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accp consensus statement
Primary
Pulmonary
Chairman:
LewisJ.
Rubin,
M.D.,
1993;
104:236-50)
(Chest
PPH
=
primary
pulmonary
veno-ocelusive
disease;
PVOD
hypertension;
RAP
right
DEFINITIONS
AND
Primary
pulmonary
ferred
to as unexplained
atrial
Hypertension*
F.C.C.P
the population
ofpatients
with
pressure
(PPH),
also
is a disease
reor
and
syn-
with
this disease.
The
vast
clinical
PPH has a pulmonary
are
arteriopathy,
logic evidence
editorial
see
page
5
for
PPH
characteristic
pulmonary
pertension,
,
arteriopathy
because
ofpatients
hypertension
toxin-induced
similar
is not
pathogno-
changes
are
with congenital
associated
pulmonary
of PPH
pulmonary
subsets
PPH
have
Subsets
been
iden-
heart disease,
with
portal
hyhypertension,
HIV-related
pulmonary
hypertension.
For practical
management,
a clinical
definition
of
PPH
is sufficient
for most patients.
A useful
clinical
definition
is the presence
of pulmonary
hypertension
(mean pulmonary
artery
pressure
>25 mm Hg at rest,
In
was
distinct
entities.
the past,
plexogenic
considered
hypertension,
to be ofcritical
the
hallmark
and plexogenic
diagnostic
and
pathogenetic
significance.
The grading
system
developed by Heath and Edwards5
to assess the reversibility
of hypertensive
vascular
lesions
in biopsies
heart disease
was extrapolated
congenital
unproven
assumption
that
of patients
to PPH
the pathogenesis
and
evolution
ofplexogenic
pulmonary
arteriopathy
would
be identical
regardless
ofcause.
Several
recent
studies
in large
series
of patients
with
clinical
PPH
have
shown
also
arteriopathy
of primary
pulmonary
lesions
were considered
on the
although
a few patients
will have pathoof other
diseases
or even normal
lung
Pulmonary
monic
comment
three
felt at present
to represent
Pulmonary
Arteriopathy:
with
For
of Pathologic
tified pathologically.
However,
pulmonary
veno-occlusive disease
and pulmonary
capillary
hemangiomatosis
ETIOLOGY
hypertension
or idiopathic,
and Description
Historically,
pulmonary
constellation
of diseases
described
at both clinical
pathologic
levels.
However,
neither
the clinical
drome
nor
the
pathologic
changes
independently
define
majority
Definition
that
primary
a spectrum
pulmonary
arteriopathy
of histopathologic
classic
plexogenic
nonplexogenic,
includes
lesions
artenopathy
forms.
The three
ranging
from
to microthrombotic,
major
types
of pul-
and
or
>30
artery
causes
5Consensus
mm
Hg
wedge
(Table
during
exercise),
pressure,
1).
Conference
F.C.C.P
(Chairman),
and Critical
Care
and
normal
absence
pulmonary
of
secondary
Lung
C
Professor
Medicine,
Lewis
J.
Rubin,
M.D.,
1 -Secondary
ofPulmonary
Causes
Hypertension
disease
Parenchymal
lung
disease
. Disorders
of ventilation
. Congenital
anomalies
. Hypoxia-induced,
le, altitude
Heart
Participants:
and Head,
Division
of Pulmonary
University
of Maryland
School
of
Medicine,
Baltimore;
Robyn j Barst, M.D.,
Associate
Professor
of
Clinical
Pediatrics,
Columbia
University,
New
York; Larry
R.
Kaiser, M.D. , F.C.C.P,
Chief,
General
Thoracic
Surgery,
Associate
Professor
of Surgery,
University
of Pennsylvania,
Philadelphia;
Spencer
K. Koernet; M.D. , EC.C.P,
Director,
Pulmonary
Division, Cedars-Sinai
Medical
Center,
Professor
of Medicine,
UCLA
School
of Medicine,
Los Angeles;
James E. Lyd,
M.D.,
F.C.C.P,
Associate
Professor,
Division
of Pulmonary
and Critical
Care
Medicine,
Vanderbilt
University,
Nashville,
Tenn;
Michael
D.
McGoon,
M.D. , Associate
Professor
of Medicine
and Consultant
in Cardiovascular
Diseases,
Mayo
Clinic,
Rochester,
Minn;
Giuseppe Pietra, M.D. , F.C.C.P,
Professor
of Pathology,
University
of Pennsylvania
Medical
School,
Department
of Pathology
and
Laboratory
Medicine,
Philadelphia;
Stuart Rich, M.D.,
F.C.C.P,
Professor
of Medicine,
Chief,
Section
of Cardiology,
University
of
Illinois,
Chicago;
Melvyn
Rubenfire,
M.D.,
F.C.C.P,
Professor
of
Internal
Medicine,
University
of Michigan,
Ann Arbor;
James
Theodore,
M.D.,
F.C.C.P,
Associate
Professor
of Medicine,
Division ofPulmonary
and Critical
Care Medicine,
Stanford
University
School
of Medicine,
Palo Alto, Calif.
Reprint requests: ACCI
3300 Dundee
Road, Northbrook,
IL 60062
236
Table
.
disease
Disorders
ofleft
C Congenital
Thromboembolic
.
heart
systemic
disease
Pulmonary
C
Mediastinal
.
Congenital
.
Foreign
filling
-
to
-
pulmonary
or obstruction
shunts
of pulmonary
vessels
thromboembolism
fibrosis
stenosis
ie, talc
bodies,
. Tumor
C Hemoglobinopathies
.
Schistosome
Collagen
eggs
vascular
Conditions
associated
Exogenous
substances
.
Anorexic
Portal
with
and
pulmonary
pulmonary
vasculitides
hypertension
agents
. Toxic rapeseed
. L-tryptophan
. Crack cocaine
HIV
diseases
oil
infection
hypertension
Primary Pulmonary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
Hypertension
(Lewis
J. Rubin et a!)
monary
are
arteriopathy
as
follow:
medial
involving
(1)
isolated
hypertrophy
the
muscular
medial
and
concentric
tosis,
which
may
or may
plexiform
lesions,
angiomatoid
sis, and necrotizing
arteritis;
arteries
Clinical
hypertrophy;
laminar
(2)
fibroelas-
soon
not be associated
with
lesions,
fibrinoid
necroand (3) medial
hypertro-
the Heath-Edwards
with hemodynamic
grading
indices
PPH:
after
the
Families
different
the
NIH
between
PPH
do
Histopathologic
changes
timal fibrosis
of muscular
veno-occlusive
of pulmonary
would
be
pulmonary
occlusive
similar
capillaries
pulmonary
disease
preferable
to call
angiopathy
rather
disease.
Although
and
this
than
its
arteries
suggests
in cases
that
it
entity
obstructive
pulmonary
venocause
is unknown,
cases
have
histopathologic
presence
of
pulmonary
hallmark
organized
veins
and
and
of
this
disease
recanalized
venules.
These
thrombi
rence
thrombi
are often
pads not only
arteries.
The
arterialization,
the alveolar
capillaries
are extremely
pleural and peribronchial-perivascular
dilated,
the pulmonary
and pleural
congested,
lymphatics
centric
and the alveoli
macrophages.
the
are
interstitium
contain
Medial
numerous
hypertrophy,
is
ec-
concentric
nonlaminar
intimal
fibrosis,
and fibrinoid
necrosis
of pulmonary
arteries
are
also
present.
Pulmonary
is a rare
Capi&iry
condition
of thin-walled
chial-perivascular
the affected
elastic
muscular
characterized
microvessels
interstitium,
and the
walls of pulmonary
expansion
Hemangiomatosis
1
infiltrating
the peribronthe lung parenchyma,
These
microvessels
veins
of different
infiltrate
diameter,
ofthe
media,
fibrous
luminal
vessels,
and destruction
fibers.
