Download Acute pulmonary oedema: rare causes and

Clinical Science (2003) 104, 259–264 (Printed in Great Britain)
Acute pulmonary oedema: rare causes and
possible mechanisms
Yung-Hsiang HSU*, Shang Jyh KAO†, Ru-Ping LEE‡§ and Hsing I. CHEN‡
*Department of Pathology, Tzu Chi University, Hualien, Taiwan, †Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan,
‡Institute of Medical Sciences, Tzu Chi University, 701, section 3, Chung-Yan Road, Hualien 97004, Taiwan, and §Department
of Nursing, Tzu Chi University, Hualien, Taiwan
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Acute pulmonary oedema usually has a fatal outcome. In this clinical report, we present rare
cases of pulmonary oedema that were associated with Japanese B encephalitis, lymphangitis in
breast carcinoma, fat embolism due to long-bone fracture, and the rupture of cerebral mycotic
aneurysms. A total of 18 patients in the four disease categories were collected in two teaching
hospitals in Taipei and Hualien. Upon admission, routine and specific examinations were taken
and all patients showed clear lungs by chest X-ray ; however, signs of acute pulmonary oedema
occurred within 7 days. After resuscitation, all patients died of acute pulmonary oedema. In
patients with fat embolism, the levels of non-esterified plasma fatty acids, cGMP, 5-hydroxytryptamine (serotonin) and nitrates/nitrites were increased during pulmonary oedema.
Immunohistochemical staining revealed virus infection and neuronal death, predominantly in
the medial, ventral and caudal medulla in cases of Japanese B encephalitis. The pulmonary
oedema due to central sympathetic activation in Japanese B encephalitis may be related to
destruction of depressor mechanisms in the medulla. The rupture of mycotic aneurysms is
known to cause cerebral compression that results in acute pulmonary oedema. Blockade of
lymphatics, capillaries and venules in breast carcinoma with lymphangitis causes the development
of rapid lung oedema. The pathogenesis of pulmonary oedema is much more complicated in fat
embolism. Mediators such as cGMP, 5-hydroxytryptamine, nitric oxide and presumably other
chemical substances may also be involved.
INTRODUCTION
Oedema formation depends on the balance between
hydrostatic and oncotic forces in capillaries and their
interstitial forces and lymphatic drainage [1,2]. In humans
and animals, acute pulmonary oedema can occur owing
to cerebral compression [3–5], enterovirus infection in
hand, foot and mouth disease [6], endotoxin shock [7,8],
air embolism [9,10] and ischaemia–reperfusion [11,12]. In
this clinical investigation, we investigated 18 cases of
acute pulmonary oedema associated with Japanese B
encephalitis, breast carcinoma with lymphangitis, fat
embolism and ruptured cerebral mycotic aneurysms. We
report rare types of death associated with pulmonary
oedema caused by different mechanisms.
MATERIALS AND METHODS
Patient population
Data from all patients were collected over a period of
more than 2 years. Patients were evaluated in two
Key words : breast cancer, fat embolism, Japanese B encephalitis, mycotic aneurysm, pulmonary oedema.
Correspondence : Professor Hsing I. Chen (e-mail chenhi!mail.tcu.edu.tw).
# 2003 The Biochemical Society and the Medical Research Society
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Table 1
Basic data, major clinical findings and autopsy findings in patients that died from acute pulmonary oedema
F, female ; M, male ; BW, body weight ; BH, body height ; MBP, mean blood pressure ; LW, lung weight ; PAP, pulmonary arterial pressure.
n
Sex
Age
(years)
BW
(kg)
BH
(cm)
MBP
(mmHg)
LW
(g)
PAP
(mmHg)
Japanese B encephalitis
6
3F ; 3M
25–44
48–67
162–178
114–136
870–969
56–68
Breast carcinoma
with lymphangitis
2
F
44–58
62–70
158–172
118–124
658–832
28–32
Fat embolism
6
3F ; 3M
58–62
68–74
164–180
112–120
520–634
34–39
Rupture of cerebral
mycotic aneurysm
4
2F ; 2M
42–72
58–71
146–186
146–186
962–1004
62–72
teaching hospitals. Table 1 shows the basic major
laboratory and pathological findings. After obtaining the
consent from either patients or their relatives, a total of 18
patients was studied : six with Japanese B encephalitis,
two with breast carcinoma and lymphangitis, six with fat
embolism and four in which mycotic aneurysms ruptured
into cerebral ventricles.
