Noncardiogenic pulmonary edema

Official reprint from UpToDate® www.uptodate.com

©2022 UpToDate®

Noncardiogenic pulmonary edema

Author: Michael M Givertz, MD
Section Editor: Stephen S Gottlieb, MD
Deputy Editor: Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2022. | This topic last updated: Jul 21, 2021.

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".)

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 [3]. 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 (delta hydraulic pressure - delta oncotic pressure)

- Page 1 of 19 -
Noncardiogenic pulmonary edema

= (Lp x S) x [(Pcap - Pif) - s(πcap - πif)]

where:

● 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) [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 DUE TO ARDS

- Page 2 of 19 -
Noncardiogenic pulmonary edema

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 [5].

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
- Page 3 of 19 -
Noncardiogenic pulmonary edema

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 unilateral cardiogenic pulmonary edema, which is chiefly
caused by eccentric mitral regurgitation [11] or following minimally invasive cardiac surgery
[12].

Distinction from heart failure — 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 "Approach to diagnosis and evaluation of acute decompensated heart failure
in adults".)

● 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,
contraindications, and complications in adults".)

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 "Approach to diagnosis and
evaluation of acute decompensated heart failure in adults".)

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
- Page 4 of 19 -
Noncardiogenic pulmonary edema

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.

● 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 [15]. 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 [16], as levels may increase with
the development [17]and severity [18] of ARDS. (See "Approach to diagnosis and
evaluation of acute decompensated heart failure in adults".)

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.

● 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 hemorrhage syndromes".)

● Cancer sometimes disseminates throughout the lungs so rapidly that the ensuing
- Page 5 of 19 -
Noncardiogenic pulmonary edema

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".)

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 [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

- Page 6 of 19 -
Noncardiogenic pulmonary edema

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 longterm physical, cognitive, and
psychological sequelae have been described [37,38]. (See "Acute respiratory distress
syndrome: Prognosis and outcomes in adults".)

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 [39,40].
An abnormally pronounced degree of hypoxic pulmonary vasoconstriction at a given
altitude appears to underlie the pathogenesis of this disorder [14]. (See "High altitude
- Page 7 of 19 -
Noncardiogenic pulmonary edema

illness: Physiology, risk factors, and general prevention" and "High-altitude pulmonary
edema".)

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 [41].
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 [42]. 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 frothy sputum or hemoptysis. Symptom onset tends to be
rapid and most cases resolve within 48 to 72 hours. The outcome is determined by the
course of the primary neurologic insult. It is important to distinguish neurogenic pulmonary
edema from cardiogenic pulmonary edema in the setting of stress cardiomyopathy. (See
"Neurogenic pulmonary edema" and "Clinical manifestations and diagnosis of stress
(takotsubo) cardiomyopathy".)

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 [43-45]. At
experienced centers, venovenous extracorporeal life support has been used as a bridge to
recovery or transplant when all other conventional strategies have failed [46,47] (see
"Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy"). A
similar condition may occur following lung transplantation due to ischemia-reperfusion
injury. (See "Primary lung graft dysfunction".)

Re-expansion pulmonary edema — Re-expansion pulmonary edema (RPE) usually occurs

unilaterally after rapid re-expansion of a collapsed lung (typically for greater than three
days) in patients with a pneumothorax [48], with rates ranging from 16 to 33 percent. Risk
factors include diabetes, size of pneumothorax, and presence of pleural effusion [49,50]. It
may rarely follow evacuation of large volumes of pleural fluid (>1 to 1.5 liters) (<1 percent)
[51-54] or removal of an obstructing endobronchial tumor.

The pathophysiologic mechanism is unknown. Proposed mechanisms include direct injury

- Page 8 of 19 -
Noncardiogenic pulmonary edema

from surfactant dysfunction in chronic atelectatic lung, increased transpleural pressures

when excessively negative pleural pressures are created during fluid or air removal in the
setting of an unexpandable lung, or indirect injury from reperfusion.

RPE 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
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].

Treatment is supportive, mainly consisting of supplemental oxygen and, if necessary,

mechanical ventilation. The disease is usually self-limited.

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.

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/or cerebral
edema has been proposed [61,62]. 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
- Page 9 of 19 -
Noncardiogenic pulmonary edema

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 hours [63].
Supportive care also includes use of naloxone to reverse the opioid effects. The alarming
increase in opioid use and dependency suggests that clinicians will see more cases of
pulmonary edema related to opioid overdose in the emergency room and intensive care unit
[64,65].