There
arteries
and
The proliferating
to bleeding,
by the
is also medial
muscularization
macrophages
the
with
hypertrophy
ofthe arterioles.
are prone
accumulation
in alveolar
spaces.
of
patients,
not
and has
analysis
by incomplete
transmitted
is
manifest
to
predisposfeatures,
is complex
The genetic
is confounded
the
gene
ex-
was diagnosed
probably
due
the
disease.
by
A few
reported
and
for
generations,
.
both
capillary
A
is
familial
occur-
pulmonary
veno-
hemangiomatosis.’
10.16
in Children
the
histopathologic
differences
appear
children.
Syncope,
findings
to be most
with
in children
presenting
symptom
often
effort-related
patients
younger
with PPH.
children,
over
10 years
Childhood
ratio
with
occurs
of symptoms
in children
severe,
with
long-standing
equal
4
frequency
and time
of diagnosis
than in adults,
particularly
to the 2- to 3-year
median
patients.
The age at diagnosis
most
important
useful
PPH
of survival
(mean
pressures
and
hemodynamics
and
responses
significantly.’7
lator
predictor
parameters
PPH.
to male
between
is usually
in those
for PPH,
diagnosis
as
survival
appears
in adult
to be the
in children.
The
pulmonary
cardiac
index)
artery
that
are
in predicting
survival
in adult
patients
with
may not be applicable
to the pediatric
population.
Baseline
younger
a
in female
to 1.7:1 female
The interval
PPH
and right atnal
is
children
and
than in adult
children
who present
with syncope.
Prior
to the era of vasodilator
treatment
most
children
died
within
1 year
of
hemodynamic
younger
seizures,
in young
in children
male children
as opposed
seen
in adult
onset
shorter
in the
without
Right
heart
failure
is rare in the
occurring
most
often
in children
of age
PPH
apparent
or
frequent
is more
opposed
obstruction
of
of the medial
thin-walled
microvessels
resulting
in hemoptysis
and
of hemosiderin-laden
(PCH):
This
proliferation
transmission
established.
The
not
with PPH are often the same as those in adult patients
with PPH, the clinical
presentation,
natural
history,
and factors
influencing
survival
may
differ.
These
and
hemo-
and
been
disease
Although
associated
with eccentric
fibrous
intimal
in venous
vessels
but also in muscular
veins
show
medial
hypertrophy
and
edematous,
siderin-laden
has
PPH
is the
in
recognized
sporadic
of onset
is younger
in subsequent
present
in many families
with PPH
occlusive
have been observed
in patients
treated
chemotherapeutic
agents,7’8
and familial
been
reported.9”#{176} As the name
indicates,
by
documented
instances
of father
to son transmission
of
the gene
suggested
it is not x-linked.
An interesting
phenomenon,
genetic
anticipation,
in which
the age
lesions
with certain
the
in the alveolar
arteries
were
considered
to be secondary
obstructions.
The
frequent
presence
of
eccentric
and concentric
nonlaminar
in-
and
PPH
Although
the gene
appears
to have dominant
who
pulmonary
to venous
widespread
for
in
recorded
15
individuals
botic
registry
familial
PPH
which
it was
thromveins.6
were
cept that in familial
PPH,
the disease
earlier
after
the onset
of symptoms,
with
in
because
PPH
and
heightened
ing to familial
obstructive
venules
and
with
disease
in 12 (6 percent)
of 187 patients.’4
manifestations
and outcome
of PPH were
of families
penetrance,
so designated
described
of PPH
1984,’
hypertension,
was
were
description
familial
clinical
the mode
of genetic
not been definitively
to be caused
by a primary
disorder
of the pulmonary
PPH
clinical
families
Pulmonary
Veno-occiusive
Disease
(PVOD):
Venoocclusive
disease,
an uncommon
cause
of pulmonary
thought
with
original
Fourteen
1951.12
phy and eccentric
and concentric
nonlaminar
fibrosis.
Plexogenic
pulmonary
arteriopathy
is a nonspecific
pattern
of response
of the pulmonary
vasculature
to
hemodynamic
injury,
and
system
does not correlate
and prognosis.2
Subsets
Familial
older
are
children,
as well as
Histopathologic
long-term
studies
CHEST
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often
although
similar
in
chronic
vasodi-
the
survival
differ
offer clues
to
I 104 I 1 I JULY, 1993
237
the findings.
In the
Wagenvoort,4
classic
not only
was
studies
by Wagenvoort
medial
hypertrophy
and
severe
in patients
the only
reactive
under
15 years ofage,
but it was also often
change
in infants,
suggesting
a more
vasopulmonary
vascular
bed
in the
youngest
children.
The youngest
children
long-term
vasodilator
kilogram)
of calcium
better
to
(per
doses
be needed
with PPH
to produce
compared
also tend to respond
treatment.
Higher
channel
blockers
may
a favorable
to adult
response
in children
for insomnia,
More
than
Exogenous
With
Vasculopathy
Pulmonary
Hypertension:
Pulmonary
Drug-Induced
Hypertension
Pulmonary
deaths.
myalgia,
disease
syndromes
infiltration,
pleural
sion.
The
Anorexic
agents
(aminorex,
fenfluramine):
An
epidemic
ofchronic
pulmonary
hypertension
occurred
in Switzerland,
Austria,
and Germany
in the late 1960s
in association
with
the use of aminorex
(2-amino-S..
phenyl-2-oxazoline),
an appetite
suppressant
with
a
chemical
structure
similar
to adrenaline
and ephedrifle.’9
This
drug
was released
into
the market
in
Switzerland
in 1965 and was withdrawn
in 1968.
A
20-fold increase
hypertension
1969, and
ofaminorex
timing,
and
mates
suggest
in
ofchronic
pulmonary
1967,
peaked
after
1972. The
from
1968
association
ofpulmonary
is strong relative
but
stood,
developed
incidence
started
disappeared
the epidemic
and
in the
the
the
hypertension
to geographic
exact
only
is not
remains
1 out of 1 ,000
pulmonary
with the use
distribution
relationship
mechanism
that
under-
unsolved.
users
hypertension.
Esti-
ofaminorex
However,
the
incidence
of pulmonary
hypertension
also was
increased
in individuals
who did not report
the use of
aminorex,
and the disease
syndrome
could
not be
reproduced
in animals,
even
after
trials
in several
species
in whom
aminorex
was
administered
for up to
2 years.
pathologic
pulmonary
condition
hypertension
idiopathic
pulmonary
were characterized
arteries
laminar
lesions,
Four
is
diffuse
hypertension
methyl
which
of fenfluramine
3(trifluromethyl)
An epidemic
myalgia
and
in New
syndrome
L-tryptophan,
238
with
progressive
developed
vasculitis,
and
veins.
was
also
Mexico
(EMS)
characterized
eosinophilia
pulmonary
The
with
that
included
pulmonary
phenomena,
of the
patients
hyper-
and
death.
vasculitis
was
widearter-
characterized
by
and transmural
infiltrates
eosinophils.
In three
patients,
intimal
arteries
and
was associated
condition
and
of
be-
five patients
showed
vasculitis
involving
both
fibromyxoid
pulmonary
of EMS
embolic
dense
perivascular
phocytes
and few
it is suspected
thickening
of lymthere
of muscular
veins. The vascular
pathologic
with
mild interstitial
pneu-
interstitial
accumulation
of lymphocytes
and eosinophils.
(c)
Chemotherapy-related
pulmonary
hypertension:
Several
therapy
agents
patients
with PVOD
developing
after chemohave been
reported.
Some
of the implicated
include
carmustine,
bleomycin,
cyclophospha-
mide,
etoposide
and
(d) Crack
cocaine
four young women
hypertension
pulmonary
cocaine.m
disease
males.
mitomycin-C.7’8
inhalation:
who developed
A recent
clinical
and hypertensive
arteries
in association
The authors
suspected
in
females,
since
changes
in muscular
with smoking
crack
a predisposition
for
the
Pulmonary
report
cited
pulmonary
majority
Hypertension:
at
risk
were
Toxins
oil syndrome:
The toxic oil syndrome
disorder
which
was related
to the
from
reported
cases
of muscular
sumption
of an
oil in Spain
in 1981.”