Major clinical and autopsy findings
Haemorrhagic pulmonary oedema,
increase in neutrophils, lymphocytes
and monocytes, virus infection in
lower brain-stem
Jaundice, pleural effusion and ascites,
disseminated intravascular
coagulation, progressive
leukocytopnea and anaemia
Focal lung congestion and oedema,
thromocytopnea, increase in nonesterified plasma fatty acids,
cGMP, 5-hydroxytryptamine and
nitrates/nitrites
Massive haemorrhagic pulmonary
oedema, hypertension, sudden
developement of malignant
hypertension, ventricular
hypertrophy, endocarditis, blood
clots in cerebral ventricles
pathological lesions. Lungs were removed, weighed
and inspected. Lung tissues were then sectioned and
stained with haematoxylin and eosin. In patients with
Japanese B encephalitis, an immunohistochemical stain
with mouse anti-Japanese B encephalitis monoclonal
antibody was used to localize virus infection in the brain
stem [20,21]. Fat in tissues from patients with fat
embolisms was stained using methods described by
Schemitsch et al. [22].
Examinations
Upon admission, all patients received routine check-ups
including measurement of body weight, body height and
blood pressure, and analysis of blood, urine and stool
samples ; chest X-rays were also taken. Free plasma
fatty acid, cGMP, 5-hydroxytryptamine (serotonin) and
nitrates\nitrites were determined according to methods
that were described previously [13–16]. These were
measured because pulmonary oedema might be induced
by chemical factors [9,17,18] ; for example, our recent
report [19] and many others [8,11,18] have revealed that
nitric oxide (with nitrate and nitrite end-products) is
toxic to the lung and may be the mediator that causes
severe lung injury after endotoxin shock and ischaemia–
reperfusion. We further demonstrated that lung itself is
the major site for the production of nitric oxide that
causes pulmonary oedema [19]. In the case of fat
embolism, the levels of non-esterified fatty acids, cGMP
and 5-hydroxytryptamine were found to be increased
[17] ; however, it is uncertain if nitric oxide is involved.
At post mortem, all organs were examined for gross
# 2003 The Biochemical Society and the Medical Research Society
RESULTS
Table 1 summarizes the basic data and major clinical
findings for patients who died from acute pulmonary
oedema due to Japanese B encephalitis, breast carcinoma
with lymphangitis, fat embolism and disruption of
mycotic aneurysms into cerebral ventricles. X-rays
revealed that all patients had clear lungs on admission ;
however, dyspnoea, cyanosis, generalized weakness and
heart arrest occurred within 7 days of hospitalization
and all patients subsequently died as a result of an acute
episode of pulmonary oedema. Before death, measurement of pulmonary arterial pressure using a Swan–Ganz
catheter revealed a high level in all patients, compared
with the normal value of 12–17 mmHg [2]. The lung
weight in all patients increased remarkably from the
normal value (350–400 g), particularly in cases of
ruptured cerebral aneurysm and Japanese B encephalitis
with viral infection in lower brain-stem.
Rare causes of pulmonary oedema
Figure 1 Pathological images in the lung of patients with
Japanese B encephalitis
(A) Section of lung tissue stained with haematoxlin and eosin showing severe
haemorrhagic oedema (magnification i200). (B) A brain-stem section showing
diffuse neurological nodules and neurophagia (haematoxlin and eosin ; magnification i200).
Figure 1 shows the pathological changes that occurred
in the lung of a representative Japanese B encephalitis
patient. The normal alveolar structure had disappeared
and air spaces were filled with red blood cells and
exudates (Figure 1A). Staining of the brain-stem revealed
extensive virus infection in neurons and the formation of
nodules (Figure 1B).
