1. Emerg Med Clin N Am
21 (2003) 385–393
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 differentiated into two categories—cardiogenic and
noncardiogenic. Both result from acute fluid 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 ultrafiltrate to cross the pul-
monary capillary membrane into the interstitium. In contrast, noncar-
diogenic pulmonary edema most often results from permeability changes
in the pulmonary capillary membrane itself. Understanding the differences
between cardiogenic and noncardiogenic pulmonary edema is essential for
effective therapeutic intervention to occur.
Definition
Noncardiogenic pulmonary edema also is called acute respiratory distress
syndrome (ARDS). It is characterized by diffuse alveolar damage, marked
increased permeability of the alveolar-capillary membrane, and accumula-
tion of protein-rich fluid in the alveolar air sacs. This entity first was
recognized and described by the military in relation to battlefield casualties
in World War I and World War II. Increased understanding of the patho-
physiology that produces this clinical state led to universally accepted diag-
nostic 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.
Definitions have been established for the severe form, ARDS, and the milder
E-mail address: dgp3a@virginia.edu
0733-8627/03/$ - see front matter Ó 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0733-8627(03)00020-8

2. 386 D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393
form, acute lung injury (ALI) [1,2]. ARDS and ALI are acute in onset
with normal pulmonary arterial occlusion pressure and bilateral infiltrates
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 inflammatory mediators (Box 2). Indirect
mechanisms result from the overexpression of the normal inflammatory
response, resulting in an inflammatory 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

3. D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393 387
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 inflammatory 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 amplification 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, fluid flows from the capillary system to the
interstitial space and returns to the systemic circulation through the pul-
monary lymphatic system. When capillary fluid efflux 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 fluid accumulation in the alveolar air sacs.
This fluid accumulation ultimately results in the formation of hyaline mem-
branes that are derived from fibrin and other proteins. Oxygenation is
further hampered by decreased surfactant production secondary to cellular
damage. Ultimately, alveolar collapse results, producing decreased pulmo-
nary compliance, increased work of breathing, respiratory distress, and
eventually respiratory failure. The natural evolution of the disease process is
resolution of the neutrophilic inflammation and proliferation of other cells,
leading to either architectural restoration of lung tissue or the development
of interstitial fibrosis and chronic pulmonary dysfunction or death over days
to weeks.

4. 388 D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393
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 findings consistent with a cardio-
genic source, such as peripheral edema, jugular venous distention, and ven-
tricular gallop, are not present.
Chest radiograph initially is normal, with the development of diffuse
bilateral interstitial or alveolar infiltrates in a homogeneous pattern as
the disease process worsens. The heart shadow is normal sized, in sharp con-
trast 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 specific patterns identified exclusively with noncardiogenic pulmo-
nary edema. Pulmonary capillary wedge pressure measurements, which are
elevated in cardiogenic pulmonary edema, are generally normal or near-
normal 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 (non-
cardiogenic) from cardiogenic pulmonary edema. Patients with non-
cardiogenic 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 effects of systemic illnesses. The most common
indirect causes are severe sepsis and major multisystem trauma. Pulmonary
aspiration and diffuse 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.

5. D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393 389
Treatment
Treatment is largely supportive and aimed at ensuring adequate
ventilation and oxygenation. There are no specific treatments to correct
the underlying alveolar-capillary membrane permeability problems, or to
control the inflammatory cascade once triggered, beyond mechanical venti-
lator management and intensive care support.
Ventilatory management
For ALI, the less severe form of noncardiogenic pulmonary edema, non-
invasive 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 significant portion of alveoli are fluid filled 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 overinflation of normal lung structures.
Ventilatory strategies for severe noncardiogenic pulmonary edema focus
on limiting airway pressure to a maximum inflation 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 baro-
trauma 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 effects of breathing through a defined
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 patient’s arterial oxygen tension could not be
maintained at 60 mm Hg with an inspired oxygen concentration of 100%.
The beneficial effects of PEEP in improving oxygenation result from in-
creasing 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
flow are promising [10]. These devices allow for titration of PEEP against
the pulmonary blood flow, resulting in optimization of flow with the lowest
amount of PEEP possible and decreasing the degree of resultant barotrau-
mas while maintaining adequate ventilation and oxygenation. Combination
of PEEP with low tidal volumes seems to have the most beneficial outcomes.
Patients ventilated in this manner have an improved 28-day survival and
overall less mechanical ventilation time. This has been termed the ‘‘lung-
protective strategy’’ [11–13].
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 end-
expiratory 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 affect 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 benefit 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 perfluorocarbon, into the
trachea of intubated patients with severe noncardiogenic pulmonary edema
[17,18]. This technique has been successful in allowing oxygenation of in-
tubated patients with only routine mechanical ventilation techniques.
Circulating volume management
Optimizing fluid 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 fluid overload, elevation in circulating
blood volume and subsequent intravascular pressure can result in worsening
of alveolar fluid 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 significant reductions in extracellular
alveolar edema, enhancing ventilatory function and oxygenation. Excessive

7. D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393 391
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 fluid 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 efficacious in the
treatment of noncardiogenic pulmonary edema. In theory, surfactant re-
placement should be useful because surfactant loss occurs secondary to
cellular damage [19]. Studies using aerosolized synthetic surfactant have
shown no significant effects on outcome, however. Synthetic surfactant
is deficient in essential associated proteins that may affect effectiveness.
Further studies are ongoing with modified preparations. Glucocorticoids in
high doses have been the mainstay of treatment in severe noncardiogenic
pulmonary edema secondary to their anti-inflammatory properties. They do
not seem beneficial, however, in the early phases on the disease.
Inhaled nitric oxide has a vasodilatory effect of the pulmonary vas-
culature. 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 signifi-
cant systemic hemodynamic effects. Inhaled nitric oxide seems to have a
transient improvement in oxygenation in ARDS patients, but long-term
effects 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

8. 392 D.G. Perina / Emerg Med Clin N Am 21 (2003) 385–393
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 ab-
normalities in pulmonary function, with more than 50% having chronic
dysfunction that is most often a decline in diffusion capacity or restrictive
impairments. Long-term treatment is aimed at enhancing pulmonary func-
tion with bronchodilators and frequently some degree of home oxygen use.
Some improvement in lung function may occur in survivors but reach max-
imum 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 differentiated into two categories—cardiogenic 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 fluid
ventilation, are promising but are in the early stages of clinical testing.
Mortality rates remain high despite increasing intensive care unit care.
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