More
than 20,000
cases were
and many deaths
were related
to pulmonary
subsequent
or dexfenfluramine
benzene-ethanamine
amine
complex
Both epidemics
polyneuropathy,
Lung
biopsies
from
spread
nonnecrotizing
ies
but
pulmonary
hyperten-
(a) Toxic
multisystem
indistinguishable
arteriopathy.
The
by medial
hypertrophy
drochloride),
a sympathomimetic
as an appetite
suppressant.
(b) L-tryptophan-associated
sion:
aminorex-associated
and muscularization
of arterioles,
concentric
intimal
fibrosis,
plexiform
and angiomatoid
fibrinoid
necrosis,
and siderosis.
patients
have been
reported2#{176}’2’ with pulmo-
the use
and
of
to
toxic byproduct
or contaminant
analogy
has been
suggested
symptom
oil syndrome.
Exogenous
The
nary
the
is unknown,
ofa
An
toxic
monia
to
of
have included
diffuse
effusion,
and pulmonary
mechanism
tension,
( a)
syndrome.
reported
for Disease
Control,
including
several
Common
clinical
manifestations
have included
arthralgia,
dyspnea,
and cough.
Pulmonary
to be the result
L-tryptophan.
18
or premenstrual
cases
have been
the Center
tween
Associated
Conditions
depression,
1,400
EMS
reported,
to
distress
and
by a second
developed
hy-
Pulmonary
use
this second
scleroderma,
hyperten-
by a syndrome
was first recognized
marketed
hypertension.
The syndrome
an early
systemic
syndrome
(N-ethyl
in current
illegally
of
in 1989.
The
eosinophilia-myalgia
was soon linked
to consumption
of
which was available
over the counter
had several
that included
pulmonary
infiltrates,
stage
in which
one
fever,
was
A later
weight
a common
stage
loss
cooking
stages,
with
respiratory
which
was followed
third
of the patients
and neurologic
myalgias,
hypertension
stage.
with
rapeseed
is a
con-
symptoms.
problem
appeared
similar
and
neuromuscular
in
to
disorders.
In 1986 and 1987, severe
pulmonary
hypertension
was the leading
cause
of death
from toxic oil
syndrome.m
The
specific
toxic
agent
has not been
identified,
but oleoanilides
or toxic compounds
derived
from
them
The pathology
or both
are
is unique
Primary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
believed to be important.
but most closely resembles
Pulmonary
Hypertension
(Lewis
J. Rubin
eta!)
pulmonary
veins are
thelial
thelial
veno-occlusive
involved.
disease;
both arteries
consist
of
The initial lesions
injury
with marked
cells and vasoformative
proliferation
reserve
uisite
and
endo-
pulmonary
or of the
vascular
inflammatory
infiltrates.
The intimal lesions
subsequently
evolve
into obliterative
intimal
and luminal fibrosis
of arteries
and veins.
Medial
hypentrophy of muscular
arteries,
musculanization
of arterioles
plexiform
lesions
have been
(b) Portal
Hypertension-Associated
pertension:
Although
numerous
reports
four
decades
suggested
with portal
hypertension
ship is sufficiently
been
an
A large
strated
conclusively
McDonnell
et aP
Hopkins
from
occurred
in
that
reviewed
1944
to
percent
ofpatients
clinical
clinical
patients
prevalence
during
of pulmonary
the relation-
series
1981
and
found
of all patients,
with
cirrhosis
with
but
(p’(O.OOl).
biopsy-proven
of PPH
was
prospective
study
incidence
of pulmonary
is real;
at Johns
be contributory.
creased
nhosis
by
finding
with portal
hospitalized
mechanisms
rather
10 (2 percent)
that
are
than
unclear,
cirrhosis
of 507
positive
for
hypertension,
in 0.73
Of 2,459
HIV
itself,
appears
/
Endoth
to be the
been
either
type.
material
A recent
from a cohort
hypertension,
reported
of the
to have
plexogenic
type
Hypertenpatients
with
clinical syndrome
Pulmonary
described
the
on talc
vascular
obstruc-
granulomatosis
prospective
of 1,200
study
patients
HIV. Six patients
developed
supporting
an association
may
reported
who were
pulmonary
of PPH and
positivity.
AND
PATHOGENESIS
PATHOPHYSIOLOGY
Pat hogenesis
the inin cm-
The
patients
had PPH.
hypertension,
hypertension
but
portal
embolic
74 patients
PPH
cirrhosis,
the
0.61
percent
substantiated
hypertension
portal
that pulmonary
concern
tion from
(p<0.001).
A recent
have
HIV Infection-Associated
Several
case reports
have
infection
who developed
demon-
that
cirrhosis,
arteniopathy
micnothrombotic
additional
has
first
the relationship
17,901
autopsies
0. 13 percent
Hythe last
Pulmonary
that its existence
autopsy
HIV
hypertension.
with
of PPH.
One
early
report11
described
five patients
with hemophiliawho
developed
PPH;
all had received
intravenous
factor
VIII
for several
years
and tested
positive
for HIV
In individuals
who
develop
HIV
infection
related
to intravenous
drug
use,
there
is
reported.
association
hypertension,
infrequent
debated.
(c)
sion:
ofpulmonary
patients
with or without
of myoendocells and pen-
and even
for development
Pathologically,
The
prereq-
pathogenesis
of PPH
remains
speculative.
Fig-
ure 1 shows
the
for the pathogenesis
accepted
proposed
suggested
mechanisms
responsible
of this disease.
The most widely
mechanism
for the pathogenesis
of
PPH-pulmonary
vasoconstriction
is based
on
histo-
Ivury
and
Pu
Vasoconstricon
in Suscep8ble
Indvis
CoagtMtion
I7m
Pracoegulallon
Damaged
Pulmanaiy VascularBed
with Loss
PulmanyArriolea
of
PI-Ende1i
C
/
lnons
Throinbosas
m aftu
Abnormal
Vascular
A
Vascular
Pulmonaty
Response
Iniu,y with VIcious Cycle
Hyperlension
T Perpe’ua8gPu1monary
+
Crass-.ectlonalAre.
of
Pulmonary VascularBed
Plexc
and ThrOmbedc
PuknonaryMedopathy
FIGURE
1.
Possible
pathogenesis
CHEST/104/1/JULY,1993
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of PPH.
239
pathologic
studies
therapy.4”8’’#{176}
disease
stimuli
clinical
responses
studies
suggest
of predisposed
may initiate
the
istic vascular
is the primary
lesions.
event
an important
sible
and
These
triggers
individuals,
development
in whom
various
of the character-
ofpulmonary
include
(high altitude)
vasoconstrictor
endothelium,
balance
between
boxane
versus
derived
factors.
initiating
occur,
vascular
vasoactive
ments
surface
For
example,
not
also activate
between
the
and may contribute
injury.49’5#{176}
Migration
of smooth
to
of
vasocon-
aggregation.
and cellular
The
ele-
injured
endothelial
cell
ofthe
pulmonary
vascular
the
process
in situ,
muscle
cells
in the
cell
surface
and
transforming
the
pulmonary
of
in the
pathogenesis
that treatment
also resulted
in
of PPH
comes
with anticoagincreased
sun-
the
to the
hypertension
with a normal
ventricular
right
prolonged
filling
without
cardiac
pressure
exercise.
With
prolonged
an anatomic
decrease
in
and distensibility
of pulmonary
occurs
in addition
to vasoconstricresistance
vessels.
