REVIEW ARTICLE

Cardiogenic Pulmonary Edema

Logan Dobbe, MD1, Rubayat Rahman, MD2, Mohamed Elmassry, MD2,
Pablo Paz, MD2 and Kenneth Nugent, MD2
1
Department of Graduate Medical Education, Madigan Army Medical Center,
Tacoma, Washington; 2 Department of Internal Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas

ABSTRACT
The initial events in cardiogenic pulmonary edema involve hemodynamic pulmonary congestion with high capillary pres-
sures. This causes increased fluid transfer out of capillaries into the interstitium and alveolar spaces. High capillary pressures
can also cause barrier disruption which increases permeability and fluid transfer into the interstitium and alveoli. Fluid in
alveoli alters surfactant function and increases surface tension. This can lead to more edema formation and to atelectasis
with impaired gas exchange. Patients with barrier disruption have increased levels of surfactant protein B in the circulation,
and these levels often remain high after the initial clinical improvement. Routine clinical assessment may not identify
patients with increased extravascular fluid in the lungs; pulmonary ultrasound can easily detect pulmonary edema in patients
with acute decompensation and in patients at risk for decompensation. Studies using serial pulmonary ultrasound could
help characterize patients with cardiogenic pulmonary edema and help identify subgroups who need alternative manage-
ment. The conventional management of cardiogenic pulmonary edema usually involves diuresis, afterload reduction
and in some cases noninvasive ventilation to reduce the work of breathing and improve oxygenation. Patients with persis-
tent symptoms, abnormal chest x-rays and diuretic resistance might benefit from alternative approaches to management.
These could include beta agonists and pentoxifylline which warrant more study in patients with cardiogenic pulmonary
edema.
Key Indexing Terms: Cardiogenic pulmonary edema; Capillary permeability; Pulmonary surfactant-associated protein B;
Ultrasonography; Pentoxifylline. [Am J Med Sci 2019;358(6):389–397.]

INTRODUCTION The pathophysiology, clinical presentation and man-

P
ulmonary edema, especially when associated
with acute respiratory failure, often leads to
poor outcomes in hospitalized patients. A sub-
set of this disorder, cardiogenic pulmonary edema,
occurs when the edema is secondary to acute cardiac
failure. There were approximately 1 million hospital
discharges for heart failure in the United States in
2003 with mortality and readmission rates of 4% and
25%, respectively.1 The European Society of Cardiol-
ogy Heart Failure Pilot Registry reported outcomes
from October 2009 to May 2010 for acute heart failure
admissions.2 This study involved 136 cardiology cen-
ters in 12 European countries and reported a 1-year
all-cause mortality rate of 17.4% in the 1,892 patients
admitted for acute heart failure. The 1-year hospitali-
zation rate in these patients was 43.9%. Samsky et al
analyzed the trends in length of stay and readmission
rates for heart failure in Canada and the United States
between 2005 and 2015. In the United States, 3.8%
of patients (2,891,030 total admissions) admitted with
heart failure died during the index hospitalization; the
survivors had a mean length of stay of 4.9 § 3.6 days
and a 19.9% readmission rate.3 Clearly, hospitaliza-
tion with acute heart failure has important clinical and
economic implications.
agement of patients with acute cardiogenic pulmonary
edema are not adequately described by the traditional
teaching on pulmonary edema formation, and under-
standing other events during the development of acute
cardiogenic pulmonary edema could change treatment
approaches and improve outcomes. High hydrostatic
pressures can cause barrier disruption in the alveolar epi-
thelium and capillary endothelium in the lung. This can
result in increased permeability, increased pulmonary
edema formation, surfactant dysfunction and acute
inflammation. These events likely contribute to the
development and maintenance of pulmonary edema in
some patients with acute heart failure and need more
investigation to identify therapeutic alternatives. This review
will discuss fluid formation, fluid detection and potential
treatment options in patients with acute heart failure.