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 [66,67], but should be considered in all patients following aspirin
overdose. The medical history is critical to making the diagnosis, as misdiagnosis or delayed
diagnosis can lead to a significant increase in morbidity and mortality [67]. 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
[68]. (See "Salicylate (aspirin) poisoning in adults".)

Other exogenous agents — Several commonly-prescribed medications have been

associated with noncardiogenic pulmonary edema, including amiodarone, bortezomib, and
immunosuppressive agents (eg, sirolimus, everolimus) [69,70]. It may be difficult to
distinguish noncardiogenic pulmonary edema from heart failure in cardiac patients or
infection in immunosuppressed patients. Additional objective data, including invasive
hemodynamics and tissue biopsy, may be helpful in these cases. Acute lung injury and death
have also been reported with use of electronic cigarettes (vaping), and direct injury to lung
epithelial cells with capillary leak has been proposed as a mechanism. (See "E-cigarette or
vaping product use associated lung injury (EVALI)" and "Vaping and e-cigarettes".)

Pulmonary embolism — Acute pulmonary edema in association with a massive pulmonary

embolus (PE) or multiple smaller emboli is uncommon but well described [71,72]. 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

- Page 10 of 19 -
Noncardiogenic pulmonary edema

delayed [73]. Older studies showed that 20 percent of PE-related effusions are transudates,
suggesting that hydrostatic changes can also be important [74]. 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 [75].

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") [76], dengue hemorrhagic
fever/dengue shock syndrome (see "Dengue virus infection: Clinical manifestations and
diagnosis"), and most recently with COVID-19 infection (see "COVID-19: Clinical features").
Enteroviral 71 infection in young children [77] and SARS coronavirus infection in adults [78]
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 to 2010 pandemic caused severe ARDS in some patients (see "Seasonal influenza in
adults: Clinical manifestations and diagnosis"). There have also been reports of vascular
leakage and respiratory failure in the setting of severe Ebola virus disease [79].

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 "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of
pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Transfusion-related acute lung injury — Transfusion-related acute lung injury (TRALI) is a

rare but potentially fatal complication of blood product transfusion that involves neutrophil
activation and pulmonary edema. Further details are provided separately. (See "Transfusion-
related acute lung injury (TRALI)".)

ABSENCE OF PULMONARY EDEMA WITH HYPOALBUMINEMIA

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
- Page 11 of 19 -
Noncardiogenic pulmonary edema

heart failure and in-hospital mortality [83].

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 [84]. 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'.)

SUMMARY

● 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. The opioid epidemic and increasing incidence of vaping may increase the
incidence of acute pulmonary edema due to heroin overdose or use of vaping

- Page 12 of 19 -
Noncardiogenic pulmonary edema

products, respectively. Other less common causes include pulmonary edema due to
pulmonary embolism and eclampsia, and transfusion-related acute lung injury. (See
'Permeability pulmonary edema due to ARDS' above and 'Other noncardiogenic forms
of pulmonary edema' above.)

● Hypoalbuminemia alone is not a cause of pulmonary edema, but can contribute to

pleural effusions and increased mortality in patients with acute heart failure as well as
in those with acute coronary syndrome. (See 'Absence of pulmonary edema with
hypoalbuminemia' above.)

REFERENCES

1. Clark AL, Cleland JG. Causes and treatment of oedema in patients with heart failure. Nat
Rev Cardiol 2013; 10:156.
2. Huppert LA, Matthay MA, Ware LB. Pathogenesis of Acute Respiratory Distress
Syndrome. Semin Respir Crit Care Med 2019; 40:31.
3. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med 2005;
353:2788.
4. Scheel PJ, Liu M, Rabb H. Uremic lung: new insights into a forgotten condition. Kidney
Int 2008; 74:849.
5. Fein A, Grossman RF, Jones JG, et al. The value of edema fluid protein measurement in
patients with pulmonary edema. Am J Med 1979; 67:32.
6. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;
342:1334.
7. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with
the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485.
8. Kanner C, Hardy SM. An unusual cause of unilateral pulmonary edema. Ann Intern Med
2013; 158:639.
9. Neerukonda SK, Petty TL. Unilateral pulmonary edema. Hosp Pract (Off Ed) 1992; 27:85,
88.
10. Calenoff L, Kruglik GD, Woodruff A. Unilateral pulmonary edema. Radiology 1978;
126:19.
11. Attias D, Mansencal N, Auvert B, et al. Prevalence, characteristics, and outcomes of
patients presenting with cardiogenic unilateral pulmonary edema. Circulation 2010;

