Transcript of "SDRA - Non-cardiogenic pulmonary edema - UpToDate 2013"
Noncardiogenic pulmonary edema
Michael M Givertz, MD
Stephen S Gottlieb, MD
Susan B Yeon, MD, JD, FACC
All topics are updated as new evidence becomes available and our peer review process is
Literature review current through: Jun 2013. | This topic last updated: abr 22, 2013.
INTRODUCTION — Pulmonary edema is due to the movement of excess fluid into the alveoli as a
result of an alteration in one or more of Starling's forces. In cardiogenic pulmonary edema, a high
pulmonary capillary pressure (as estimated clinically from the pulmonary artery wedge pressure) is
responsible for the abnormal fluid movement . (See "Pathophysiology of cardiogenic pulmonary
edema" and "Evaluation of acute decompensated heart failure".)
In contrast, noncardiogenic pulmonary edema is caused by various disorders in which factors other
than elevated pulmonary capillary pressure are responsible for protein and fluid accumulation in the
alveoli . The distinction between cardiogenic and noncardiogenic causes is not always possible,
since the clinical syndrome may represent a combination of several different disorders. The
diagnosis is important, however, because treatment varies considerably depending upon the
underlying pathophysiologic mechanisms.
THE STARLING RELATIONSHIP — Fluid balance between the interstitium and vascular bed in the
lung, as in other microcirculations, is determined by the Starling relationship, which predicts the net
flow of liquid across a membrane. This can be expressed in the following equation:
Net filtration = (Lp x S) x (Δhydraulic pressure - Δoncotic pressure)
= (Lp x S) x [(Pcap - Pif) - s(πcap - πif)]
Lp is the unit permeability (or porosity) of the capillary wall
S is the surface area available for fluid movement
Pcap and Pif are the capillary and interstitial fluid hydraulic pressures
πcap and πif are the capillary and interstitial fluid oncotic pressures; the interstitial oncotic
pressure is derived primarily from filtered plasma proteins and to a lesser degree from
proteoglycans in the interstitium.
s represents the reflection coefficient of proteins across the capillary wall (with values
ranging from 0 if completely permeable to 1 if completely impermeable).
In normal microvessels, there is ongoing filtration of a small amount of low protein liquid. In
noncardiogenic pulmonary edema, the most common mechanism for a rise in transcapillary filtration
is an increase in capillary permeability. At a given increase in capillary permeability, the rate of
accumulation of lung liquid is related in part to the functional capacity of the lymphatic vessels to
remove the excess fluid.
Definition of noncardiogenic pulmonary edema — Noncardiogenic pulmonary edema is
identified clinically by the presence of radiographic evidence of alveolar fluid accumulation without
hemodynamic evidence to suggest a cardiogenic etiology (ie, pulmonary artery wedge pressure ≤18
mmHg). The accumulation of fluid and protein in the alveolar space leads to decreased diffusing
capacity, hypoxemia, and shortness of breath.
The major causes of noncardiogenic pulmonary edema are the acute respiratory distress syndrome
(ARDS) and, less often, high altitude and neurogenic pulmonary edema. Other less common
causes include pulmonary edema due to narcotic overdose, pulmonary embolism, and eclampsia,
and transfusion-related acute lung injury . Hypoalbuminemia alone is not a cause of pulmonary
edema (see 'Absence of pulmonary edema with hypoalbuminemia' below).
PERMEABILITY PULMONARY EDEMA DUE TO ARDS — The alveolar-capillary membrane
becomes damaged and leaky in cases of permeability pulmonary edema, allowing increased
movement of water and proteins from the intravascular space to the interstitial space. In most
patients, the concentration of protein in the interstitium exceeds 60 percent of the plasma value,
compared to less than 45 percent in cardiogenic pulmonary edema .
Permeability pulmonary edema is the most prominent feature of acute respiratory distress
syndrome (ARDS) . In the past, many authors equated the clinical disorder ARDS with the
pathological entity of permeability pulmonary edema. However, these two terms should NOT be
used interchangeably. Although some degree of permeability edema is invariably present at the
onset of ARDS, other important structural abnormalities of the lung typically emerge as ARDS
evolves. Furthermore, many episodes of permeability pulmonary edema never result in the severe
physiological impairment that is required for the designation ARDS. (See "Acute respiratory distress
syndrome: Clinical features and diagnosis".)