FLUID FORMATION
The Starling Equation Alone Does Not Explain
Alveolar Edema Observed in Heart Failure
The conventional analysis of cardiogenic pulmonary
edema cites the Starling Equation to describe the relation-
ship between hydrostatic pressures and oncotic pressures
and net fluid formation in the lung. This is mathematically

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Dobbe et al
expressed as Jv ¼ Lp Sð½Pc Pi   s ½pp  pi Þ.a This analy-
sis maintains that left ventricular failure leads to fluid over-
load in the pulmonary circuit, which increases hydrostatic
pressure, and this promotes net fluid transfer from the
capillaries into the interstitial space and alveoli.4 If the
Starling Equation completely described cardiogenic pul-
monary edema, the syndrome should resolve quickly with
standard medical care focused on reductions in afterload
and preload of the left ventricle. However, some hospi-
talized patients with acute heart failure and pulmonary
edema have persistent respiratory symptoms, hypox-
emia and pulmonary infiltrates after medical manage-
ment including diuresis. This clinical scenario could be
explained by acute lung injury (ALI) during the formation
of pulmonary edema, and relevant literature related to
this possibility will be reviewed below.
Barrier Disruption-Tissue and Cellular Pathology
Associated With Acute Cardiogenic Edema
The active cellular barrier model explains why the
Starling Equation is an oversimplification of alveolar fluid
mechanics. Pappas described this by stating that
oncotic and hydrostatic gradients are not isolated pro-
cesses since the “combination of high hydrostatic pul-
monary capillary pressure and high permeability of the
alveolar-capillary barrier” can lead to a significant overlap
between the 2 syndromes.5 Cardiogenic pulmonary
edema is secondary to an abrupt rise in pulmonary capil-
lary hydrostatic pressure, which not only promotes a net
fluid shift out of capillaries but can cause mechanical
injury to the blood gas barrier, a mechanism defined as
“stress failure.”5 This barrier is a thin walled structure, a
compromise between stability and permeability, facilitat-
ing rapid exchange of carbon dioxide for oxygen within a
0.7 second timeframe for blood flow through capillaries.6
With stress failure, both hydrostatic pressures and
increased permeability increase fluid and protein transfer
into alveolar spaces. This occurs in association with dis-
ruption of the complex cellular transport mechanisms
(discussed below).
Surfactant Dysfunction
An important consequence of stress failure is the loss
of surfactant function at several levels. Animal studies
have demonstrated that high levels of hydrostatic pressure
in capillaries can cause disruptions in both the capillary
endothelium and in the alveolar epithelium with the collec-
tion of edema fluid in both the interstitial regions and the
alveolar spaces.7,8 Alveolar edema disrupts the continuity
of the surfactant layer and increases surface tension.9,10
Surfactant is also “lost” into the systemic circulation
a
Jv is trans endothelial solvent filtration volume per second (m3  s 1 ). Lp is
hydraulic conductivity of the membrane (m  s 1  mmHg 1 ). S is the surface
area of filtration (m2). Collectively LpS is the filtration coefficient. Pc is capillary
hydrostatic pressure. Pi is interstitial hydrostatic pressure. pp is plasma pro-
tein oncotic pressure. pi is the interstitial oncotic pressure. s represents Sta-
verman’s reflection coefficient.
390
through the breaks in the barrier and is lost into the edema
foam which develops with pulmonary edema.11,12 Finally,
inflammation associated with stress failure modifies the
composition and stability of surfactant.13
Stretching the alveolar type I epithelium controls the
intercellular signaling for the release of surfactant from type
II cells through the release of extracellular ATP. High levels
of epithelial distortion through either mechanical ventilation
or possibly through hydrostatic pressures increase the
release of extracellular ATP to pathologic levels.14 Then,
type II alveolar cells no longer release surfactant through
P2 £ 4-mediated fusion-activated calcium entry lamellar
body exocytosis but instead release “clumps” of surfactant
through cell lysis. These aggregates are nonfunctional due
to their size and are disrupted by extracellular mechanical
forces that shear the protein-complex structure. High levels
of extracellular adenosine triphosphate (ATP) also function
as “danger” molecules and cause capillary leakage which
increases edema in alveolar spaces and inactivates surfac-
tant through the accumulation of fluid and proteins.13 If
fluid accumulates in pathologic quantities, surfactant func-
tion is no longer adequate to prevent alveolar collapse,
and respiratory failure develops.15
De Pasquale et al measured surfactant protein-A and
surfactant protein-B levels in the serum in 28 patients
presenting with acute cardiogenic pulmonary edema.