- Page 13 of 19 -
Noncardiogenic pulmonary edema

122:1109.
12. Kesävuori RI, Vento AE, Lundbom NMI, et al. Unilateral pulmonary oedema after
minimally invasive and robotically assisted mitral valve surgery. Eur J Cardiothorac Surg
2020; 57:504.
13. Jardin F, Fourme T, Page B, et al. Persistent preload defect in severe sepsis despite fluid
loading: A longitudinal echocardiographic study in patients with septic shock. Chest
1999; 116:1354.
14. Dunham-Snary KJ, Wu D, Sykes EA, et al. Hypoxic Pulmonary Vasoconstriction: From
Molecular Mechanisms to Medicine. Chest 2017; 151:181.
15. Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid B-natriuretic peptide
assay in differentiating congestive heart failure from lung disease in patients presenting
with dyspnea. J Am Coll Cardiol 2002; 39:202.
16. Komiya K, Akaba T, Kozaki Y, et al. A systematic review of diagnostic methods to
differentiate acute lung injury/acute respiratory distress syndrome from cardiogenic
pulmonary edema. Crit Care 2017; 21:228.
17. Determann RM, Royakkers AA, Schaefers J, et al. Serum levels of N-terminal proB-type
natriuretic peptide in mechanically ventilated critically ill patients--relation to tidal
volume size and development of acute respiratory distress syndrome. BMC Pulm Med
2013; 13:42.
18. Sun YZ, Gao YL, Yu QX, et al. Assessment of acute lung injury/acute respiratory distress
syndrome using B-type brain natriuretic peptide. J Int Med Res 2015; 43:802.
19. Schmickl CN, Pannu S, Al-Qadi MO, et al. Decision support tool for differential diagnosis
of Acute Respiratory Distress Syndrome (ARDS) vs Cardiogenic Pulmonary Edema (CPE):
a prospective validation and meta-analysis. Crit Care 2014; 18:659.
20. García-Laorden MI, Lorente JA, Flores C, et al. Biomarkers for the acute respiratory
distress syndrome: how to make the diagnosis more precise. Ann Transl Med 2017;
5:283.
21. Nanjappa S, Jeong DK, Muddaraju M, et al. Diffuse Alveolar Hemorrhage in Acute
Myeloid Leukemia. Cancer Control 2016; 23:272.
22. Federici AB, Intini D, Lattuada A, et al. Supportive transfusion therapy in cancer patients
with acquired defects of hemostasis. Thromb Res 2014; 133 Suppl 2:S56.
23. Sears CR, Peikert T, Possick JD, et al. Knowledge Gaps and Research Priorities in Immune

- Page 14 of 19 -
Noncardiogenic pulmonary edema

Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society

Research Statement. Am J Respir Crit Care Med 2019; 200:e31.
24. Cheng IW, Matthay MA. Acute lung injury and the acute respiratory distress syndrome.
Crit Care Clin 2003; 19:693.
25. Mi MY, Matthay MA, Morris AH. Extracorporeal Membrane Oxygenation for Severe
Acute Respiratory Distress Syndrome. N Engl J Med 2018; 379:884.
26. Humphrey H, Hall J, Sznajder I, et al. Improved survival in ARDS patients associated with
a reduction in pulmonary capillary wedge pressure. Chest 1990; 97:1176.
27. Vignon P, Evrard B, Asfar P, et al. Fluid administration and monitoring in ARDS: which
management? Intensive Care Med 2020; 46:2252.
28. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS)
Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-
management strategies in acute lung injury. N Engl J Med 2006; 354:2564.
29. Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with
acute respiratory distress syndrome. Cochrane Database Syst Rev 2019; 7:CD004477.
30. National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD,
Bernard GR, et al. Rosuvastatin for sepsis-associated acute respiratory distress
syndrome. N Engl J Med 2014; 370:2191.
31. Touchon F, Trigui Y, Prud'homme E, et al. Awake prone positioning for hypoxaemic
respiratory failure: past, COVID-19 and perspectives. Eur Respir Rev 2021; 30.
32. Kor DJ, Carter RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk
Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical
Trial. JAMA 2016; 315:2406.
33. Malhotra A, Drazen JM. High-frequency oscillatory ventilation on shaky ground. N Engl J
Med 2013; 368:863.
34. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute
respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995; 273:306.
35. Zambon M, Vincent JL. Mortality rates for patients with acute lung injury/ARDS have
decreased over time. Chest 2008; 133:1120.
36. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for
Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50
Countries. JAMA 2016; 315:788.

