Emerg Med Clin N Am 21 (2003) 385393

Noncardiogenic pulmonary edema

Debra G. Perina, MD
Department of Emergency Medicine, University of Virginia Health Systems, PO Box 800699, Charlottesville, VA 22908, USA

Pulmonary edema is dierentiated into two categoriescardiogenic and noncardiogenic. Both result from acute uid accumulation in the alveoli, with resultant varying degrees of oxygen desaturation and respiratory distress. Cardiogenic shock primarily results from increased pulmonary hydrostatic pressure, which causes plasma ultraltrate to cross the pulmonary capillary membrane into the interstitium. In contrast, noncardiogenic pulmonary edema most often results from permeability changes in the pulmonary capillary membrane itself. Understanding the dierences between cardiogenic and noncardiogenic pulmonary edema is essential for eective therapeutic intervention to occur.

Denition Noncardiogenic pulmonary edema also is called acute respiratory distress syndrome (ARDS). It is characterized by diuse alveolar damage, marked increased permeability of the alveolar-capillary membrane, and accumulation of protein-rich uid in the alveolar air sacs. This entity rst was recognized and described by the military in relation to battleeld casualties in World War I and World War II. Increased understanding of the pathophysiology that produces this clinical state led to universally accepted diagnostic criteria. Noncardiogenic pulmonary edema is thought to represent a wide spectrum of lung injury with progressive respiratory distress and increasing hypoxemia refractory to oxygen therapy. This is believed to be secondary to parenchymal cellular damage which is characterized by endothelial cell destruction, deposition of platelet and leukocyte aggregates, destruction of type I pneumocytes, and hyperplasia of type II pneumocytes. Denitions have been established for the severe form, ARDS, and the milder

E-mail address: dgp3a@virginia.edu 0733-8627/03/$ - see front matter 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0733-8627(03)00020-8

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form, acute lung injury (ALI) [1,2]. ARDS and ALI are acute in onset with normal pulmonary arterial occlusion pressure and bilateral inltrates on chest radiograph. They are differentiated by degrees of oxygen desaturation, with ALI having a PaO2-to-fraction of inspired oxygen ratio of less than or equal to 300 mm Hg while the same ratio is less than or equal to 200 mm Hg with ARDS. If promptly recognized, ALI is reversible in the early stages.

Pathophysiology The causes of noncardiogenic pulmonary edema are diverse and myriad. It can result from direct and indirect pathologic processes (Box 1). Some conditions injure the lung and alveolar epithelium directly, whereas others are systemic processes that produce damage through indirect mechanisms and hematogenous delivery of inammatory mediators (Box 2). Indirect mechanisms result from the overexpression of the normal inammatory response, resulting in an inammatory cascade that can injury not only

Box 1. Etiologies of noncardiogenic pulmonary edema Direct injury Aspiration Inhalation injuries Near drowning Pulmonary contusion Diffuse pulmonary infection Indirect injury Systemic sepsis and septic shock Blood products transfusion reaction High altitude effects Drug overdose Neurogenic insults Pancreatitis Cardiopulmonary bypass Severe non-thoracic trauma Fat emboli Uremia Coagulopathies Disseminated intravascular coagulation Post-cardiopulmonary bypass

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Box 2. Common drugs and inhaled toxins associated with noncardiogenic pulmonary edema Drug overdose Heroin Methadone Aspirin Propoxyphene Ethchlorvynol Inhaled toxins Smoke Ammonia Chlorine Nitrous oxide Phosgene