The surfactant proteins were elevated on the day of pre-
sentation, continued to increase until day 3 of hospitali-
zation and remained elevated through day 14. The time
course for changes in surfactant protein levels in the
plasma was clearly longer than the time course for clini-
cal improvement based on symptoms, gas exchange
and chest x-ray scores.12 The measurement of these
proteins provides an additional approach to evaluate
lung injury associated with acute increases in hydrostatic
pressures in pulmonary capillaries.
Injury and Inflammation
Stress failure associated with cardiogenic pulmonary
edema is associated with biochemical and cellular pro-
cesses that can lead to tissue damage. De Pasquale
measured tumor necrosis factor-alpha (TNF-alpha) in 28
patients presenting with acute cardiogenic pulmonary
edema; this protein was elevated for 14 days after admis-
sion and should reflect acute tissue injury.12 In their dis-
cussion of this study, these investigators argue that the
TNF-alpha likely had a pulmonary origin since macro-
phages, endothelial cells and alveolar type II epithelial
cells can synthesize TNF-alpha. The acute disruption of
alveolar epithelium injures both type I and II alveolar cells,
and fluid in the alveoli is no longer cleared by a normal
apical-basolateral transfer process. This fluid can include
inflammatory products, such as TNF-alpha, neutrophils,
reactive oxygen species, reactive nitrogen species,
neutrophil-activating peptide and platelet-activating
factor, and these contribute to maladaptive changes in
the pulmonary tissue.12 Pappas et al measured the pH,
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interleukin-6 (IL-6), TNF-alpha and 8-isoprostane levels in
the exhaled breath condensates collected from patients
with either acute heart failure or chronic heart failure and
demonstrated that patients with acute heart failure had
elevated levels of IL-6, TNF-alpha and 8−isoprostane.16
These inflammatory mediators may be associated with
ongoing tissue injury.
Finally, the type IV collagen alveolar membrane thick-
ens during pathologic remodeling and probably impairs
fluid and gas exchange.17,18 However, if stress failure per-
sists without repair, increased hydrostatic pressure sec-
ondary to left ventricular dysfunction is no longer the
primary factor in the transfer of fluid into the alveoli, and
increased permeability in the blood gas barrier explains
persistent edema. Pappas and Filippatos discussed the
mechanical events associated with increased capillary
pressures that resulted in a stress barrier failure and noted
that pulmonary edema fluid in patients with acute heart
failure has increased concentrations of neutrophils, cyto-
kines and biomarkers of oxidative stress.5 These observa-
tions indicate that there is acute inflammation in alveoli
which may contribute to more tissue injury. Consequently,
the lungs in patients with acute hydrostatic pulmonary
edema may have fluid overload, barrier disruption, surfac-
tant dysfunction, acute sterile inflammation and areas of
atelectasis, possibly superimposed on chronic remodeling
changes if the patient has had prior episodes of pulmo-
nary edema. These pathophysiologic events are evident
in some patients by persistent pulmonary infiltrates after
significant diuresis.
FLUID CLEARANCE
Alveolar Fluid Clearance as a Multifactorial Process
Lymphatic drainage of fluid in the interstitial region
and bronchovascular bundles prevents edema formation
and compensates for increased edema formation in
patients with cardiogenic pulmonary edema. Seeger et al
measured the cervical segment of the thoracic duct in
265 healthy volunteers and 39 patients with congestive
heart failure (CHF) using ultrasonography.19 The median
diameter in healthy subjects was 2.4 mm (interquartile
range of 1.8-3.0 mm); the median diameter in patients
with CHF was 5.5 mm (interquartile range 5.0-8.15 mm).
This study found that heart failure increases the size of
the thoracic duct, and this likely helps compensate for
increased fluid formation in the interstitial space. Witte
cannulated the external thoracic duct in 12 patients
whose heart failure was unresponsive to standard medi-
cal management.20 Lymph flow rates in these patients
ranged from 3 mL/minute to 38 mL/minute. These
patients had significant decreases in weight, improved
symptoms, and decreased central venous pressures
with this drainage. This study demonstrates that lym-
phatics can have an important role in the clearance of
extra capillary fluid in the lung parenchyma.