Immunohischemical staining of the brain-stem in
patients with Japanese B encephalitis showed virus
infection in neurons and in axonal and dendritic processes
(Figure 2A). Cross sections (Figure 2B) and longitudinal
sections (Figure 2C) revealed positive staining for virus
infection, predominately in the medial, ventral and caudal
areas of the medulla oblongata.
Figure 3 shows pathological changes occurring in the
lungs from patients with breast carcinoma and lymphangitis (Figure 3A) and from patients with fat embolism (Figure 3B). In two cases of breast carcinoma (one
on the left breast, and the other on the right), a marked
lymph oedema was found in the arm on the cancer side.
Approx. 700 ml of fibrinosanguinous pleural effusion
was collected from the lesioned side, with 50–70 ml
present on the contralateral side. Multiple metastatic
cancer masses were found in the axillary, para-aortic
lymph nodes, chest wall, pleura, kidney and liver. In fat
embolism caused by fracture of the femur and tibia,
progressive decreases in haemoglobin levels and oxygen
saturation were observed. Microscopic examination
revealed fat droplets, not only in the lungs, but also in
other organs. In four cases with ruptured mycotic
aneurysm, the episode of acute pulmonary oedema was
very sudden and patients died within 2 days ; they were
admitted with symptoms such as headache, weakness and
dizziness. Measurement of blood pressure in these
patients revealed hypertension with a mean blood pressure of 146–186 mmHg. Patients were given anti-hypertensive drugs and then received a detailed physical
examination ; however, they developed vomiting and a
rapid loss of consciousness on the following day. A
sudden episode of acute pulmonary oedema occurred and
mean blood pressure was high, exceeding 210 mmHg.
Measurement of intracranial pressure through a puncture
into the foraman magna revealed that intracranial pressure was also elevated to more than 170 mmHg and
cerebrospinal fluid contained blood. Histological section
of the brain revealed massive blood clots in cerebral
ventricles (results not shown).
The changes in free plasma fatty acid, cGMP, 5hydroxytryptamine and nitrate\nitrite concentrations
before and after pulmonary oedema are shown in Table 2.
Although these substances were significantly elevated in
six patients with fat embolism after the onset of signs of
pulmonary oedema, chemical changes in other types
of pulmonary oedema were not significant.
DISCUSSION
Acute oedema occurring in the lung has a high clinical
risk because it can affect the pulmonary gas exchange
[2,5,23]. Guyton and Hall [2] studied the effect of elevated
left atrial pressure and decreased plasma proteins on the
development of pulmonary oedema. They found that left
atrial pressure greater than 25 mmHg caused fluid accumulation in the lung ; the degree of oedema increased
with the level of left atrial pressure. Fishman and Pietra
[23] used haemoglobin as a tracer ; the studies in dogs had
similar findings. When the pulmonary arterial pressure
was kept at 15 mmHg for 10 min, the electron micrograph showed that haemoglobin was confined in the
vascular lumen. Endothelial and epithelial junctions, and
the interstitial space appeared normal. Increasing pulmonary arterial pressure to 40 mmHg for 10 min induced
interstitial oedema. Endothelial junctions were widened
and the lung interstitial space was filled with tracer
haemoglobin ; however, the epithelial junctions prevented the escape of oedema fluid into the alveolar space.
# 2003 The Biochemical Society and the Medical Research Society
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Y.-H. Hsu and others
Figure 2
Immunohistochemical stain showing brain-stem lesions in patients with Japanese B encephalitis
(A) Immunohistochemical staining of the brain-stem with anti-Japanese B encephalitis viral monoclonal antibody in the brain stem (magnification i400). The virus
infection involves both neurons and dendrites. In six cases of Japanese B encephalitis infection, the distribution of positive staining is predominant in the medial and
caudal portions of the medulla (horizontal section) (B). The cross-section (C) indicates that lesions are found mainly in the ventral portion of the medulla. In (B)
and (C), the scales are divided into 1-mm segments.