the lung, but also other body organs, causing multiple organ dysfunction syndrome. This inammatory response has been described to occur classically in three phases: (1) the initiation phase, which includes the precipitating event causing a variety of mediators and cytokines to be released; (2) the amplication phase, in which neutrophils are activated and become sequestered in the target organ (in this case the lung); and (3) the injury phase, in which the sequestered cells release reactive oxygen metabolites causing cellular damage [3]. Under normal conditions, uid ows from the capillary system to the interstitial space and returns to the systemic circulation through the pulmonary lymphatic system. When capillary uid eux into the interstitial space exceeds the lymphatic absorption, pulmonary edema occurs. With cardiogenic pulmonary edema, this is due to increased capillary hydrostatic pressure. In contrast, the major pathophysiologic abnormality causing noncardiogenic pulmonary edema is increased vascular permeability to proteins, resulting in protein-rich uid accumulation in the alveolar air sacs. This uid accumulation ultimately results in the formation of hyaline membranes that are derived from brin and other proteins. Oxygenation is further hampered by decreased surfactant production secondary to cellular damage. Ultimately, alveolar collapse results, producing decreased pulmonary compliance, increased work of breathing, respiratory distress, and eventually respiratory failure. The natural evolution of the disease process is resolution of the neutrophilic inammation and proliferation of other cells, leading to either architectural restoration of lung tissue or the development of interstitial brosis and chronic pulmonary dysfunction or death over days to weeks.

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Clinical presentation Noncardiogenic pulmonary edema presents with varying degrees of respiratory distress that may progress rapidly to respiratory failure. A moderate-to-severe degree of decreased oxygen saturation is evident on pulse oximetry and arterial blood gas measurement. The earliest clinical sign is increased work of breathing evidenced by tachypnea and dyspnea. Rales are evident on lung auscultation and are indistinguishable from those heard in cardiogenic pulmonary edema. Other ndings consistent with a cardiogenic source, such as peripheral edema, jugular venous distention, and ventricular gallop, are not present. Chest radiograph initially is normal, with the development of diuse bilateral interstitial or alveolar inltrates in a homogeneous pattern as the disease process worsens. The heart shadow is normal sized, in sharp contrast to the cardiomegaly usually viewed in chest radiographs of patients with cardiogenic pulmonary edema. General laboratory values represent abnormalities associated with the underlying disease process, and there are no specic patterns identied exclusively with noncardiogenic pulmonary edema. Pulmonary capillary wedge pressure measurements, which are elevated in cardiogenic pulmonary edema, are generally normal or nearnormal in noncardiogenic pulmonary edema. Studies have suggested possible laboratory tests that may be of some value, but ongoing research is needed to prove clinical usefulness. In one study, Arif and colleagues [4] suggested that serum protein levels may be useful for differentiating permeability-induced pulmonary edema (noncardiogenic) from cardiogenic pulmonary edema. Patients with noncardiogenic pulmonary edema seemed to have hypoproteinemia that was reversible during recovery, suggesting that hypoproteinemia may be a marker for acute noncardiogenic pulmonary edema. Another potential laboratory marker is raised interleukin-8 level in lung lavage washings. Interleukin-8 production is stimulated by hypoxia and has been noted to increase rapidly in the early stages of ALI before full development of ARDS [5]. As stated previously, noncardiogenic pulmonary edema results from direct injury and indirect eects of systemic illnesses. The most common indirect causes are severe sepsis and major multisystem trauma. Pulmonary aspiration and diuse pulmonary infections are the most common direct causes. In general, 40% of patients with one of these diagnoses develop ARDS [3]. The risk of development of ARDS increases incrementally with more than one at-risk condition. In addition, a history of chronic alcohol dependency results in an increased risk of development of noncardiogenic pulmonary edema when associated with other at-risk disease processes. Noncardiogenic pulmonary edema commonly develops within 24 hours of onset of the initial insult or disease process, but presentation may be delayed 5 days.