Alveolar fluid clearance also depends on complex,
cellular processes and active transport of fluid across
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Cardiogenic Pulmonary Edema
the epithelial barrier is the more scalable mechanism
available to clear large amounts of extravascular fluid.21
The apical surfaces of both type I and type II alveolar
cells have epithelial sodium channels which transfer
sodium from the extracellular spaces into the cell where
it is then transferred into the interstitium through a baso-
lateral Na+-K+ ATPase transporters. Other channels in
these apical cells include nonselective cation channels,
cyclic nucleotide-gated channels and selective cation
channels. Chloride moves through the cystic fibrosis
transmembrane conductor. The movement of ions
through these channels creates an osmotic gradient
which favors water transfer through aquaporins and
paracellular routes into the interstitial space. Alveolar
type II cells utilize P2 £ 4-mediated fusion-activated
calcium entry lamellar body exocytosis to secrete sur-
factant.22 This signaling cascade increases extracellular
ATP, and the increased intracellular cation influx pro-
motes electrochemically favorable fluid absorption. Pro-
tein moves from alveoli into the interstitium by diffusion
through paracellular pathways.23
The requirements for a favorable gradient for fluid
absorption is controlled by several signaling pathways,
including cAMP, extracellular ATP, endogenous epineph-
rine, exogenous dobutamine/epinephrine, with minor influ-
ences from dopamine, thyroid hormone, corticosteroids
and growth factors, including of keratinocyte growth
factor.15 Fluid absorption is inhibited by hypoxia and
reactive oxygen species.15 Ultimately, this multifactorial
mechanism of control and clearance provides a dynamic
process for the apical to basolateral transport of fluid
from the alveoli, which can rapidly adapt to physiologic
stress. However, barrier disruption adversely affects these
pathways.
Verghese et al measured alveolar epithelial fluid
transport in 65 patients with acute severe hydrostatic
pulmonary edema who required mechanical ventila-
tion.24 Forty-nine of these patients had normal rates of
alveolar fluid clearance; 16 patients (25%) had impaired
alveolar fluid clearance. There were no definite clinical
differences between these 2 groups of patients that
might explain the impaired alveolar fluid clearance. The
overall mortality in this study was 31%; the mortality in
patients with normal or intact alveolar fluid clearance
was 26%, and the mortality in patients with reduced
alveolar clearance was 44%. This difference suggests
that impaired alveolar fluid clearance translates into
worse outcomes in patients with severe cardiogenic pul-
monary edema. This study indicates that these patients
may not have normal alveolar fluid clearance rates even
during maximum medical management and that this
likely contributes to their clinical course.
In summary, hydrostatic pressures and oncotic pres-
sures do not adequately explain the formation of pulmo-
nary edema in some patients. This process is complicated
by ALI with barrier disruption leading to more fluid forma-
tion, surfactant dysfunction leading to more fluid formation
and alveolar collapse, acute inflammation and impaired
391
Dobbe et al
clearance of ions and water from the alveolar and intersti-
tial spaces. Clinicians need better methods to detect
residual fluid during the medical management, and clinical
investigators need to study new management strategies
to limit fluid formation and facilitate fluid removal in some
patients.
FLUID DETECTION
Chest x-Rays and Computed Tomography Scans
The chest x-ray remains an important test for the eval-
uation of acute pulmonary disorders, and adequate inter-
pretation of radiologic signs can help distinguish between
cardiogenic pulmonary edema and noncardiogenic pul-
monary edema. Some radiologic findings correlate with
the pulmonary capillary wedge pressure (Table 1).25 Milne
et al identified important radiological signs that help iden-
tify cardiogenic pulmonary edema; these include inverted
distribution of blood flow in the lung, basal and homoge-
neous distribution of edema from chest wall to heart,
enlarged vascular pedicle and azygos width, normal or
small lung volumes and the presence of peribronchial cuff-
ing, septal lines and effusions.26
Specific patterns on chest x-rays have been associ-
ated with the underlying cause of edema (Table 2). Cardi-
omegaly and pleural effusions are additional radiologic
findings frequently found in cardiogenic pulmonary
edema and help identify the underlying cause of pulmo-
nary edema. A metadata analysis found that the ultra-
sound has both a high specificity (92.4%) and sensitivity
(94.1%) in the identification of pulmonary edema.27 How-
ever, the characteristic features described in chest x-rays
have only moderate specificity (75-83%) and poor sensi-
tivity (50-68%) in the diagnosis of cardiogenic pulmonary
congestion.28,29
Hammon et al described a method for improving the
diagnostic accuracy of identifying pulmonary edema on
chest radiographs using the standardized scoring sys-
tem.30 This study included 10 patients with no pulmonary
edema and 10 patients with pulmonary edema, based on
extravascular lung water measurements. Seven radiolog-
ists read the films using either their standard interpreta-
tion approach or a customized software that listed
characteristics of pulmonary edema and applied scores
to the abnormalities on the film. The standardized scor-
ing method took 23 seconds and improved the sensitivity
TABLE 1. Pulmonary capillary wedge pressure (PCWP) correlations
with radiologic findings.