Initially,
the
output
remains
appropriately
pressures
becomes
overload
normal
at nest but does not
with exercise,
despite
an in-
and
ischemia.
decreased
develops
to increasing
heart
rate,
Eventually,
producing
the
cardiac
at rest. Right
ventricular
with tricuspid
regurgitation,
right
uting to failure.
also affects
left
ventricular
wall
stress
right
output
volume
leading
and contrib-
Severe
right ventricular
hypertension
ventricular
diastolic
function,
incneas-
ing left ventricular
end diastolic
pressure
and decneasing left ventricular
filling.
The pulmonary
capillary
wedge
and left ventricular
filling
pressures
may be
increased
episodes
in this setting.
in PPH are usually
effort-related
to a limitation
in cardiac
output.
Other
including
sympathetic
and parasympa-
alterations,
may
also play
Based
on the pathogenesis
PPH,
the two most frequent
progressive
right ventricular
a role.
and pathophysiology
of
mechanisms
ofdeath
are
failure
and sudden
death,
with the former
occurring
more often.M
sive right ventricular
failure,
the scenario
With pnogresas described
above leads to dyspnea,
hypoxemia,
and a progressive
decrease
in cardiac
output.
Pneumonia
commonly
is
fatal due to alveolar
hypoxia
causing
further
pulmonary
vasoconstriction,
with an inability
to maintain
adequate cardiac
and death.
occur,
vival.
return
crease
in right
ventricular
filling
pressure.
Right
ventricular
myocandial
blood
flow may be compnomised
by increases
in right
ventricular
systolic
and
thetic
vas-
in response
right
to
venous
in filling pressures.
artery
hypertension,
a normal
area
accommodates
systemic
Pulmonary
failure
occurs
vessels
pulmonary
cardiac
increase
that
in
at rest as well as during
pulmonary
hypertension,
and are due
mechanisms,
pulmonary
that in situ thrombosis
is occurring.
Further
support
for the role of coagulation
abnormalities
at the endothelial
output
Syncopal
cular
bed from
its usual
anticoagulant
state
(due to
release
of prostacycin
and
plasmmnogen
activator
inhibitors)
to a procoagulant
state.52 Fibrinopeptide
A
levels
are elevated
in patients
with
PPH
suggesting
from the demonstration
ulation
therapy
has
pressure
overload.
right ventricular
modestly
of vascular
occurs
with release
ofan unidentified
chemagent
from
injured
pulmonary
endothelial
Endothelial
cell
damage
can
also
produce
thrombosis
hypentrophies
ventricular
levels
pulmonary
platelet
humoral
an
bed
elevated
only
ventricle
diastolic
endothelial-
Coagulation
abnormalities
may
or further
exacerbating
the pulmonary
promote
but
other
large changes
pulmonary
tion
studies
pump
variations
without
With
resistance
the pulin the
Several
muscular
considerable
cross-sectional
blood
shear
tone
Many
of an imbalance
including
throm-
and
of the blood
and
result
in remodeling
arterioles
otactic
cells.5’
mediators.
possible
role
mediators
disease.47’
stniction,
interactions
can damage
in alterations
prostacyclin,
thromboxane
pulmonary
pressure
and
sympathetic
injury.’
stimuli
resulting
have
looked
at the
favoring
vasoconstrictor
it is
Pos-
vasoconstriction
in suscepthe following:
normobaric
or
hypoxia,
autoimmune
disor-
dens,
drugs
and toxins,
increased
flow with
or without
increased
stress,
lung
injury,
and increased
resulting
in catecholamine-induced
of these
monary
is a
in its pathophysiology.
tible individuals
hypobaric
PPH
Whether
or not vasoconstriction
in the pathogenesis
of PPH,
component
distensible
to vasodilator
that
output
When
and resulting
in cardiogenic
arterial
hypoxemia
and
life-threatening
arnhythmias
may
also
shock
acidosis
develop.
Postulated
Pat hophysiology
The
normal
pulmonary
low resistance,
circulation.
nary
blood
flow increases
resistance
decreases
due
opened
blood
marked
circulation
is a high
During
exercise,
and pulmonary
to both
recruitment
vessels
and distension
vessels.
These
two normal
increases
in pulmonary
of patent
pulmonary
adaptations
prevent
artery
pressure
even
when
pulmonary
blood
flow increases
by threefivefold.
The normal
right ventricle
is a thin-walled,
240
flow,
pulmovascular
of un-
to
mechanisms
for sudden
death
with
PPH
include
the following:
bnadyarrhythmias
and tachyarrhythmias,
acute
pulmonary
embolus,
massive
pulmonary
hemorrhage,
and
sudden
right ventricular
ischemia.
DIAGNOsIS
Although
the
diagnosis
it can be made with
is taken
to exclude
thorough
and
detailed
of PPH
history
Primary Pulmonary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
is one
of exclusion,
a high degree
of accuracy
if care
all likely
secondary
causes.
A
and
physical
Hypertension
(Lewis
examinaJ. Rubin
eta!)
Table
2-Evaluation
ofUnexplained
Mmonary
HypertensiOn
Information
Data
Obtained
Riskt
Secondary
Quality
Causes
Detectable
Screen
History
Dyspnea,
Physical
Exam
P,,
CXR
angina,
RV lift,
Heart
syncope
clubbing
size,
lung
parenchyma,
vascular
0
+ + + +
PE, CHD,
0
+ + + +
Lung
disease,
CHD
0
+ +
Lung
disease,
PVOD,
0
++
CHD
0
+ + + +
CHD,
0
+ + +
Chronic
lung
disease,
LV dysfunction
LV dysfunction
pattern
ECG
RVH
Diagnose
Echo
WQ
scan
Shunts,
valves,
LV function,
Lobar,
segmental
perfusion
PETs
Lung
ABG
Po,,
PA pressure
function
Pco,
valve
disease,
LV dysfunction
thromboembolism
0
+ + +
Parenchymal
+
+ + +
Hypoxemia,
disease
hypoventilation
Confirm/Refine
Catheterization
Pressures,
Pulmonary
shunts,
Vascular
angiography
cr/Mm
+
+ + + +
PVOD,
+
+ + +
PE,
0
+ + +
Proximal
PE, lung
+ +
+ + +
Proximal
PE
+ +
+ +
Vasculitis,
PVOD
+
Vasculitis,
collagen
flow
anatomy
Central
pulmonary
vascular
anatomy,
CHD
pulmonary
stenoses
disease
parenchyma
Angioscopy
Intraluminal
Lung
Histopathology
biopsy
Serologies
ANA,
anatomy
1W, CH,,
0
vascular
disease
Management
Catheterization
Dose-response
+
+ + + +
Drug
efficacy
& safety,
Echo
RV size,
0
+ +
Drug
efficacy
treatment
+
+ +
Treatment
Exercise
Study
*Abbretions:
Quantitate
PE
RV=right
function
pulmonary
RVH
ventricle;
exercise
embolism;
right
tolerance
CHD=congenital
ventricle
hypertrophy;
heart
disease;
PA=pulmonary
PVOD
artery;
=pulmonary
response
response
venocclusive
CT=computerized
prognosis
disease;
LVleft
ventricle;
Mill
magnetic
resonance
tomography;
imaging.
tNote:
risk
ofperformance
and
information
quality
are
rated
on a scale
ofO
to 4+.
lion, as well as appropriate
tests, must be performed
to uncover
potential
causative
on contributing
factors,
many of which
In the National
an algorithm
secondary
patient
may not be readily
apparent
Institutes
of Health
registry
Echo
developed
listing
essential
tests and
diagnoses
to be excluded’4
(Fig 2). No
with
a secondary
cause
of pulmonary
Presenting
PPH
/
No secondaly
caisa
registry
Norn
common
symptom
of PPH
initial symptom
in 60 percent
leer prok
with
population.
no
curs
greaten
Angina
Edema
is generally
failune
and
advanced
that
suggests
Raynaud’s
phenomenon
frequency
than
is also common
a reflection
is more
likely
disease.