At this point, the lung oedema was reversible when the
pulmonary arterial pressure was returned to 15 mmHg.
As pulmonary arterial pressure was further elevated to
70 mmHg for only 3 min, the tracer leaked into the
alveolar space, with disruption of the epithelial junctions.
The severity of this lung oedema was irreversible and
caused alveolar flooding.
Since 1973, our laboratory has carried out a series of
studies in the neural and haemodynamic mechanisms
of neurogenic pulmonary oedema caused by either head
injury or intracranial hypertension [3,4,24]. We found
that cerebral compression caused a rapid increase in
systemic arterial pressure and left atrial pressure. Microscope images showed the alveolar space filled with blood
cells and the perivascular space was severely distended.
High-power microscopy revealed congestion and rupture of vascular wall, with leakage of blood cells into
surrounding spaces. Electron microscopic observation
showed that endothelial and epithelial junctions were
markedly stretched and ruptured. Leaking of blood
cells and plasma through the damaged endothelial and
epithelial barriers resulted in severe alveolar oedema,
similar to the lung pathology of alveolar flooding [3].
In a later study of the mechanism of volume and
pressure loading in the pulmonary circulation, we found
that cerebral compression or increased intracranial pressure caused imbalance in the right and left cardiac output.
The aortic flow rapidly decreased to 45–50 % of the
normal value, but the pulmonary arterial flow increased
at first and then decreased with the aortic flow. In the rat,
# 2003 The Biochemical Society and the Medical Research Society
the cardiac output imbalance caused an approx. 6-ml shift
of the blood volume from the systemic circulation to the
lung. Finally, left atrial pressure increased to 40–
50 mmHg and fulminant pulmonary oedema occurred
[4,24]. These studies suggested that over-activation
of the medullary sympathetic vasomotor mechanisms
was the major cause of these pulmonary changes, because
vagotomy, decerebration and adrenalectomy did not
affect these pulmonary pathological changes [3,4,24]. In
the present report, four patients had long-term hypertension without treatment and acute pulmonary oedema
suddenly occurred following intracranial hypertension
due to the rupture of cerebral aneurysms. It is interesting
that one patient was relatively young, only 42 years old.
Accordingly, long-term hypertension, as evidenced by
ventricular hypertrophy, can also occur in the relatively
young adult. The mechanisms of pulmonary pathological
changes may be similar to those in the rat that underwent
cerebral compression as described above. In addition,
the levels of plasma chemicals were not increased in
these patients, suggesting that compression of the brain
was the major cause of pulmonary oedema.
Japanese B encephalitis virus is among of the most
common causes of arthropod-borne human encephalitis.
Major epidemics of encephalitis have been recorded in
Japan since 1870s, and the virus was discovered in 1934.
The prevalence of Japanese B encephalitis has declined in
Taiwan because of routine immunization of children
[6,25]. We studied six cases in two Taiwanese hospitals
over a 2-year period. Clinical manifestations and patho-
11.4p1.2 (8.0–12.6)
11.8p1.4
48.6p10.2* (42.8–54.4)
13.8p4.2 (11.9–15.6)
10.2p0.9 (8.2–12.4)
11.7p1.2
19.5p4.8 (18.6–20.4)
13.3p2.6 (12.2–14.4)
22.2p5.6 (19.0–24.9)
20.4p4.8
1055.6p41.2* (988.4–1122.8)
27.1p6.3 (19.8–34.4)
20.4p6.8 (18.2–24.8)
18.6p5.6
21.1p7.4 (19.4–22.6)
26.5p5.8 (20.4–32.6)
4.83p1.74 (0.35–0.53)
4.52p0.06
51.63p4.48* (46.82–56.44)
4.87p1.23 (4.52–5.22)
4.68p1.63 (0.37–0.52)
4.54p0.09
11.33p1.33 (9.86–12.80)
4.51p1.49 (4.42–4.60)
0.44p0.07 (0.33–0.46)
0.52p0.08
57.34p3.22* (52.34–62.42)
0.44p0.12 (0.40–0.48)
0.46p0.08 (0.38–0.48)
0.51p0.07
0.48p0.09 (0.44–0.52)
0.46p0.08 (0.38–0.54)
6
2
6
4
Japanese B encephalitis
Breast carcinoma with lymphangitis
Fat embolism
Rupture of cerebral mycotic aneurysm
Before
After
Before
After
Before
After
Before
n
0.01). Results are expressed as meanspS.E.M.