- Page 15 of 19 -
Noncardiogenic pulmonary edema

37. Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute
respiratory distress syndrome. N Engl J Med 2011; 364:1293.
38. Sasannejad C, Ely EW, Lahiri S. Long-term cognitive impairment after acute respiratory
distress syndrome: a review of clinical impact and pathophysiological mechanisms. Crit
Care 2019; 23:352.
39. Bärtsch P, Swenson ER. Clinical practice: Acute high-altitude illnesses. N Engl J Med 2013;
368:2294.
40. Luks AM, Swenson ER, Bärtsch P. Acute high-altitude sickness. Eur Respir Rev 2017; 26.
41. Finsterer J. Neurological Perspectives of Neurogenic Pulmonary Edema. Eur Neurol
2019; 81:94.
42. Busl KM, Bleck TP. Neurogenic Pulmonary Edema. Crit Care Med 2015; 43:1710.
43. Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with
chronic thromboembolic pulmonary hypertension: results from an international
prospective registry. J Thorac Cardiovasc Surg 2011; 141:702.
44. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J
Med 2011; 364:351.
45. Papamatheakis DG, Poch DS, Fernandes TM, et al. Chronic Thromboembolic Pulmonary
Hypertension: JACC Focus Seminar. J Am Coll Cardiol 2020; 76:2155.
46. Boulate D, Mercier O, Mussot S, et al. Extracorporeal Life Support After Pulmonary
Endarterectomy as a Bridge to Recovery or Transplantation: Lessons From 31
Consecutive Patients. Ann Thorac Surg 2016; 102:260.
47. Martin-Suarez S, Gliozzi G, Fiorentino M, et al. Role and management of extracorporeal
life support after surgery of chronic thromboembolic pulmonary hypertension. Ann
Cardiothorac Surg 2019; 8:84.
48. Sohara Y. Reexpansion pulmonary edema. Ann Thorac Cardiovasc Surg 2008; 14:205.
49. Yoon JS, Suh JH, Choi SY, et al. Risk factors for the development of reexpansion
pulmonary edema in patients with spontaneous pneumothorax. J Cardiothorac Surg
2013; 8:164.
50. Taira N, Kawabata T, Ichi T, et al. An analysis of and new risk factors for reexpansion
pulmonary edema following spontaneous pneumothorax. J Thorac Dis 2014; 6:1187.
51. Mynarek G, Brabrand K, Jakobsen JA, Kolbenstvedt A. Complications following
ultrasound-guided thoracocentesis. Acta Radiol 2004; 45:519.
- Page 16 of 19 -
Noncardiogenic pulmonary edema

52. Jones PW, Moyers JP, Rogers JT, et al. Ultrasound-guided thoracentesis: is it a safer
method? Chest 2003; 123:418.
53. Feller-Kopman D, Berkowitz D, Boiselle P, Ernst A. Large-volume thoracentesis and the
risk of reexpansion pulmonary edema. Ann Thorac Surg 2007; 84:1656.
54. Lin YJ, Yu YH. Reexpansion pulmonary edema after large-volume thoracentesis. Ann
Thorac Surg 2011; 92:1550.
55. Gleeson T, Thiessen R, Müller N. Reexpansion pulmonary edema: computed
tomography findings in 22 patients. J Thorac Imaging 2011; 26:36.
56. Sherman SC. Reexpansion pulmonary edema: a case report and review of the current
literature. J Emerg Med 2003; 24:23.
57. Sagar AES, Landaeta MF, Adrianza AM, et al. Complications following symptom-limited
thoracentesis using suction. Eur Respir J 2020; 56.
58. Osler W. Oedema of the left lung—morphia poisoning. Montreal General Hospital Repor
ts Clinical and Pathological, vol 1, Dawson Bros Publishers, Montreal 1880. p.291.
59. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-Associated Out-of-Hospital Cardiac
Arrest: Distinctive Clinical Features and Implications for Health Care and Public
Responses: A Scientific Statement From the American Heart Association. Circulation
2021; 143:e836.
60. Farkas A, Lynch MJ, Westover R, et al. Pulmonary Complications of Opioid Overdose
Treated With Naloxone. Ann Emerg Med 2020; 75:39.
61. Radke JB, Owen KP, Sutter ME, et al. The effects of opioids on the lung. Clin Rev Allergy
Immunol 2014; 46:54.
62. Dettmeyer R, Schmidt P, Musshoff F, et al. Pulmonary edema in fatal heroin overdose:
immunohistological investigations with IgE, collagen IV and laminin - no increase of
defects of alveolar-capillary membranes. Forensic Sci Int 2000; 110:87.
63. Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary edema : a case series.
Chest 2001; 120:1628.
64. Cobaugh DJ, Gainor C, Gaston CL, et al. The opioid abuse and misuse epidemic:
implications for pharmacists in hospitals and health systems. Am J Health Syst Pharm
2014; 71:1539.
65. Winklhofer S, Surer E, Ampanozi G, et al. Post-mortem whole body computed
tomography of opioid (heroin and methadone) fatalities: frequent findings and