ARDS can be seen in a number of disorders, including sepsis, acute pulmonary infection, non-
thoracic trauma, inhaled toxins, disseminated intravascular coagulation, shock lung, freebase
cocaine smoking, postcoronary artery bypass grafting (especially in patients on amiodarone),
inhalation of high oxygen concentrations, and acute radiation pneumonitis. Regardless of etiology,
the clinical scenario is similar in most patients once membrane damage has occurred. Sepsis- or
ischemia-induced release of cytokines, such as interleukin-1, interleukin-8, and tumor necrosis
factor, may play an important role in the increase in pulmonary capillary permeability, at least in part
via the recruitment of neutrophils . (See "Acute respiratory distress syndrome: Epidemiology;
pathophysiology; pathology; and etiology".)
Presentation and diagnosis — Patients with ARDS present with severe respiratory distress
(dyspnea) in association with the acute appearance of diffuse chest radiographic infiltrates and
hypoxemia. The onset of ARDS is often within the first two hours after an inciting event, although
this can be delayed as long as one to three days. Chest radiographs usually progress to a bilateral
alveolar filling pattern. The diagnosis of permeability pulmonary edema requires distinction from
cardiogenic pulmonary edema and from other causes of lung disease or injury.
Patients with noncardiogenic (or cardiogenic) pulmonary edema rarely have unilateral edema [6-8].
Unilateral noncardiogenic pulmonary edema may be caused by conditions ipsilateral to the edema
such as aspiration, contusion, reexpansion, and pulmonary vein occlusion (eg, veno-occlusive
disease or extrinsic compression) and by conditions contralateral to the edema such as pulmonary
embolism and lobectomy . These lesions should be distinguished from unilateral cardiogenic
pulmonary edema, which is chiefly caused by eccentric mitral regurgitation .
Distinction from HF — Clinically and radiographically, ARDS closely resembles severe
cardiogenic pulmonary edema. The distinction between these disorders is often apparent from the
clinical circumstances at the onset of respiratory distress. As examples, pulmonary edema
occurring in the setting of an acute coronary syndrome is almost always cardiogenic, while that
occurring in the setting of sepsis strongly suggests a noncardiac etiology. Pulmonary edema
occurring in the setting of multiple transfusions could be due to a combination of cardiogenic
pulmonary edema (eg, due to volume) and acute lung injury. (See "Clinical manifestations and
diagnosis of cardiogenic shock in acute myocardial infarction" and "Evaluation of acute
decompensated heart failure".)
Pulmonary artery catheter — A pulmonary artery (or Swan-Ganz) catheter should be placed
if the mechanism of edema formation cannot be discerned with confidence. A pulmonary
artery wedge pressure less than 18 mmHg favors acute lung injury over cardiogenic
pulmonary edema. (See "Pulmonary artery catheterization: Indications and complications".)
It is important to appreciate that pulmonary artery catheterization can be misleading in certain
settings. Most important, myocardial ischemia can cause severe but transient left ventricular
dysfunction, leading to "flash" pulmonary edema. If the wedge pressure is first measured after the
ischemia has resolved (and left ventricular function has improved), a relatively normal value may be
obtained, leading to the erroneous conclusion that the respiratory distress was caused by acute
lung injury. (See "Evaluation of acute decompensated heart failure".)
On the other hand, an elevated wedge pressure does not exclude the possibility of acute lung
injury. It is estimated that as many as 20 percent of patients with ARDS have concomitant left
ventricular dysfunction , and the percentages are much higher in patients with ARDS secondary
to sepsis . Right ventricular dilation is also commonly present in ARDS, while right ventricular
dysfunction may be present in the most severe cases and predict worse outcomes . The
diagnosis of acute lung injury cannot be made easily when the wedge pressure is elevated; thus,
the clinical course must be observed as the wedge pressure responds to treatment. If pulmonary
infiltrates and hypoxemia do not improve appreciably within 24 to 48 hours after fluid restriction
(with or without diuresis) and normalization of the wedge pressure, then acute lung injury probably
coexists with cardiogenic edema.
Plasma BNP — Measurement of plasma B-type natriuretic peptide (BNP), or N-terminal
pro-BNP, has been used to distinguish heart failure (high BNP) from lung disease (normal
or mildly elevated BNP) as a cause of dyspnea with a high degree of accuracy even in
patients with both lung and heart disease . However, intermediate values are often not
helpful. The role of these biomarkers in the diagnosis of pulmonary edema has been less
well studied. Data in the ICU setting suggested limited ability to discriminate ARDS from
cardiogenic pulmonary edema . (See "Evaluation of acute decompensated heart
Other lung diseases — Two pulmonary disorders are sometimes confused with ARDS: diffuse
alveolar hemorrhage and cancer.