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Treatment Treatment is largely supportive and aimed at ensuring adequate ventilation and oxygenation. There are no specic treatments to correct the underlying alveolar-capillary membrane permeability problems, or to control the inammatory cascade once triggered, beyond mechanical ventilator management and intensive care support. Ventilatory management For ALI, the less severe form of noncardiogenic pulmonary edema, noninvasive ventilation techniques can be employed successfully. Randomized studies have shown lower rates of endotracheal intubation, barotrauma, and reductions in mortality if these techniques are used early enough in the course of the disease [5,6]. When severe noncardiogenic pulmonary edema (ARDS) has developed, mechanical ventilation is necessary to achieve adequate ventilation and oxygenation. Because a signicant portion of alveoli are uid lled or collapsed, high airway pressures and positive end-expiratory pressure (PEEP) frequently are necessary. Much of the calculated tidal volume may be delivered to relatively few normal alveoli depending on the extent of lung involvement. The end result is increased risk for development of barotrauma complications, such as pneumothorax, pneumomediastinum, and primary alveolar damage from overination of normal lung structures. Ventilatory strategies for severe noncardiogenic pulmonary edema focus on limiting airway pressure to a maximum ination pressure of 35 cm H2O [7]. As mentioned previously, overall lung compliance is decreased and an adjustment downward is required from normal tidal volume. The end result is that minute ventilation is reduced from normal and a small degree of respiratory acidosis and hypercapnia is produced. This strategy has been termed permissive hypercapnia and is believed to limit the degree of barotrauma often seen in these patients, while maximizing ventilatory efforts [8,9]. PEEP is the most useful strategy in achieving successful oxygenation and ventilation of patients with severe ARDS. A certain amount of PEEP is physiologic secondary to the natural eects of breathing through a dened tubular structure and a mobile glottis. In general, physiologic PEEP is thought to be approximately 5 cm H2O. The indication for more than the physiologic amount of PEEP in a patient with noncardiogenic pulmonary edema would be if the patients arterial oxygen tension could not be maintained at 60 mm Hg with an inspired oxygen concentration of 100%. The benecial effects of PEEP in improving oxygenation result from increasing the mean alveolar pressure, facilitating opening of collapsed alveoli, and preventing further damage by reducing the repetitive opening and closing of the alveoli in a normal respiratory cycle. Complications of higher

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PEEP levels include cardiac output decline secondary to decreased venous return to the atria from positive pressure in the chest cavity and varying degrees of barotrauma. New noninvasive devices that measure nonshunted pulmonary blood ow are promising [10]. These devices allow for titration of PEEP against the pulmonary blood ow, resulting in optimization of ow with the lowest amount of PEEP possible and decreasing the degree of resultant barotraumas while maintaining adequate ventilation and oxygenation. Combination of PEEP with low tidal volumes seems to have the most benecial outcomes. Patients ventilated in this manner have an improved 28-day survival and overall less mechanical ventilation time. This has been termed the lungprotective strategy [1113]. The relatively new technique of high-frequency oscillatory ventilation seems to hold promise for maximizing gas exchange while minimizing lung injury secondary to barotrauma [14,15]. This type of ventilatory support simultaneously avoids end-inspiratory alveolar overdistention and endexpiratory alveolar collapse. Further studies of this ventilation mode are ongoing, and it is not employed routinely in practice at present. Body position also seems to aect ventilation in these patients. Mechanically ventilated patients placed in a prone position have been shown to have improvements in ventilation-perfusion mismatches [15,16]. Changing the inspiratory-to-expiratory ratio from the normal 1:3 timing to one in which the ratio is closer to 1:1 has been shown to maintain higher constant airway pressures which enhances oxygenation. This has been termed inverse ratio ventilation. A further benet of this ventilatory strategy is that peak airway pressures necessary for adequate ventilation are reduced decreasing the risk for barotrauma. Other experimental ventilation methods include administration of liquids that carry a large quantity of oxygen, such as peruorocarbon, into the trachea of intubated patients with severe noncardiogenic pulmonary edema [17,18]. This technique has been successful in allowing oxygenation of intubated patients with only routine mechanical ventilation techniques. Circulating volume management Optimizing uid balance in patients with noncardiogenic pulmonary edema is important to maximize patient outcomes, but in many ways is a balancing act to achieve proper hydrational status. Although the pulmonary edema is not due to uid overload, elevation in circulating blood volume and subsequent intravascular pressure can result in worsening of alveolar uid collection and deoxygenation. Fluid restriction should occur, but not to the degree to produce hypotension or decrease perfusion to end organs. Judicious use of small amounts of diuretics can produce small reductions in intravascular volume but signicant reductions in extracellular alveolar edema, enhancing ventilatory function and oxygenation. Excessive