The time
symptom
until
diagnosis
in
2.03 ± 4.9
years,’4
indicating
generally
made
late.
of right
The
PFTs-
No PE
Distal PE
Wntiledon
disease
No significant
ventilation
cflseue
+ Serology
PPH
Exercise.
lfctnical
suspicion vasculitis
to be associated
with
of onset
from the first
of patients
assessment
fUncOn
ventricular
registry
diagnosis
Cath
Suspect
was
is
PVOO
with
PPH
are
\
Drug study
/
\
Thorac
biopsy
Confirm
Algorithm
for diagnosis
perfusion;
PVFs
pulmonary
function
gas determinations;
and CKfH
= right
findings
Pros PE
____e
\
V
oc-
Examination
physical
detect
ABOs
Semiogy
Ficuns
Physical
I Segment
rio9raPhY
in the general
(47 percent).
the NIH
that
the
>
is dyspnea,
of patients
and is eventually
present
in virtually
all patients.
Syncope
may also be an early
symptom
of PPH
(8
percent).
In contrast
to the olden literature,
current
experience
Shunt. vthes
c&omyopaIhy
wo
Symptoims
most
is the
PH
NOPH
hyper-
in the
No suspicion
/\
was
tension
was diagnosed
as having
when this algorithm
was followed.
The
which
Suspidon
(Table 2).
on PPH,
2.
PH
of PPH.
V/Q=ventilation/
tests; ABCs =arterial
blood
heart
hemodynamic
catheri-
zation.
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
I 104 I 1 1 JULY,
1993
241
typical
of any
patient
with
An increase
in the pulmonic
heart
sound
and
early
findings.
pulmonary
a right-sided
may
be heard
of the second
fourth
Tricuspid
heart
regurgitation
common.
A right ventricular
third
erally
reflects
advanced
disease.
ciency
hypertension.
component
and
usually
sound
is also
are
very
can
heart
sound
genPulmonic
insuffirelates
and
should
suggest
an alternative
also
be
used
pressure.tm
Pulmonic
valve
seen,
and characteristics
flow velocity
or changes
profile
across
the pulmonic
to estimate
to dilatation
patent
diagnosis.
foramen
The
Evaluation
commonly
shows
triculan
hypertrophy
but
does
not
The
scintigraphy.
right
axis deviation
with secondary
necessarily
parallel
and right yenT-wave
changes
the
severity
of the
underlying
pulmonary
hypertension.
Atrial
fibrillation is a particularly
uncommon
rhythm
in PPH and
may not be well-tolerated
because
of the dependence
upon atrial
Imaging:
systole
for ventricular
Radiograph.
Chest
filling.m
The chest
with
radiograph
out chronic
pulmonary
thnomboemboli
artery
pressure.
ventilation-perfusion
Therefore,
a normal
rules
out
sion, and no further
workup
Pulmonary
angiography.
pletely
diagnosis,
exercised,
dication
with
normal
chest
x-ray
it should
be noted
PPH
enrolled
in the
radiograph.
Echocardiography.
useful
to look for
film speaks
that 6 percent
NIH
registry
against
the
of patients
had
a normal
echocardiogram
dysfunction,
disease,
or congenital
heart
disease.
The
typical
echocardiographic
appearance
ofthe patient
with PPH
shows
right
ventricular
and right
atrial
enlargement
with
a normal
to reduced
left ventricular
cavity.
Pulmonic
and tricuspid
insufficiency
is also easily
detected
normal
with
Doppler
curvature
septal
interrogation.
associated
ular pressure
overload
disease.
Hemodynamic
pulmonary
findings
vascular
reveal
an
ventricular
internal
with
Reversal
of the
right ventric-
states
is seen
correlations
in advanced
between
the
resistance
and echocardiographic
inverse
relationship
between
the
left
dimension
and
pulmonary
of left ventricular
filling
as a reflection
of reduced
ventricle.’
to noninvasively
pressure.
Most
vascu-
Doppler
determine
commonly,
ultrasound
the
from early
compliance
can
be
to
of
used
the pulmonary
artery
magnitude
of the tri-
242
reproducible
measurements
of
the
right
often
probability
pulmonary
is necessary
Ifthe
lung
thnomboembolism.
pulmonary
to pulmonary
pulmonary
two
or
lung
hyperten-
in this regard.
scan shows one
interpret.
or magnetic
While
cane
hypertension
angiography.
hypertension,
into
the
and endothelialized
mate
the extent
of the
clots
be
resonance
necessary
imaging
those
centers
with
diagnostic
evaluation
are
be
actually
pulmonary
so the angiogram
of obstruction
or
It may
to
should
is not a contrainIn thromboem-
the
wall
copy has had very limited
in few centers.
It should
artery
may undenestibe difficult
to
to employ
angioscopy
in these
cases. Angios-
application
and
not be performed
is performed
except
in
considerable
experience
in the
of thnomboembolic
pulmonary
hypertension.
Radionuclkk
giography
angiocardiography.
can be utilized
to assess
function.
However,
in interpreting
in the presence
taken
tions
cuspid
regurgitant
flow velocity
can be determined
and enhanced
using
saline
solution
contrast
to give
relatively
out
ventricular
left
lan resistance,
suggesting
that underfilling
of the left
ventricle
is a reflection
ofthe severity
ofthe pulmonary
vascular
disease.
Doppler
studies
have also shown
a
redistribution
late diastole
rule
bolic
can be
valvular
small,
patchy
pulmonary
at least one
or more
segmental,
on greaten,
ventilation-perfusion
mismatches,
an angiogram
should
be performed
incorporated
The
myocardial
mismatch,
on low
thnomboembolic
shows evidence
ofpulmonary
hypertension
in over 90
percent
ofcases.’4
Prominence
ofthe
main pulmonary
artery
occurs
in 90 percent,
hilar vessel
enlargement
in 80 percent,
and pruning
of the vessels
with hyperlucent
lung periphery
in 51 percent.
While
a com-
undergo
to rule
as the cause ofthe elevated
In PPH,
the lung scan is
normal
on low probability
with
14 Conversely,
in thromboembolic
hypertension,
the lung scan demonstrates
scan
echof
It is mandatory
either
major
more.
pnes-
It has an
of intnacardetection
of a
pulmonary
hypertension
lung
scanning
in order
ventilation-perfusion
electrocardiogram
artery
ovale.
that patients
Electrocardiogram:
insufof the
in the
valve
transesophageal
in the evaluation
patients
with
pulmonary
hypertension.62
advantage
of offering
precise
assessment
diac defects
and is very sensitive
in the
Ventilation-perfusion
Diagnostic
pulmonary
sure noninvasively.6#{176}’6’ Recently,
ocardiognaphy
has been employed
ofthe
main pulmonary
artery.
Peripheral
cyanosis
and
edema
are often
seen.
Edema
is a sign
of right
ventricular
dysfunction.
Clubbing
is not a feature
of
PPH
ventricular
systolic
ficiency
is frequently
pulmonic
regungitant
systolic
flow velocity
ular chambers,
Radionuclide
anboth left and right
caution
should
be
right ventniculan
ejection
fracof lange right atrial and ventric-
as true
isolation
ofthe
right
ventricular
blood pool can be difficult.
Right ventricular
ejection
fraction
has been
shown
to be inversely
proportional
to
the
pulmonary
estimation
of
right ventricular
MRI
and
artery
pulmonary
ejection
and ultrafast
CT scanners
pressure,
artery
fraction
CT As newer
have
evolved
although
pressure
is difficult.
direct
from
the
generations
of Mifi
and
software
has
improved,
these
imaging
techniques
have begun
to
offer great promise.
Thnombi
in proximal
pulmonary
arteries
can be visualized
without
the necessity
of an
Primary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
Pulmonary
Hypertension
(Lewis
J. Rubin
et a!)
angiogram.
In addition,
motion
can be evaluated
left ventricular
ejection
ventricular
and septal
with calculation
of right
fractions.
The sensitivity
wall
and
of
these
tests for detection
of central
clots sufficient
to
cause
pulmonary
hypertension
has not been
determined,
but this may become
pant of the diagnostic
algorithm
for PPH in the near future.