- Page 17 of 19 -
Noncardiogenic pulmonary edema

comparison to autopsy. Eur Radiol 2014; 24:1276.

66. Heffner JE, Sahn SA. Salicylate-induced pulmonary edema. Clinical features and
prognosis. Ann Intern Med 1981; 95:405.
67. Glisson JK, Vesa TS, Bowling MR. Current management of salicylate-induced pulmonary
edema. South Med J 2011; 104:225.
68. Papacostas MF, Hoge M, Baum M, Davila SZ. Use of continuous renal replacement
therapy in salicylate toxicity: A case report and review of the literature. Heart Lung 2016;
45:460.
69. Almeida F, Amorim S, Sarmento A, Santos L. Life-Threatening Everolimus-Associated
Pneumonitis: A Case Report and a Review of the Literature. Transplant Proc 2018;
50:933.
70. Wang WL, Yu LX. Acute respiratory distress attributed to sirolimus in solid organ
transplant recipients. Am J Emerg Med 2015; 33:124.e1.
71. Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med 2010; 363:266.
72. Jaber WA, Fong PP, Weisz G, et al. Acute Pulmonary Embolism: With an Emphasis on an
Interventional Approach. J Am Coll Cardiol 2016; 67:991.
73. Porcel JM, Light RW. Pleural effusions due to pulmonary embolism. Curr Opin Pulm Med
2008; 14:337.
74. Brown SE, Light RW. Pleural effusion associated with pulmonary embolization. Clin
Chest Med 1985; 6:77.
75. Porcel JM, Madroñero AB, Pardina M, et al. Analysis of pleural effusions in acute
pulmonary embolism: radiological and pleural fluid data from 230 patients. Respirology
2007; 12:234.
76. Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic
fever. Clin Infect Dis 2002; 34:1224.
77. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan
Enterovirus Epidemic Working Group. N Engl J Med 1999; 341:929.
78. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe
acute respiratory syndrome. N Engl J Med 2003; 348:1953.
79. Wolf T, Kann G, Becker S, et al. Severe Ebola virus disease with vascular leakage and
multiorgan failure: treatment of a patient in intensive care. Lancet 2015; 385:1428.
80. Arquès S, Ambrosi P, Gélisse R, et al. Hypoalbuminemia in elderly patients with acute
- Page 18 of 19 -
Noncardiogenic pulmonary edema

diastolic heart failure. J Am Coll Cardiol 2003; 42:712.

81. Uthamalingam S, Kandala J, Daley M, et al. Serum albumin and mortality in acutely
decompensated heart failure. Am Heart J 2010; 160:1149.
82. Bonilla-Palomas JL, Gámez-López AL, Moreno-Conde M, et al. Hypoalbuminemia in
acute heart failure patients: causes and its impact on hospital and long-term mortality. J
Card Fail 2014; 20:350.
83. González-Pacheco H, Amezcua-Guerra LM, Sandoval J, et al. Prognostic Implications of
Serum Albumin Levels in Patients With Acute Coronary Syndromes. Am J Cardiol 2017;
119:951.
84. Taylor AE. Capillary fluid filtration. Starling forces and lymph flow. Circ Res 1981; 49:557.

Topic 3456 Version 22.0

© 2022 UpToDate, Inc. All rights reserved.

- Page 19 of 19 -