PCWP Chest x-ray findings
5-12 mmHg Normal findings
12-17 mmHg Cephalization of pulmonary vessels
(in chronic conditions)
17-20 mmHg Kerley lines, subpleural effusions
>25 mmHg Pulmonary edema
Adapted from Gluecker et al.25
392
of detecting pulmonary edema from 57% to 77% and
the specificity from 90% to 100%. Consequently, this
study demonstrates systematic radiograph interpretation
using a scoring tool can improve the detection of pulmo-
nary edema without a significant increase in the time
involved.
When diffuse parenchymal lung disease is being con-
sidered in the differential diagnosis, computed tomogra-
phy scans (CT scans) of the chest can have an important
role in diagnosis. The main findings in cardiogenic pul-
monary edema are ground-glass opacities, thickening
of major fissures, interstitial edema and interlobular,
peribronchovascular and interstitial thickening.30 In
comparison to CT scans, chest x-rays provide impor-
tant information that helps rule out many pulmonary
conditions at a low cost. However, CT scans are more
sensitive in the diagnosis of many conditions and can
identify the early phase of cardiogenic pulmonary edema.
Ultrasound
Pulmonary ultrasound provides a promising radio-
graphic technique for the identification and quantification
of pulmonary edema. Ultrasound can easily identify B-
lines or “comet tails,” which are vertical hyperechoic
reverberation artifacts that arise at the pleural line and
extend through the lung. These B-lines represent alveo-
lar-interstitial edema and can be characterized by the
number in an image screen and the location (Figure 1).
Agricola et al studied 20 patients who underwent cardiac
surgery and had right heart catheters in place.31 The
investigators analyzed chest x-rays for extravascular
lung water and ultrasound images of the lung for B-lines;
they also measured cardiac hemodynamics, including
the wedge pressures and pulmonary artery pressures,
and extravascular lung water using a thermodilution
method. They found a significant positive correlation
between the number of B-lines and the extravascular
lung water determined by thermodilution and a signifi-
cant correlation between the B-line score and wedge
pressures. This study indicates that ultrasonography
provides an easy method to evaluate patients for pulmo-
nary congestion or extravascular lung water.
Coiro et al studied the prognostic value of pulmonary
congestion assessed by lung ultrasound during heart
failure hospitalizations.32 This study involved 2 separate
hospitals and included 110 patients; 50 were studied
within the first 3 days of hospitalization and the other 60
were studied at discharge. Lung scanning collected
images from 28 bilateral hemithorax locations. The num-
ber of B-lines recorded at each site was summed and
could range from 0 to 280. The mean number of B-lines
in all patients was 32 § 2, the mean number of the lines
during early hospitalization was 47 § 4 and the mean
number at discharge was 23 § 3. Outcomes included a
composite of either heart failure hospitalization or death
within 3 months. The number of B-lines predicted brain
natriuretic peptide levels greater than 400 pg/mL and
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 Cardiogenic Pulmonary Edema

TABLE 2. Chest x-ray findings associated with certain etiologies of edema.

