right ventricular
SVR—systemic vascular resistance
Pulmonary edema of either type is typically manifested by bilateral, symmetrical alveolar opacities that involve all four quadrants, as seen on a standard anteroposterior chest radiograph [see Table 1].2 A predominantly perihilar distribution is common, and occasionally, there is a very sharp demarcation between the central area of pulmonary edema and the lung periphery, leading to a so-called bat’s-wing or butterfly pattern. This pattern is more typical of cardiogenic pulmonary edema than noncardiogenic pulmonary edema [see Figure 1]. This sharp line of demarcation does not correspond to any anatomic boundaries but may be caused by physiologic gradients of ventilation, perfusion, and lymph flow from the central to the peripheral portions of the lung. Less often, the edema is markedly asymmetrical or entirely unilateral. Asymmetrical pulmonary edema can occur as a result of the patient’s lying on the involved side as the edema develops, or it may result from vascular obstruction (thromboembolism) or attenuation (emphysema) in the more radiolucent regions of the lung. However, the reasons why some cases are asymmetrical and others are unilateral are often impossible to determine.
Ancillary features that can be routinely visualized on an an-teroposterior chest radiograph made with a portable x-ray machine may help differentiate cardiogenic from noncardiogenic pulmonary edema. A widened vascular pedicle and an increase in the cardiothoracic ratio suggest increased pulmonary capillary pressure3; distinct air bronchograms are more common with noncardiogenic pulmonary edema. The presence or absence of pleural effusions have less value in making the differential diagnosis. Unfortunately, cardiogenic and noncardio-genic pulmonary edema often cannot be confidently differentiated using bedside radiography, owing to anteroposterior exposure and lack of full inspiration, both of which magnify the cardiac silhouette.
Bedside echocardiography can be very useful in differentiating cardiogenic from noncardiogenic pulmonary edema [see Table 1]. In patients with cardiogenic pulmonary edema, echocardiography can detect and quantitate the abnormal left ventricular function and can be used to diagnose many of the causes (e.g., valvular dysfunction, diastolic dysfunction, car-diomyopathy, and focal wall motion abnormalities). In patients with noncardiogenic pulmonary edema, a normal or hyperdy-namic left ventricle is seen.
If differentiation of cardiogenic from noncardiogenic pulmonary edema is not possible with the noninvasive evaluation outlined above, placement of a pulmonary arterial catheter may be considered. Pulmonary capillary wedge pressure (PCWP) is the most helpful measurement, but other measurements can support the diagnosis and may help in treating the patient [see Table 1].4
Despite the logical appeal of the use of pulmonary arterial catheters, no beneficial effect on outcome has been attributed to their use. A study of a large number of patients in intensive care units has suggested that patients who had pulmonary arterial catheters had a higher mortality at a higher financial cost than patients who did not undergo catheterization.5 The report has been criticized but is currently the only published analysis of the effect of the use of these catheters on the outcome of patients in the ICU.
Figure 1 Bat’s-wing pattern characteristic of acute pulmonary edema is evident in this chest radiograph.
Cardiogenic Pulmonary Edema
Pathogenesis
Pulmonary edema caused by increased capillary pressure can occur as a result of systolic or diastolic dysfunction of the left ventricle, mitral valvular disease, hypervolemia associated with normal left heart function (as might occur in a patient with renal failure), or pulmonary venous obstruction. The most common cause of cardiogenic pulmonary edema is left ventricular dysfunction. In congestive cardiomyopathy, the systolic performance of the left ventricle is impaired, the ventricle is dilated, and left ventricular end-diastolic pressure (LVEDP) is increased. The rise in LVEDP leads to an increase in pulmonary capillary pressure. Other types of heart disease can also increase LVEDP, despite normal systolic function and euvolemia, by reducing left ventricular compliance and producing diastolic dysfunction.6 Reduced compliance may be persistent (as seen with left ventricular hypertrophy or restrictive cardiomyopathy from infiltrative heart disease) or transient (as from myocardial ischemia). Increased capillary pressure despite normal LVEDP is uncommon but does occur with mitral stenosis or as a result of obstructed flow in the pulmonary veins (pulmonary venoocclusive disease).
