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Literature review current through: Oct 2022. | This topic last updated: Jun 14, 2022.
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 [1,2]. (See "Pathophysiology of
cardiogenic pulmonary edema" and "Approach to diagnosis and evaluation of acute
decompensated heart failure in adults".)
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:
where:
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.
The major causes of noncardiogenic pulmonary edema are the acute respiratory distress
syndrome (ARDS) [2] and, less often, high altitude and neurogenic pulmonary edema. Other
less common causes include pulmonary edema due to opioid overdose, pulmonary embolism,
eclampsia, transfusion-related acute lung injury and acute kidney injury (sometimes referred
to as “uremic lung”) [4]. Hypoalbuminemia alone is not a cause of pulmonary edema. (See
'Absence of pulmonary edema with hypoalbuminemia' below.)
Permeability pulmonary edema is the most prominent feature of acute respiratory distress
syndrome (ARDS) [6]. 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, diagnosis, and complications in adults".)
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 [7]. (See "Acute respiratory
distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults".)
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
[8-10]. Unilateral noncardiogenic pulmonary edema may be caused by conditions ipsilateral to
the edema such as aspiration, contusion, re-expansion, and pulmonary vein occlusion (eg,
veno-occlusive disease or extrinsic compression) and by conditions contralateral to the edema
such as pulmonary embolism and lobectomy [8]. These lesions should be distinguished from
On the other hand, an elevated pulmonary artery 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 [7], and the percentages are much higher in
patients with ARDS secondary to sepsis [13]. 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 [14]. 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.
Clinical prediction tools have been developed to distinguish acute lung injury from cardiogenic
pulmonary edema [19]. These may provide a guide to expediting initial therapy, but require
further prospective evaluation. A number of novel biomarkers have also been proposed to aid
in this distinction [20].
Other lung diseases — Two pulmonary disorders are sometimes confused with ARDS:
diffuse alveolar hemorrhage and cancer.
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 hemorrhage syndromes".)
● 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 [21], but lymphangitic spread of solid tumors, acute toxicity from
chemotherapy (eg, mitomycin [also known as Mitomycin-C], methotrexate), and cancer-
associated DIC occasionally behave in a similar fashion [22]. Newer cancer treatments,
including immune checkpoint inhibitors, have also been associated with pneumonitis
[23]. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
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 [24]. Patients with severe ARDS may require
extracorporeal membrane oxygenation in addition to supportive medical therapies [25]. (See
"Ventilator management strategies for adults with acute respiratory distress syndrome" and
"Acute respiratory distress syndrome: Supportive care and oxygenation in adults" and
"Evaluation and management of suspected sepsis and septic shock in adults".)
Lowering the pulmonary artery wedge pressure with diuretics and fluid restriction can
improve pulmonary function and perhaps outcome [26,27]. One study, for example, analyzed
survival and length of stay in the intensive care unit for 40 patients with ARDS [26]. 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 [28]. (See
"Predictive scoring systems in the intensive care unit".)
A number of pharmacologic therapies for ARDS have been evaluated [29]. These include
inhaled vasodilators (nitric oxide, prostacyclin), anti-inflammatory therapies (glucocorticoids,
statins [30], prostaglandin E1), antioxidants (dietary oil supplementation), and exogenous
surfactant. Novel mechanical ventilation strategies, including high-frequency ventilation, liquid
ventilation, and prone positioning [31], as well as preventive strategies (eg, aspirin) [32] have
also been investigated. At present, NONE has shown consistent and unequivocal clinical
benefit [33]. Preclinical and early clinical data suggest that human mesenchymal stem cells may
attenuate lung injury and promote tissue repair in ARDS. (See "Acute respiratory distress
syndrome: Investigational or ineffective therapies in adults".)
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 [34]. 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 [35]. The enhanced
survival is probably related to a variety of improvements in supportive care. Despite these
encouraging data, ARDS remains a world-wide problem with high mortality that is both under
recognized and undertreated [36].
Most deaths are due to the severity of the underlying disease, particularly multiorgan failure,
rather than the respiratory disease. While early deaths are typically due to the underlying
cause of the ARDS, later deaths often result from nosocomial pneumonia and sepsis. Long-
term survivors of ARDS typically show only mild abnormalities in pulmonary function and are
usually asymptomatic, although long-term physical, cognitive, and psychological sequelae have
been described [37,38]. (See "Acute respiratory distress syndrome: Prognosis and outcomes in
adults".)
Other more unusual types of noncardiogenic pulmonary edema, often with unclear
pathophysiology, have been described.
RPE appears to be related to the rapidity of lung re-expansion and to the severity and duration
of lung collapse. However, a study examining development of re-expansion 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 H2O does not
develop [53].
Patients typically present soon (minutes to hours) after the inciting event, although
presentation can be delayed for up to 24 to 48 hours in some cases. The clinical course varies
from isolated radiographic changes to complete cardiopulmonary collapse but most patients
present with acute onset dyspnea, cough and hypoxemia. Typical CT findings include ipsilateral
ground-glass opacities, septal thickening, focal consolidation, and areas of atelectasis [55].
A mortality rate as high as 20 percent has been described in one small review [56]; however
consistent with our experience, the mortality is much lower with later and larger series
reporting a mortality rate less than 5 percent [52,53,57].
Opioid overdose — First described by Osler in 1880 [58], pulmonary edema can sometimes
complicate an overdose of heroin or methadone [59]; other related agents, including fentanyl
and naloxone, have also been implicated [60]. Risk factors include male sex 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.
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 edema [80]. In patients with acute heart failure, hypoalbuminemia has also been
associated with pleural effusions [81], and is an independent predictor of in-hospital and post-
discharge mortality [82]. In a study of more than 7000 patients with acute coronary syndrome,
serum albumin level ≤3.50 g/dL was an independent predictor of new-onset heart failure and
in-hospital mortality [83].
SUMMARY
● Pathogenesis – 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
● Etiologies
• Less common causes are high altitude and neurogenic pulmonary edema. (See 'High
altitude pulmonary edema' above and 'Neurogenic pulmonary edema' above.)
• Other less common causes include pulmonary edema due to pulmonary embolism
and eclampsia, viral infections, pulmonary veno-occlusive disease, and transfusion-
related acute lung injury. (See 'Pulmonary embolism' above and 'Viral infections' above
and 'Pulmonary veno-occlusive disease' above and 'Transfusion-related acute lung
injury' above.)