Etiology Chest x-ray findings

Increased hydrostatic pressure edema Loss of definition of subsegmental and segmental vessels
Interstitial Edema Mild enlargement of peribronchovascular spaces
Presence of Kerley lines
Subpleural effusions
Peribronchial cuffing
Alveolar flooding- tiny nodular or acinar areas of increased opacity that
coalesce into frank consolidations
Bat wing edema Central, nongravitational distribution of alveolar edema with lung cortex
Rapidly developing severe cardiac failure (e.g., acute free of alveolar or interstitial fluid
mitral insufficiency)
Asymmetric distribution of increased pressure edema Patchy distribution of edema
Cardiac failure associated with marked destruction and
fibrosis of lung parenchyma
Unilateral pulmonary edema Asymmetric distribution of pulmonary edema into the right upper lobe due
Large, acute myocardial infarctions that cause mitral to the flow vector of regurgitation directed predominantly into the right
valve insufficiency superior pulmonary vein
Adapted from Gluecker et al and Cardinale et al.25,27

predicted adverse outcomes independent of whether or
not the patient had atrial fibrillation, a reduced ejection
fraction, or the study was done early in hospitalization or at
discharge. Forty-five or more B-lines present early during
hospitalization and 30 or more B-lines present at discharge
predicted poor outcomes. These authors concluded that
ultrasonography provides important information regarding
pulmonary congestion during hospitalization and at dis-
charge, which predicts adverse short-term outcomes.
Gargani used lung ultrasonography to determine pul-
monary congestion in 100 patients hospitalized for heart
failure.33 The mean number of B-lines at admission was
48 § 48; the mean number at discharge was 20 § 23.
Twenty-seven percent of patients with a large number of
B-lines on admission did not have pulmonary crackles on
physical examination. In most patients, but not all, the
mean number of B-lines decreased during hospitalization.
Factors that predicted heart failure readmission within

FIGURE 1. Physical basis of lung ultrasound. B-lines are vertical hyperechoic reverberation artifacts that arise at the pleural line and extend to
the bottom of the screen. Their presence correlates with the extent of edema. In the normal state (A), there are no B-lines. In a state of mild to
moderate interstitial edema (B), an overall hypoechoic appearance is maintained with sparse B-lines forming. As the edema progresses to
become more clinically severe (C), the hypoechoic appearance is lost, with a high density of B-lines. Frank consolidation (D) leads to fluid being
represented by a hypoechoic area with clear hyperechoic boundaries of the consolidation. The graphic (E) indicates the amount of air versus fluid
present in the alveoli in these various physiologic states. (Source: Open Access).

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Dobbe et al
6 months in multivariable analysis included New York
Heart Association class, hemoglobin levels <10 gm/dL,
pro-brain natriuretic peptide levels >635 ng/L, >50
B-lines at admission and >15 B-lines at discharge. This
study demonstrated that persistent congestion at dis-
charge predicts readmission and that some patients
who do not improve with medical management have an
increase in the number of B-lines during hospitalization.
In summary, lung ultrasound can identify occult
pulmonary congestion. The number of B-lines predicts
rehospitalization in patients hospitalized with acute
heart failure and correlates well with other clinical and
laboratory markers for decompensated heart failure. In
addition, ultrasound studies can provide information
about pleural effusions and the collapsibility of the
inferior vena cava, another indicator of fluid overload.34
FLUID MANAGEMENT
The National Heart Foundation of Australia and the
Cardiac Society of Australia and New Zealand have pub-
lished specific recommendations for the medical manage-
ment of CHF.35 Signs of congestion and hypoperfusion
usually guide treatment decisions.36,37 Diuretics and vaso-
dilators are indicated for congestion; hypoperfusion
requires treatment with inotropes and occasionally vaso-
pressors. Gheorghiade has described acute heart failure
syndromes as a continuum that evolves from hemody-
namic congestion to clinical congestion.1,38 He notes that
most patients who develop acute cardiogenic pulmonary
edema have elevated left ventricular end-diastolic pres-
sures, also known as hemodynamic constriction. How-
ever, this may not cause changes on chest x-ray or
clinical symptoms. Patients then deteriorate if capillary
pressures continue to increase, fluid overload develops or
high pressures cause either additional cardiac dysfunc-
tion, pulmonary alveolar capillary damage or neurohor-
monal activation. In addition, fluid overload in the lung in
acute heart failure may not represent additional fluid accu-
mulation but rather redistribution of fluid to the lungs sec-
ondary to decreased venous capacitance resulting in
increased preload and impaired ventricular emptying
secondary to increased arterial vasoconstriction caus-
ing increased afterload.39 Considerations related to
acute barrier dysfunction can lead to additional man-
agement strategies in patients with acute heart failure
and will be discussed below.