Diagnosis
The salient clinical features of cardiogenic pulmonary edema are extreme breathlessness, tachypnea, and signs of increased sympathetic activity, such as tachycardia, hypertension, and diaphoresis [see Table 1 and Approach to the Patient with Suspected Pulmonary Edema, above]. Hypotension is uncommon but may occur if pulmonary edema results from a large myocardial infarction. Breathlessness is rarely alleviated by correction of hypoxemia, suggesting that the cause may be activation of in-trapulmonary stretch receptors rather than hypoxemia. In car-diogenic pulmonary edema, central cyanosis may be observed if there is profound arterial hypoxemia; more often, cyanosis is peripheral and results from intense cutaneous vasoconstriction and a decreased cardiac output. Use of accessory muscles of respiration is common because of the marked increase in the work of breathing. The effort required to breathe is often so great that endotracheal intubation and mechanical ventilation are required to correct or prevent the development of frank hyper-capnic respiratory failure. Early in the acute course, there may be wheezing caused by airway edema and intraluminal liquid; later, diffuse coarse rales are heard.
Treatment
Supplemental oxygen should be given by mask or nasal can-nula. If hypoxemia cannot be corrected by establishing maximum oxygen flow rates and by use of reservoir bags, mechanical ventilation with a mask7 or endotracheal tube will be required [see 14:VIII Respiratory Failure]. The positive intrathoracic pressures created by the ventilator open collapsed alveoli and impede venous return. While hypoxemia is being treated, one or more of several therapeutic options should simultaneously be exercised, depending on the underlying pathophysiologic processes [see Table 2]. The proper combination of therapeutic measures depends on the pathophysiology. For example, when pulmonary edema occurs as a complication of malignant hypertension, vasodilators and diuretics may suffice. In the case of a causative or strongly contributing tachyarrhythmia, antiar-rhythmic therapy may be the key intervention. Specific interventions for causative cardiac conditions are described elsewhere [see Section 1 Cardiovascular Medicine].
Outcome
Patients with acute cardiogenic pulmonary edema often are elderly and have multiple medical problems, including is-chemic heart disease, diabetes, and valvular heart disease. As a consequence, the mortality for these patients ranges from 6% to 30%.8 Of those patients who survive to discharge, approximately 70% will survive 1 year, and 50% will have relatively good functional status for longer periods.9
Noncardiogenic Pulmonary Edema: Acute Respiratory Distress Syndrome
ARDS is characterized by diffuse pulmonary endothelial injury, which leads to pulmonary edema as a result of an increase in capillary permeability to water, solutes, and macromole-cules.10,11 The pulmonary edema seen in patients with ARDS is characterized by a higher concentration of protein in the edema liquid than is seen in patients with cardiogenic pulmonary edema. In patients with ARDS, this concentration is often as high as 80% to 90% of the plasma protein. Furthermore, in ARDS patients, the underlying inflammatory response causes high levels of neutrophils and their secretory products in bronchoalveolar lavage liquid; this characteristic distinguishes noncardiogenic edema from cardiogenic edema.
Table 2 Treatment of Cardiogenic Pulmonary Edema
|
Effect Sought |
Therapeutic Approach |
|
Decrease venous return Decrease impedance to ventricular systole |
Venodilator Arteriolar dilator |
|
Decrease intravascular volume |
Diuretic agent |
|
Stimulate the myocardium Correct arrhythmias |
Inotropic agent Antiarrhythmic agent, pacemaker |
|
In the Presence of Coronary Arterial Occlusion |
|
|
Alleviate ischemia |
Angioplasty, thrombolytic agent, coronary bypass |
|
Prevent clot propagation |
Aspirin, other antiplatelet agent, anticoagulant |
Table 3 Causes of ARDS11
|
Condition |
Examples |
|
Direct Lung Injury |
|
|
Diffuse pulmonary infection |
Bacterial, viral (including SARS53) or fungal pneumonia; Pneumocystis carinii pneumonia; tuberculosis |
|
Chemical pneumonitis caused by aspiration |
Aspiration of gastric contents or of water in near-drowning |
|
Inhalation injury |
Inhalation of smoke, chlorine, or nitrous oxide |
|
Direct pulmonary trauma |
Automobile accident |
|
Indirect Lung Injury |
|
|
Systemic reaction to nonpulmonary infection |
Bacteremias, nonbacteremic sepsis, toxic-shock syndrome |
|
Systemic reaction to nonpulmonary tissue |
Pancreatitis, trauma, fat embolism, amniotic fluid embolism |
|
inflammation or injury |
|
|
Transfusion reaction |
Red cell transfusion |
|
Drug toxicity |
Salicylates, cytotoxic agents |
|
Reperfusion injury |
Cardiopulmonary bypass, post-lung transplantation |
|
Other |
Marathon running |
SARS—severe acute respiratory syndrome
Many clinical disorders are associated with the development of ARDS [see Table 3], which may arise from direct injury to the lung or from extrapulmonary processes that injure the lung in-directly.10,12 A patient’s risk of developing ARDS varies with the predisposing disorder, and the risk increases as the number of predisposing disorders increases.11 The risk of ARDS may be further increased in patients with a history of alcohol abuse13 or cigarette smoking,14 or it may be increased by the presence of low serum pH or hypoproteinemia15 at the time of the insult. Genetic factors may also play a role in predisposition.