Diffuse alveolar hemorrhage, often due to a pulmonary capillaritis or diffuse alveolar
damage, should be considered whenever respiratory distress develops in association with a
large, otherwise unexplained drop in the blood hemoglobin concentration. Hemoptysis may
be minimal or absent prior to intubation; however, bronchoscopy after intubation invariably
reveals bloody secretions throughout the airways during active hemorrhage.
Bland alveolar hemorrhage, which is characterized by hemorrhage into the alveolar spaces without
inflammation or destruction of the alveolar structures, may be caused by elevated LV end diastolic
pressure, coagulopathy, and rarely anticoagulant or antiplatelet therapy. (See "The diffuse alveolar
Cancer sometimes disseminates throughout the lungs so rapidly that the ensuing
respiratory failure may be mistaken for ARDS. This is most often due to lymphoma or acute
leukemia, but lymphangitic spread of solid tumors, acute toxicity from chemotherapy (eg,
mitomycin-C, methotrexate) and cancer-associated DIC occasionally behaves in a similar
Treatment — There are currently no known measures to correct the permeability abnormality in
ARDS. Clinical management involves treatment of the underlying disease (eg, antibiotics for
infection) and supportive measures to maintain cellular and metabolic function, while waiting for the
acute lung injury to resolve. These supportive measures include mechanical ventilation,
maintenance of adequate nutrition, and hemodynamic monitoring when necessary to guide fluid
management and cardiovascular support . (See "Mechanical ventilation in acute respiratory
distress syndrome" and "Supportive care and oxygenation in acute respiratory distress
syndrome" and"Evaluation and management of severe sepsis and septic shock in adults".)
Lowering the pulmonary artery wedge pressure with diuretics and fluid restriction can improve
pulmonary function and perhaps outcome [15,16]. One study, for example, analyzed survival and
length of stay in the intensive care unit for 40 patients with ARDS . The patients were divided
into two groups: those with a reduction in pulmonary capillary wedge pressure (PCWP) of at least
25 percent; and those with less or no reduction in PCWP. Survival was greater in the patients with a
large fall in PCWP (75 versus 29 percent). This difference remained statistically significant after
stratifying patients by age and by the APACHE II severity of illness index. In a later study in which
1000 patients with acute lung injury were randomized to a conservative versus liberal fluid
management strategy, the conservative strategy improved oxygenation and shortened duration of
mechanical ventilation and ICU stay, but did not reduce the incidence of shock, use of dialysis or
mortality during the first 60 days . (See"Predictive scoring systems in the intensive care unit".)
A number of pharmacologic therapies for ARDS have been evaluated. These include inhaled
vasodilators (nitric oxide, prostacyclin), anti-inflammatory therapies (corticosteroids, prostaglandin
E1), antioxidants, and exogenous surfactant. Novel mechanical ventilation strategies, including
high-frequency ventilation and liquid ventilation, have also been investigated. At present, NONE has
shown consistent and unequivocal clinical benefit. (See "Novel therapies for the acute respiratory
Prognosis — The outcome of patients with ARDS has improved over time; hospital mortality was
approximately 60 percent in the years 1967 to 1981 and declined to 30 to 40 percent in the 1990s.
As an example of this trend, one study evaluated 918 patients with ARDS at a single institution
between 1983 and 1993 . The mortality from sepsis-related ARDS declined from 67 percent in
1990 to 40 percent in 1993; the improvement was largely confined to patients under age 60. In a
systematic analysis of ARDS studies published between 1994 and 2006, a decline in overall
mortality rates of 1.1 percent per year was demonstrated . The enhanced survival is probably
related to a variety of improvements in supportive care.
Most deaths are due to the severity of the underlying disease, particularly multiorgan failure, rather
than the respiratory disease. Long-term survivors of ARDS typically show only mild abnormalities in
pulmonary function and are usually asymptomatic. (See "Acute respiratory distress syndrome:
Prognosis and outcomes".)
OTHER NONCARDIOGENIC FORMS OF PULMONARY EDEMA — Other more unusual types of
noncardiogenic pulmonary edema, often with unclear pathophysiology, have been described.