In the patient presenting with acute cardiac failure,
medical management beyond ventilatory management
and diuresis is needed in some cases, and biomarkers
could help identify patients at risk for poor responses to
medical therapy. For example, serum surfactant protein
B levels provide evidence of barrier disruption. Surfac-
tant protein B has alveolar fluid to plasma ratios
>1,500:1; this ratio is lowered substantially with alveolar
membrane damage. Elevated surfactant protein B levels
after partial resolution of acute pulmonary edema indi-
cate that there is continued damage, and fluid flux will be
394
highly sensitive to increases in capillary pressure. Clini-
cians could use surfactant protein B levels to identify
high risk patients, alerting them to the need to identify
and treat all possible causes of increased pulmonary
capillary pressure.12
TNF-alpha is elevated in these patients secondary to
both cardiac and pulmonary disease and can cause
widespread damage, extending beyond the local tissue
into other organ systems. Consequently, outcomes in
cardiac failure and ALI might be improved by lowering
serum levels of TNF-alpha, and TNF-alpha inhibitors, for
example, infliximab and etanercept, have been studied in
these patients. However, several studies in patients with
rheumatoid arthritis have found these drugs are associ-
ated with cardiomyopathies.40 Chung theorized that the
biological drugs paradoxically increase damage by trig-
gering cell lysis by attaching to TNF-alpha proteins
embedded in the cell matrix.41-43 Also, TNF-alpha appears
to have a dual effect on alveolar fluid clearance.44 It inhib-
its alveolar fluid clearance and increases microvascular
permeability in patients with acute respiratory distress
syndrome (ARDS). However, the lectin-like domain of
TNF-alpha activates the epithelial sodium channel on type
II alveolar cells and increases alveolar fluid clearance.
Therefore, the use of antibodies to TNF-alpha may have
unpredictable effects and could have a negative effect on
alveolar fluid clearance.
Interleukin-1 (IL-1) is a systemic inflammatory marker
elevated in both heart failure and pulmonary edema, and
elevated levels have been linked to impaired cardiac con-
tractility, relaxation and wound healing, which together
promote heart failure.45 Inflammatory markers, such as IL-
6, IL-1b and TNF-alpha, have been found to peak within
12 hours of hospital admission for decompensated failure,
and the latter 2 remain elevated for more than 4 weeks.46
Blockade of IL-1 is possible with anakinra, an IL-1 recep-
tor antagonist. Short-duration studies found improved
outcomes for acute decompensated heart failure, stable
heart failure and ST-elevation myocardial infarctions. In
addition to improved mortality and readmission rates,
C-reactive peptide (CRP) levels were reduced and phys-
iologic improvements in peak velocity of oxygen uptake
and ventilatory efficiency occurred.47-50 Research on
IL-1 blockade in pulmonary edema is very limited, but
this blockade could have a detrimental effect on heal-
ing. An in vitro alveolar wound model found that adding
plasma from patients with ARDS or ALI increased epi-
thelial wound repair rates by 33%, compared to healthy
donor plasma.51 The addition of IL-1b receptor antago-
nists to the ALI/ARDS plasma reduced repair by 46%.
Therefore, the complex pathophysiology of cardiogenic
pulmonary edema presents a paradox for the use of
anakinra; heart failure could be improved, but the recov-
ery of pulmonary tissue from injury may be delayed with
its use.
Beta-2 adrenergic agonists have been studied as a
possible therapeutic intervention in pulmonary edema.