Pulmonary
monary
in the
Testing:
Function
functional
abnormalities
may
either
the mechanical
the lung, with changes
prominent
The
include
and
reflect
and
(Dco),
carbon
in
gas
diffusing
exchange
as
PPH
dys-
capacity
reflected
by
studies
registry
performed
disclosed
on
only
Pul-
the 187 pamild neduc-
lung
volumes
and no evidence
of airways
14 The
presence
of moderate
or severe
or obstructive
physiologic
defects
should
restrictive
suggest
described
in
small
airways
hypocapnia
(alveolar
hyperventilation),
alveolar.arterial
(A-a)O2
gradient.
monary
function
tients
in the PPH
tion
in
greater.
monoxide
impaired
hypoxemia,
and increased
derangements
or gas exchanging
properties
of
in the latter tending
to be more
disproportionately
reduced
of pul-
in PPH,
particularly
of the disease.
The
functional
abnormalities
mild
restrictive
defects,
function,
cur
Abnormalities
function
may be present
more
advanced
stages
another
due
in PPH,
patent
foramen
output
with
diagnosis.
Severe
either
to intracardiac
ovale
or a severely
resultant
mixed
Cardiopulnwnary
venous
Tests:
Exercise
exercise
tests are useful
with nonapparent
causes
hypoxemia
can
shunting
ocvia a
Elevations
in PPH
in antinuclear
collagen
nuclear
vascular
antibodies
associated
with
.
antibodies
As all of the
imply
are com-
Lung
in
selected
necessary
factors
that
Biopsy:
making
Lung biopsy
an accurate
collagen
vascular
is not considered
essendiagnosis
of PPH.
In
patients,
a lung biopsy
may be desirable
to establish
a diagnosis
when
confounding
make
the diagnosis
otherwise
uncertain.
respect,
an accurate
patient
as having
hypertension
may
primary
be very
diagnosis
management.
value
Transbronchial
in
pulmonary
hypertension
blood
vessels
adequately
the
lung
diagnosis
because
and may
it
also
of
hi-
primary
does not sample
be risky due to
elevated
pulmonary
artery
pressure.
Open
lung hiopsy,
possibly
using
a thoracoscope,
would
be preferred.
Care should
be taken
in obtaining
the tissues,
preferably
from
right
or left lower
lobes
during
full
lung inflation.
difficult,
and
ferred
vascular
A correct
to a pathologist
disease.
Cardiac
with
expertise
Catheterization:
be taken
accurately
with
either
determination
to exclude
It should
terization.
filling pressures
is
the diagnosis
Particular
care
intracardiac
shunting
ventricular
capillary
with left
be recognized
rise modestly
may
be
re-
catheterization
for confirming
management.
ascertain
left
a pulmonary
or directly
can
be
in pulmonary
Cardiac
an absolute
requirement
of PPH
and for guiding
should
histologic
diagnosis
material
should
the pathologic
filling
wedge
ventricular
and
pressure
pressure
cathe-
that left ventricular
in severe
PPH due
to diastolic
dysfunction
related
to the
pulmonary
hypertension.
Pulmonary
veno-occiusive
disease
can
result in a gradient
between
the wedge
pressure
and
left ventricular
wedge
pressure
elevated.
Typical
to the
pressure,
output,
Although
end-diastolic
is usually
ofveno-occlusive
pressure
the lung.
accurate
disease
artery
they
direct
although
the
only
mildly
or
is variabil-
determinations
from
various
Particular
attention
should
be
measurement
pulmonary
since
the
pressure,
normal
of the
pressure,
specifically
measurement
right
and
atrial
cardiac
relate
to prognosis.
of cardiac
output
through
the Fick method
is preferred
in low
output
states,
a reasonably
accurate
assessment
thermodilution
can be obtained
in most patients.
cardiac
using
Flow-
directed
catheters
for the right side of the heart
an internal
guidewine
are commercially
available
have
been
particularly
helpful
in positioning
catheter
in the pulmonary
artery.
with
and
the
an associated
diseases
have been associated
with pulmonary
hypertension,
it is possible
that some
patients
with
PPH
have a collagen
vascular
disease
that is confined
to the
lung.
tial
no
paid
of patients
there
is a
disease.
No specific
pattern
of antior titer
has been
consistently
PPH
of
hypoxemia.
in the evaluation
of dyspnea
since
and do not necessarily
and
is
Cardiopulmonary
cardiac
ease.67
Since
their
sensitivity
and specificity
in the
diagnosis
of pulmonary
hypertension
are unknown,
exercise
testing
is not considered
essential
in the
evaluation
ofa patient
with suspected
PPH.
Connective
flssue
(Collagen
Vascular)
Serologic
Studies:
opsy
ity in wedge
sites within
depressed
characteristic
pattern
of ventilatory
and circulatory
response
in the presence
of pulmonary
vascular
dis-
mon
prognosis
distinguishing
or
In
the
or secondary
pulmonary
important
with respect
to
THERAPY
There
approach
However,
is no cure
for PPH,
nor is there
which
is uniformly
accepted
treatment
for this disease
a therapeutic
or successful.
has improved
dramatically
over the past decade,
resulting
in sustamed
clinical
improvement
and prolongation
of life
in a substantial
percent
of patients.
This section
will
address
the
management
General
Measures
of PPH.
Because
PPH
is a rare disease
whose
complexity
poses tremendous
challenges
to the treating
physician,
it is recommended
that patients
be referred
to a center
with experience
in management
of this disease.
The
referring
physician
must,
nevertheless,
play a major
CHEST
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I 104 I 1 I JULY,
1993
243
role in the day
ongoing
dialogue
crucial.
Patients
to day care
between
with
substances
PPH
which
of these
patients,
and
the treating
physicians
should
may
avoid
aggravate
or
However,
preload,
the
and
For
excessive
diunesis
circumstances
the
disease
state.
exposure
hypertension
pulmonary
by producing
vasoconstriction.
generally
safe,
alveolar
While
supplemental
hypoxia-induced
airplane
travel
oxygen
when
flying
therapy
may
advisable,
particularly
cabins
or
hypoxemic
when
patients
are mildly
or moderately
at sealevel.
Additionally,
pregnancy
should
should
be
monitoring
in nonpressunized
hypoxia
frequently
parenchymal
lung
pulmonary
vasoconstriction
occurs
in the setting
of
disease,
and
hypoxic
contributes
genesis
of pulmonary
Supplemental
low-flow
vascular
oxygen
to the
patho-
disease
in this setting.
alleviates
arterial
hy-
right-sided
in these
patients
congestion
heart
ventricle
is highly
care
should
be
volume
status
failure.
dependent
taken
to
on
avoid
this
lead
since
by physical
laboratory
data. Patients
of funosemide
of greaten
treated
with
can
potassium
necessary
risk
low doses of
as needed,
examination
and
who are refractory
than
120 mg/day
metolazone
as an
adjunct.
to doses
may be
Meticulous
of serum
electrolytes
is mandatory,
and
on magnesium
supplementation
may be
when these agents
are used.
monitoring
Therapy
Alveolar
long-term
right
great
and hepatic
with
therapy
may be instituted
with
(20 to 40 mg/d) and increased
Anticoagulant
Oxygen
volume
in patients
to a fall in cardiac
output
and can compromise
the use
of other
pharmacologic
measures
such as vasodilators.
Diuretic
furosemide
be used.
Supplemental
occur
is
be avoided
since this is poorly
tolerated
in the setting
of PPH.