High altitude pulmonary edema — High-altitude pulmonary edema (HAPE), which generally
occurs among individuals who rapidly ascend to altitudes above 12,000 to 13,000 feet (3600 to
3900 m), accounts for a majority of deaths due to high altitude disease [20,21]. An abnormally
pronounced degree of hypoxic pulmonary vasoconstriction at a given altitude appears to underlie
the pathogenesis of this disorder. (See "High altitude illness: Physiology, risk factors, and general
Neurogenic pulmonary edema — Neurogenic pulmonary edema occurs after a variety of
neurologic disorders and procedures, including head injury, intracranial surgery, grand mal
seizures, subarachnoid or intracerebral hemorrhage, and electroconvulsive therapy . It is
believed that sympathetic overreactivity with massive catecholamine surges shifts blood from the
systemic to the pulmonary circulation with secondary elevations of left atrial and pulmonary capillary
pressures. Pulmonary capillary leak caused by pressure-induced mechanical injury and/or direct
nervous system control over capillary permeability may play a contributory role. The clinical
presentation is characterized by acute hypoxemia, tachypnea, tachycardia, diffuse rales, and large
amounts of frothy sputum or hemoptysis. Symptom onset tends to be rapid (ie, within 4 hours of the
neurological event), and the majority of cases resolve within 48 to 72 hours. The outcome is
determined by the course of the primary neurologic insult. (See"Neurogenic pulmonary edema".)
Reperfusion pulmonary edema — Reperfusion pulmonary edema appears to represent a form of
high-permeability lung injury that is limited to those areas of lung from which proximal
thromboembolic obstructions have been removed. It may appear up to 72 hours after surgery and is
highly variable in severity, ranging from a mild form of edema resulting in postoperative hypoxemia
to an acute, hemorrhagic and fatal complication. At experienced centers, venovenous
extracorporeal life support has been used as a therapeutic option when all other conventional
strategies have failed . (See "Chronic thromboembolic pulmonary hypertension: Surgical
Reexpansion pulmonary edema — Reexpansion pulmonary edema usually occurs unilaterally
after rapid reexpansion of a collapsed lung in patients with a pneumothorax ; it may rarely follow
evacuation of large volumes of pleural fluid (>1.0 to 1.5 liters) or removal of an obstructing
endobronchial tumor. The pathophysiologic mechanism is unknown.
The incidence of reexpansion pulmonary edema appears to be related to the rapidity of lung
reexpansion and to the severity and duration of lung collapse. However, a study examining
development of reexpansion pulmonary edema following thoracentesis found that it was
independent of the volume of fluid removed and pleural pressures, and recommended that even
large pleural effusions be drained completely as long as chest pain or end-expiratory pleural
pressure less than -20 cm H20 does not develop .
Patients typically present soon after the inciting event, although presentation can be delayed for up
to 24 hours in some cases. The clinical course varies from isolated radiographic changes to
complete cardiopulmonary collapse.
A mortality rate as high as 20 percent has been described . Treatment is supportive, mainly
consisting of supplemental oxygen and, if necessary, mechanical ventilation. The disease is usually
Opiate overdose — First described by Osler in 1880 , pulmonary edema can sometimes
complicate an overdose of heroin or methadone ; risk factors include male gender and shorter
duration of heroin use. Most cases occur immediately or within hours of drug injection. The chest
radiograph usually demonstrates a nonuniform distribution of pulmonary edema.
The pathophysiology of this form of pulmonary edema is unknown; a combination of direct toxicity of
the drug, hypoxia, and acidosis secondary to hypoventilation and/orcerebral edema has been
proposed. The observation that edema fluid contains protein concentrations nearly identical to
plasma and that pulmonary artery wedge pressures, when measured, are normal suggests an
alveolar-capillary membrane leak as the initiating cause. Resolution of this form of pulmonary
edema is rapid once hypoventilation and hypoxia are reversed by the institution of assisted
ventilation. In one case series, 9 of 27 patients (33 percent) required mechanical ventilation; all but
one were extubated within 24 hour . Supportive care also includes use of naloxone to reverse
the opioid effects.
Salicylate toxicity — Aspirin is one of many drugs occasionally associated with the development of
noncardiogenic pulmonary edema. Salicylate-induced noncardiogenic pulmonary edema and acute
lung injury (ALI) generally occur in older patients with chronic salicylate intoxication [30,31], but
should be considered in all patients following aspirin overdose. Salicylate-induced ALI and
pulmonary edema can complicate volume resuscitation and administration of sodium bicarbonate,
two mainstays of treatment in this setting. Thus, the presence of salicylate-induced pulmonary
edema is considered an absolute indication for hemodialysis. (See "Salicylate (aspirin) poisoning in
Pulmonary embolism — Acute pulmonary edema in association with a massive pulmonary
embolus (PE) or multiple smaller emboli is well described . PE can cause pulmonary edema by
injuring the pulmonary and adjacent pleural systemic circulations, elevating hydrostatic pressures in
pulmonary and/or systemic veins, and perhaps by lowering pleural pressure due to atelectasis. PE
may also decrease the exit rates of pleural fluid by increasing the systemic venous pressure
(thereby hindering lymphatic drainage) or possibly by decreasing pleural pressure (thereby
hindering lymphatic filling). The effusions are typically small and unilateral, and may become
loculated if the diagnosis is delayed . Older studies showed that 20 percent of PE-related
effusions are transudates, suggesting that hydrostatic changes can also be important .