5-Hydroxytryptamine (ng/ml)
cGMP (pmol/ml)
Non-esterified fatty acids (mmol/l)
logical findings demonstrated that these patients had viral
infections in the medulla oblongata (Figure 2) and
medullary depressor areas were destroyed [26], which led
to extensive activation of the sympathetic system, a
mechanism similar to that associated with severe haemorrhagic oedema induced by cerebral compression in the
in the lungs of the rat [3,24]. Since Chang et al. [6]
reported fulminant neurogenic pulmonary oedema in
patients with enterovirus infection, the pattern of Japanese B encephalitis and enterovirus infections certainly
suggests that viral infection involving the lower brain
stem is the major cause of acute pulmonary oedema.
In a review article, Bruce et al. [27] reported that 46 %
of patients with lymphangitis carcinomotosa developed
respiratory insufficiency. To our knowledge, breast
carcinoma with severe pulmonary hypertension and
pulmonary oedema due to multiple obstructions of
capillaries, venules and lymphatics (Figure 3) has not
been described. Jaundice, pleural effusion, ascites and
disseminated intravascular coagulation were present
in two cases of breast carcinoma with lymphangitis ;
however, non-esterified plasma fatty acid, cGMP,
5-hydroxytryptamine and nitrate\nitrite levels were not
*Significant difference compared with the level before episode of pulmonary oedema (paired t test, P
(A) The micrograph shows infiltrating ductal carcinoma with massive blockade of
venules, capillaries and lymphatics (arrows) (magnification i200). (B) Fat
staining reveals multiple fat droplets in the lung parenchyma (magnification
i200).
Table 2
Figure 3 Lung oedema in a case of breast cancer with
lymphangitis
Non-esterified fatty acid, cGMP, 5-hydroxytryptamine and nitrate/nitrite levels before and after acute pulmonary oedema
Nitrates/nitrites (pmol/ml)
After
Rare causes of pulmonary oedema
# 2003 The Biochemical Society and the Medical Research Society
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Y.-H. Hsu and others
significantly changed, which suggests that mechanical
factors play an important role in the development of
pulmonary hypertension and oedema.
Fat embolism after a crush injury is a serious clinical
problem [17]. Fat staining revealed the presence of fat
droplets, not only in lung tissue (Figure 3B), but also in
the case of fat embolism after fracture of the femur and
tibia (three cases of each). Non-esterified plasma fatty
acid, cGMP, 5-hydroxytryptamine and nitrate\nitrite
levels were significantly increased in these patients. To
our knowledge, this report is the first to suggest the
possibility of nitric oxide involvement in the lung
injury following fat embolism. The formation of nitric
oxide and other free radicals such as hydroxyl and peroxynitrite has been shown to be detrimental to lung and
other tissues [18,28]. The findings in our patients
indicate that nitric oxide may serve as a toxic substance
that causes acute pulmonary oedema. More animal or
human studies are required to clarify the role of nitric
oxide in pulmonary oedema formation associated with
fatty acid embolism.
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ACKNOWLEDGMENTS
The present study was supported in part by Grants from
the National Science Council (NSC 90-2320-B-002 and
90-2320-B-320-004), Outstanding Scholarship Development (1996-2001) and Shin Kong Wu Ho-Su Memorial
Hospital Foundations. Authors are grateful to Lucy Y. I.
Chen (Department of Psychology, Simon Fraser University) and Dr Aubrey E. Taylor (University of Alabama
College of Medicine, Mobile, AL, U.S.A.) for their help
in preparation of this manuscript.
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Received 21 June 2002/28 October 2002; accepted 9 December 2002
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