Since
oral contraceptives
may worsen
pulmonary
hypertension,
other effective
methods
of birth
control
intravascular
which
exercise
should
be guided
by symptoms,
and
to high
altitude
may
worsen
pulmonary
example,
increased
an
is
Therapy
Patients
with severe
pulmonary
for thrombotic
events
due
hypertension
are at
to their
sedentary
venous
insufficiency,
dilated
right-sided
heart
chambers,
and sluggish
pulmonary
blood
flow. Even
a
small
pulmonary
vascular
obstruction
by thrombus
can be life-threatening
in apatient
with a compromised
lifestyle,
poxemia
and attenuates
pulmonary
hypertension
in
patients
with
these
disorders;
in contrast,
most
patients with PPH do not exhibit
resting
hypoxemia
and
derive
little hemodynamic
benefit
from supplemental
pulmonary
vascular
bed which possesses
little ability
to dilate
or recruit
unused
vessels.
Indeed,
patients
with PPH frequenfly
die suddenly,
and fresh
intrapulmonary
clot may be found at post-mortem
exami-
oxygen
rience
nation.
therapy.
arterial
Some
patients,
oxygen
desatunation
to increased
oxygen
oxygen
delivery,
and
extraction
in
these
patients
ambulatory
supplemental
right-sided
heart
failure
sulting
from a markedly
even
at nest,
therapy.
arterial
Patients
to-left
should
shunt
Cardiac
useful
the face of fixed
may benefit
from
oxygen.
Patients
with severe
and resting
hypoxemia,
reincreased
oxygen
extraction
be treated
through
with
a patent
do not improve
to an appreciable
The
will expeactivity,
due
continuous
oxygen
The goal of oxygen
therapy
is to maintain
an
oxygen
saturation
above
90 to 92 percent.
with hypoxemia
solely
resulting
from a right-
teristically
known.
however,
with
degree
foramen
ovale
charac-
their level of oxygenation
with supplemental
oxygen.
function
associated
with
chronic
thenmore,
the risk ofdigitalis
toxicity
if hypoxemia
and diuretic-induced
in PPH
is unthese
drugs are
ventricular
dys-
lung
disease.m
Fun-
may be enhanced
hypokalemia
are
also present.
Some authors
have advocated
digitalis
concomitant
with calcium
channel
in PPH in order to counteract
the potentially
inotropic
effects
of the latter.x
the use of
blockers
negative
Diuretics
Diuretics
244
can
be
quite
useful
in
reducing
the
may
be
as
a prophylaxis
justified
in patients
who
received
anticoagulants
survival
when
compared
with
treated
with anticoagulants.7#{176}
for
with
manifested
improved
those
who were
not
Recently,
Rich et aF’’
demonstrated
in a small
prospective
study
coagulation
was associated
with significant
ment in survival
rates.
The
preferred
approach
to anticoagulation
administer
prothrombin
Patients
efficacy
of cardiac
glycosides
There
is little evidence
that
in patients
with isolated
right
anticoagulation
PPH.
A retrospective
study
from
the Mayo
Clinic
provided
support
for this concept.
Patients
with PPH
control
Glycosides
Thus,
thromboembolism
in doses
sufficient
to approximately
warfarin
time
(international
should
normalized
be
advised
could
heart
ratio
therapy
on any
alter the effects
of warfarin.
failure
may impair
hepatic
of the anticoagulant
effects
must be done with greater
Adjusted-dose
heparin,
is
to
to prolong
the
1.3 to 1.5 times
of 2.0
regarding
dangers
of anticoagulation
using
nonsteroidal
agents
that antiimprove-
the
to 3.0).
risks
and should
medication
Since
function,
of warfanin
frequency.
using doses
and
avoid
which
right-sided
monitoring
in this
which
setting
prolong
the partial
thromboplastin
time
to 1.3 to 1.5 times
control,
is a suitable
alternative
to warfanin,
although
its use is more cumbersome.
This approach
may be
considered
in patients
who have a greater
risk for
hemorrhagic
events,
such as prior episodes
of hemoptysis,
on who
have
had
Primary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
adverse
Pulmonary
effects
Hypertension
with
warfann,
(Lewis J. Aubin eta!)
such
Table 3-Dose
Half-Lives
as alopecia.
Ranges,
Route
Frequently
OJMOSt
ofAdministration,
Used Vasodilators
and
Vasodilators
Drug
The rationale
treat pulmonary
that
fon the use
hypertension
pulmonary
degrees,
in right
vasoconstriction
in right
supported
by
ofthe
hypertnophy
early
is pnesent,
to varying
in this disease,
and that even small
ventricular
aftenload
will produce
improvement
is
of vasodilator
agents
to
is based
on the premise
and
selective
ventricular
consistent
feature
stnated
to
experimental
The
of PPH
vasodilaton
vasodilators
agent,
although
a
have been
demon-
produce
pulmonary
vascular
and clinical
conditions
(Table
effects
3).
in
goal
ofvasodilaton
therapy
for PPH is to reduce
pressure
and increase
cardiac output
symptomatic
systemic
hypotension.
This ef-
pulmonary
artery
without
120-900 mg/day
2-24 ng/kg/min
may
is no
be
E,
Intravenous
5-30
release
preparations
(Procardia
given
once
range
tolerance
increased
listed
over
time,
for adverse
The
potent,
immediate
lators
will
increase
and
right
these
cardiac
output
without
afFecting
patients,
unknown.
the
long-term
Furthermore,
for prolonged
In the remaining
one
sustained
either
reduce
monary
artery
pulmonary
increased
“fixed”
systemic
pressure
artery
output.
vascular
effects
whether
on
this
periods
of time
fourth ofpatients,
pressure
without
or cardiac
output,
pressure
These
disease,
commensurate
patients
are
and vasodilator
survival
effect
are
can
be
is unclear.
vasodilators
Patients
with pulmonary
veno-occlusive
life-threatening
pulmonary
edema
to vasodilator
ofincreasing
persistent
There
administration,
pulmonary
downstream
are
blood
vascular
with
an
to have
therapy
is
no hemodynamic
disease
may
in response
presumably
as a result
flow in the presence
obstruction.’
on demographic
of
varia-
bles which
predict
vasoreactivity.
Patients
with symptoms for several
years suggestive
of severe
pulmonary
vascular
compromise,
such as syncope,
may manifest
nearcomplete
reversibility
others
with
irreversible
a brief
disease.
with
vasodilators,
duration
of symptoms
may
This observation
underscores
while
have
the
infusion
its short
CD)
to conventional
nontitratable
of pnostacyclin
of prostacycin
half-life
cardiac
in this
vasodilator,
(3 to 5 min).
output,
(pros-
heart catheterization
magnitude
of vasoreacsetting
its titrataProstacyclin
doses
from 1 to 12 ng/
and pulmonary
hemoand
arterial
saturation.
The
responses
to prostacyclin
have been
useful
in determining
which patients
may respond
to oral therapy. 18.75
Prostacyclin
is not
commercially
United
at the
present
time;
alternatives
for
testing
acute
reactivity
States
be
suitable
prostaglandin
Patients
who manifest
sponse
to acute vasodilaton
a reduction
in pulmonary
available
E,,
and
in the
which
include
adenosine.
a potentially
beneficial
rechallenge
defined
as either
artery
pressure
with
no
change
on an increase
in cardiac
output,
or an increased
cardiac
output
with an unchanged
pulmonary
artery
pressure,
may be treated
with oral calcium
channel
blockers.
A common
strategy
is to titrate
with hourly doses until maximal
hemodynamic
on adverse
nifedipine
effects
(Procardia
are achieved.
XL) in doses
nifedipine
effects
Sustained
release
of 120 to 240 mg/
day is often used.
In some patients
who either
have a
resting
tachycardia
or develop
unacceptable
systemic
hypotension
with
nifedipine,
diltiazem,
in doses
up
to 900 mg daily, is a suitable
alternative.
The heart
rate and
monitored
PR interval
in patients
on electrocardiogram
receiving
diltiazem,
ycardia
and atrioventricular
mil is not recommended
greaten
propensity
fects.
Additionally,
with any vasodilator
patients
elevated
blocker
as an
risk
refers
a long-acting
as a pulmonary
great variability
in the course
ofthis disease
and serves
to emphasize
the need to individualize
the approach
to therapy
for each patient.