Pathogenesis
Diffuse alveolar damage is a descriptive term for the nonspecific but predictable sequence of changes that characteristically occur in patients with ARDS.17 The causative agent or process usually cannot be determined from the histopathologic pattern. In addition, the abnormalities may resolve at any point in the clinical course.
The histologic appearance of diffuse alveolar damage varies during the period between the precipitating event and the biopsy or autopsy, progressing through the following three phases: an acute exudative phase (days 0 through 7); a subacute proliferative, or organizing, phase (days 7 through 14); and a chronic phase (after day 14).17
The earliest part of the acute exudative phase is characterized by interstitial and intra-alveolar edema, neutrophil infiltration, hemorrhage, and fibrin deposition. A mixture of fibrin and cellular debris is deposited in the alveolar space to form the so-called hyaline membranes that are prominent 3 to 7 days after injury. Sloughing of the cells of the alveolar lining leaves a denuded basement membrane, which plays an important role in subsequent repair or fibrosis. An interstitial infiltrate of inflammatory cells becomes more pronounced around day 7 and persists throughout the proliferative phase.
Denudation of the basement membrane causes type II pneu-mocytes to proliferate (days 3 through 7), producing a pattern of hyperplasia in the cells of the alveolar lining. In patients in whom the syndrome resolves, these proliferating cells ultimately differentiate into type I pneumocytes, restoring the epithelial side of the alveolocapillary wall and returning gas exchange to normal.17 The proliferative phase of ARDS is characterized by inflammation and fibroblast proliferation, initially in the interstitium. The fibroblasts invade the alveolar spaces through basement membrane defects, a process that produces regions of intra-alveolar fibrosis. During this phase, the hyaline membranes disappear as a result of phagocytosis or of organization involving the incorporation of the exudate into intra-alveolar plugs of proliferating fibroblasts.
The chronic phase of ARDS is characterized by regions of intense fibrosis, focal regions of overexpansion, and pulmonary vascular obliteration. Histologically, this phase of the disease can be similar to idiopathic pulmonary fibrosis; in contrast to id-iopathic pulmonary fibrosis, however, the chronic phase of ARDS may improve with time.17
Extensive investigations have led to a better understanding of the mechanisms that lead to ARDS10,17,18 [see Figure 2].
Diagnosis
Clinical Manifestations
The major clinical signs of noncardiogenic pulmonary edema overlap those of cardiogenic pulmonary edema [see Table 1 and Approach to the Patient with Suspected Pulmonary Edema, above]. In noncardiogenic pulmonary edema, however, there is often less sympathetic activity19; cyanosis, if present, is often caused by arterial hypoxemia. The skin may be warm (rather than cool, moist, and pallid), and the pulse may be racing.
Imaging Studies
Typically, portable anteroposterior chest radiography reveals a diffuse and homogeneous alveolar filling process.20 When examined by computed tomography, however, the air-space filling pattern frequently appears less homogeneous. Radiographs with the patient in the supine position typically show a greater degree of consolidation in posterior lung zones than in anterior lung zones; this distribution, however, may be reversed by placing the patient in the prone position for a few hours. With the patient in the prone position, the anterior regions become more consolidated, because of the influence of gravity, and the posterior portions of the lung show improved aeration. This finding demonstrates the contribution of Starling forces (i.e., capillary pressure) to the severity of edema in the setting of increased permeability.