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or rapid diuresis may be harmful, especially if the patient is being ventilated with a large amount of PEEP, due to the depletion of intravascular volume and resultant cardiac output decline. Pulmonary arterial catheters have been employed to monitor pulmonary wedge pressures and cardiac output as a means of optimizing uid management, however, studies have suggested clinical decisions based on data from these catheters do not seem to improve outcomes. Pharmacologic management Few pharmacologic agents have been found to be ecacious in the treatment of noncardiogenic pulmonary edema. In theory, surfactant replacement should be useful because surfactant loss occurs secondary to cellular damage [19]. Studies using aerosolized synthetic surfactant have shown no signicant effects on outcome, however. Synthetic surfactant is decient in essential associated proteins that may affect effectiveness. Further studies are ongoing with modied preparations. Glucocorticoids in high doses have been the mainstay of treatment in severe noncardiogenic pulmonary edema secondary to their anti-inammatory properties. They do not seem benecial, however, in the early phases on the disease. Inhaled nitric oxide has a vasodilatory eect of the pulmonary vasculature. When used in noncardiogenic pulmonary edema, vasodilatation of pulmonary vasculature adjacent to well-ventilated alveoli can improve the overall ventilation-perfusion mismatch that occurs in severe cases. Nitric oxide is readily inactivated by hemoglobin, negating any signicant systemic hemodynamic eects. Inhaled nitric oxide seems to have a transient improvement in oxygenation in ARDS patients, but long-term eects on mortality are unknown.

Prognosis No single variable has been found to predict patient outcome. Even the degree of hypoxemia has not been valuable in this regard. Ongoing research measuring pulmonary dead space fraction (particularly when measured early in the course of the disease process) has been promising, with elevated values associated with an increased risk of death [20]. Mortality rates for severe noncardiogenic pulmonary edema have been reported to range from 50% to 70% in the past but now are declining with optimized treatment [21]. Patients at increased risk include patients greater than 70 years old [22], patients with associated dysfunction of other organ systems, patients with alcohol dependency, and patients with septic shock [23]. Of patients who die, cause of death varies with length of onset of illness to death. Traditionally, this time has been divided into patients who die within 72 hours of diagnosis and patients who survive longer than 72 hours. Most deaths before 72 hours can be attributed to the original insult that

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produced noncardiogenic pulmonary edema. After 72 hours, death is more often the result of secondary infection or sepsis, multiple systemic organ dysfunction, or persistent respiratory failure. Survivors frequently have abnormalities in pulmonary function, with more than 50% having chronic dysfunction that is most often a decline in diusion capacity or restrictive impairments. Long-term treatment is aimed at enhancing pulmonary function with bronchodilators and frequently some degree of home oxygen use. Some improvement in lung function may occur in survivors but reach maximum at 6 months postevent. The end result is often suboptimal, with a reduction in overall quality of life secondary to loss of pulmonary reserve for physical activity.

Summary Pulmonary edema is dierentiated into two categoriescardiogenic and noncardiogenic. Noncardiogenic pulmonary edema is due to changes in permeability of the pulmonary capillary membrane as a result of either a direct or an indirect pathologic process. It is a spectrum of illness ranging from the less severe form of ALI to the severe ARDS. The mainstay of treatment is mechanical ventilation with maximization of ventilation and oxygenation through the judicious use of PEEP. Newer ventilation techniques, such as high-frequency oscillatory ventilation and partial uid ventilation, are promising but are in the early stages of clinical testing. Mortality rates remain high despite increasing intensive care unit care.

References
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