Theoretically, beta agonists could promote fluid clearance,
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VOLUME 358 NUMBER 6 DECEMBER 2019

reduce lung vascular permeability, increase surfactant
secretion and have anti-inflammatory effects. Lee has
summarized the mixed results of studies using b agonists
in ALI. Some studies have reported improvements in
edema resolution, but others found that damaged pulmo-
nary capillaries were further recruited by the agonists,
resulting in increased lung endothelial permeability and tis-
sue damage.52 More recent studies have found that
patients with stable CHF but no apparent pulmonary con-
gestion have increased extravascular lung fluid, and that
beta agonists can reduce this fluid load without complica-
tions.53 Albuterol was given to stable heart failure patients
and matched controls, and pre- and postadministration
lung function and volume status were measured. Both
lung tissue volume and extravascular fluid volume were
decreased by albuterol. The primary mechanisms by
which short-acting b2 agonists reduce lung fluid include
activation of epithelial sodium channels on type I and II
alveolar cells, enhanced lymphatic drainage and upregula-
tion of b2-receptors in the alveoli in stable heart failure
patients; the latter maximizes the response to b2 agonists
and fluid clearance.53,54 Beta agonists did not improve
outcomes in patients with ALI/ARDS but have not been
studied in patients with uncomplicated cardiogenic pul-
monary edema.55
Pentoxifylline is an exception to the inconclusive
results in TNF-alpha inhibition studies. Unlike most bio-
logic agents, pentoxifylline has numerous immunomodu-
latory properties, including blocking the synthesis of
TNF-alpha. This approach eliminates any concerns
about triggering TNF-alpha-bound cell lysis and may
attenuate maladaptive inflammation. A recent meta-anal-
ysis of pentoxifylline administered for 1 or 6 months fol-
lowing the diagnosis of heart failure reported a 4-fold
decrease in all-cause mortality from 18.3% to 5.4%.56
The positive effect on patient outcomes was originally
related to blocking the synthesis of TNF-alpha, but a
more recent review suggests that the drug’s other immu-
nomodulatory properties explain its benefit and that
TNF-alpha represents a surrogate marker for inflamma-
tion rather than a key component within the inflammatory
cascade.57 This surrogate marker argument is supported
by a study in which patients with idiopathic-dilated car-
diomyopathy and an elevated baseline CRP levels were
more likely to respond to pentoxifylline; high baseline
CRP correlated with decreased Fas/Apo-1 levels and
improved ejection fraction in the pentoxifylline treated
group.58 More studies investigating pentoxifylline in
patients with cardiogenic pulmonary edema, for both
cardiac effects and its potential to attenuate pulmonary
damage, are needed.
CONCLUSIONS
The initial events in cardiogenic pulmonary edema
involve hemodynamic pulmonary congestion with high
capillary pressures which causes increased fluid transfer
out of capillaries into the interstitium and alveolar spaces.
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
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www.ssciweb.org
Cardiogenic Pulmonary Edema
High capillary pressures can also cause barrier disruption
with increases in permeability and more fluid transfer into
the interstitium and alveoli. Fluid in alveoli alters surfac-
tant function and increases surface tension; this can
lead to more edema formation and to atelectasis with
impaired gas exchange. Patients with barrier disruption
have increased levels of surfactant protein B in the cir-
culation, and these levels often remain high after the ini-
tial clinical improvement. Routine clinical assessment
may not identify patients with increased extravascular
fluid in the lungs. Pulmonary ultrasound can easily
detect pulmonary edema in patients with acute decom-
pensation and in patients at risk for decompensation.
Studies using serial pulmonary ultrasound and serial
measurements of surfactant protein B levels in the
plasma could help characterize patients with cardio-
genic pulmonary edema and help identify subgroups
who need alternative management. The conventional
management of cardiogenic pulmonary edema usually
involves diuresis, afterload reduction and in some cases
noninvasive ventilator support to reduce the work of
breathing and improve oxygenation. Patients with per-
sistent symptoms, abnormal chest x-rays and diuretic
resistance might benefit from alternative approaches to
management. These could include beta agonists and
pentoxifylline, but these drugs clearly need more study
in randomized controlled trials.
AUTHOR CONTRIBUTION
All authors participated in the literature review and
manuscript drafting. All authors approved the final version
of the manuscript.
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Submitted March 28, 2019; accepted September 27, 2019.
Financial Support: None.
The authors have no conflicts of interest to disclose.
Correspondence: Kenneth Nugent, MD, Texas Tech University Health
Sciences Center, Department of Internal Medicine, 3601 4th Street,
Lubbock, TX 79430 (E-mail: Kenneth.Nugent@ttuhsc.edu).
397