However, in a later case series, 26 of 93 patients with effusions following PE underwent
thoracentesis and all of the fluids met Light's criteria for exudate (see "Diagnostic evaluation of a
pleural effusion in adults: Initial testing"), suggesting a primary role for vascular injury .
Viral infections — Rapidly progressive noncardiogenic pulmonary edema associated with profound
hypotension and a high case fatality rate has been described with hantavirus infection
(see "Hantavirus cardiopulmonary syndrome")  and with dengue
hemorrhagic fever/dengue shock syndrome (see "Clinical presentation and diagnosis of dengue
virus infections"). Enteroviral 71 infection in young children  and coronavirus infection in adults
 are other causes of viral-induced noncardiogenic pulmonary edema and hemorrhage
(see "Severe acute respiratory syndrome (SARS)"). The strain of H1N1 influenza A that caused the
2009-2010 pandemic caused severe ARDS in some patients. (See "Clinical manifestations and
diagnosis of pandemic H1N1 influenza ('swine influenza')", section on 'Respiratory'.)
Pulmonary veno-occlusive disease — Pulmonary veno-occlusive disease is a cause of
pulmonary hypertension and noncardiogenic pulmonary edema. This condition is discussed in detail
separately (see "Pulmonary veno-occlusive disease").
ABSENCE OF PULMONARY EDEMA WITH HYPOALBUMINEMIA — Although hypoalbuminemia
can lead to peripheral edema by lowering the transcapillary oncotic pressure gradient, it does not
generally produce pulmonary edema. The pulmonary capillaries appear to have a greater baseline
permeability to albumin and therefore have a higher interstitial oncotic pressure (about 18 mmHg)
than do peripheral capillaries . A fall in the plasma albumin concentration is associated with a
parallel decline in the pulmonary interstitial oncotic pressure. The net effect is little or no change in
the transcapillary oncotic pressure gradient and therefore no pulmonary edema, unless there is a
concurrent rise in left atrial and pulmonary capillary pressures. (See "Pathophysiology and etiology
of edema in adults", section on 'Compensatory factors'.)
In older patients with heart failure with preserved ejection fraction, hypoalbuminemia due to age,
malnutrition, or sepsis may lower colloid osmotic pressure and facilitate the onset of pulmonary
Noncardiogenic pulmonary edema is caused by various disorders in which factors other
than elevated pulmonary capillary pressure are responsible for protein and fluid
accumulation in the alveoli. In contrast, a high pulmonary capillary pressure is responsible
for the abnormal fluid movement in cardiogenic pulmonary edema. Noncardiogenic
pulmonary edema may be difficult to distinguish from cardiogenic pulmonary edema and a
mixed picture can occur. (See 'Introduction' above.)
Fluid balance between the interstitium and vascular bed in the lung, as in other
microcirculations, is determined by the Starling relationship, which predicts the net flow of
liquid across a membrane. In noncardiogenic pulmonary edema, the most common
mechanism for a rise in transcapillary filtration is an increase in capillary permeability.
(See 'The Starling relationship' above.)
Noncardiogenic pulmonary edema is identified clinically by the presence of radiographic
evidence of alveolar fluid accumulation without hemodynamic evidence to suggest a
cardiogenic etiology (ie, pulmonary artery wedge pressure ≤18 mmHg). (See 'Definition of
noncardiogenic pulmonary edema' above.)
The major causes of noncardiogenic pulmonary edema are the acute respiratory distress
syndrome (ARDS) and, less often, high altitude and neurogenic pulmonary edema. Other
less common causes include pulmonary edema due to narcotic overdose, pulmonary
embolism, and eclampsia, and transfusion-related acute lung injury. (See 'Permeability
pulmonary edema due to ARDS' above and 'Other noncardiogenic forms of pulmonary
Hypoalbuminemia alone is not a cause of pulmonary edema. (See 'Absence of pulmonary
edema with hypoalbuminemia' above.)
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