The experience
from the
NIH
registry
on PPH has suggested,
however,
that
with right-sided
heart failure,
defined
right atnial pressure,
are at the greatest
when
advantages
acetylchohne,
contraindicated.
develop
The
and
may
altering
pulon increase
felt
tivity.74
dynamics,
artery
mm
Cardizem
50 to 100 ng/kgfmin.
is administered
in incremental
kg/mm,
monitoring
systemic
pnessure.
While
exercise
tolerance
ventricular
function
may be improved
in
pulmonary
exceeding
intravenous
bility,
regression
2-4
XL and
infusions;
dose requirements
long-term
infusions
have
taglandin
I,) during
right-sided
to determine
the potential
and
and
pressure
ag/kg/min
shown
h
3 mm
is administered
immediately.72
approach
taken
in many
centers
is to use a
short
acting,
titratable
vasodilator
such
as
vasodilaton
ductions
artery
often
events
are its potency
hypentrophy
in such patients.
one half of PPH patients,
vasodi-
half-life
is for immediate
patients
receiving
in
one fourth
of
reported
that
sustained
re-
in pulmonary
daily;
2-4.5
preparation.
tDose
and
fect may be achievable
in approximately
patients.
Rich
and Brundage
have
calcium
channel
blockers
can produce
of right ventricular
In approximately
2-5 h
30-240
Oral
Intravenous
55usimned
There
.‘
mg/day
Oral
Prostaglandin
concept
Half-Life
Diltiazem5
Prostacyclint
reductions
This
Range
Dose
Nifedipine*
substantial
the pathologic
finding
of medial
muscular
pulmonary
arteries
as an
pulmonary
of systemic
variety
output.
Route
The
due
major
to the
block
may occur.
for use in PPH since
to produce
unmonitoned
is strongly
adverse
therapy
effects
in PPH
negative
inotropic
Verapait has a
negative
inotropic
efempiric
treatment
discouraged.
of calcium
are reduction
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
should
be
since brad-
effects,
channel
in cardiac
output
systemic
hypo-
I 104 I 1 I JULY,
1993
245
tension,
When
and
edema
calcium
edema
due to salt and water
develops
in a PPH
patient
channel
blocker
therapy,
patent
retention.
receiving
is important
it
to
differentiate
between
the effects
which
these
agents
have on renal
salt and water
reabsorption
and right
heart failure
due to negative
inotropy.
Vasodilators
can
also produce
arterial
hypoxemia
through
the following
three
mechanisms:
ventilated
lung
creasing
right
units
increasing
(decreasing
to left shunting
blood
flow to poorly
V/Q matching);
in-
through
a patent
occurs
more
hypertension
lung disease,
left shunting
through
a patent foramen
only in more severe
forms ofpulmonary
A similar
phenomenon
may occur
Eisenmenger’s
Nitrates,
treat some
with these
agents,
as hydralazine
and
diazoxide,
angiotensin
converting
disappointing,
been
enzyme
and
their
may
is
be
have
not
have
and
colleagues76
ous intravenous
infusion
onstrating
ance
with
first
reported
ofprostacyclin
using
recomcontinu-
in PPH,
in hemodynamics
in a series
of PPH
to live
prognosis
balloon
atnal
with advanced
Kerstein
et
septostomy
pulmonary
al81 reported
longer
than
in 15 patients
than
PPH
patients
septum.79
of symptoms
with
with
syncope
and
heart-lung
transplantation
has been
expertise
to perform
patients,
and the
Additional
organs.
the
procedure
and
limited
availability
problems
have
incidence
(25 to 40 percent)
in transplanted
lungs,
organ
istic infections.
Recently,
single
ofbronchiolitis
rejection,
and
and double
performed
lung
successfully
artery
has
tion,
Dose
of the
indwelling
or interruption
requirements
catheter,
of the infusion
tend
to increase
gesting
tachyphylaxis,
maintained
responses
although
for periods
years.
bridge
whom
may
This approach
to transplantation
oral vasodilator
pump
and
than
lung
246
for combined
transplantation
drug
or
malfunc-
Patients
several
patients
have
extending
beyond
5
be particularly
useful
as a
in seriously
ill patients
in
therapy
is either
contraindiexperisurvival
and IV
atomegaly,
suitable
with
severe
PPH
in whom
the
foramen
ovale
is
in
whom
right-sided
impaired.
There
right-sided
heart
hyperbilirubinemia,
and
candidates
for transplantation
an excessively
few
high
mortality
rate
heart
is no
or double
failure,
ascites
since
in this
hepare not
there
is
group.
The timing
of transplantation
is controversial
and
dependent,
in part, on the individual
patient’s
wishes.
In general,
for patients
functional
consideration
for transplantation
is advised
who fall into New York Heart
class III or IV who are refractory
Association
to medical
management.
AND
The
clinical
course
inexorable
progression
Septostomy
with
yen-
in the
heart-lung
transplantation.
may be the surgical
proce-
dune of choice
for patients
function
is not irreversibly
PRoGNosIs
Patients
right
dramatically
.
patients.
Atrial
has
PPH.
patients
evaluated
to date
Although
rejection,
infection, and bronchiolitis
may occur
with lung transplantation as well, it is likely that there
should
be a greater
availability
ofsuitable
donor organs for lung transplan-
for other reasons.
over time,
sug-
cated
or of no demonstrable
benefit.
Recent
ence
suggests
that prostacyclin
may improve
in New
York
Heart
Association
class
III
obliterans
opportun-
with
fallen,
has improved
for these
transplantation
in patients
pressure
function
care
of suitable
donor
included
the high
uniform
census
on the preference
of single
lung transplantation
for PPH at present.
infection
per-
formed
successfully
on patients
with PPH for nearly
a decade.
The major
limitations
to its widespread
use include
the limited
number
of centers
with the
cations
delivery
to the
thrombosis
heart
investigational.
triculan
has been
recently
patients
who were
attributable
included
a blade
right-sided
tation
Thus,
been
have
who
has been reported
in patients
vascular
disease.#{176} Recently,
improvement
with sept05-
treated
with long-term
continuous
intravenous
prostacyclin.73
The drug is delivered
by a portable
infusion
pump
which
is connected
to a Hickman
catheter
inserted
into the jugular
or subclavian
vein. Complihave generally
system
and
those
failure.
Thus,
blade
balloon
septostomy
may serve
as
adjunct
palliative
therapy
in selected
patients
with
severe
PPH and intractable
right-sided
heart
failure.
It should be emphasized
that this invasive
approach
is
Pulmonary
dem-
sustained
improvement
in exercise
toterthis aggressive
approach.76
Sustained
improvement
demonstrated
a better
interatrial
palliation
been
mended.
J ones
reported
foramen
ovale.78 Additionally,
patients
syndrome
due to an atnal
septal
have an intact
Successful
Combined
reactivity,
but
utility.
Results
inhibitors
use
been
Transplantation
physiology
who are given vasodilators.
either
oral or topical,
have been
used to
patients
with PPH, although
the experience
agents
to date is limited.
Direct
acting
such
with
commonly
in
secondary
to
while
right-toovale is present
hypertension.
in patients
with
useful
in select
patients
with marked
systemic
hypotension
has limited
their
defect
tomy
foramen
ovale if a greater
degree
of systemic
vasodilation
than
pulmonary
vasodilation
is produced,
and decreasing
mixed
venous
oxygen
content
ifcardiac
output
actually
falls.
The
first
scenario
patients
with
pulmonary
underlying
parenchymal
have
without
a patent
with Eisenmenger’s
ral
history
studies
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
HISTORY
of PPH
is generally
toward
death.
However,
vary
Primary
NATURAL
in
Pulmonary
reporting
Hypertension
and
(Lewis
one of
natuin
J. Rubin
case
eta!)
ascertainment,
and utilize
survival
duration
(eg, the
symptoms
on the
consensus
has been
interval
different
interval
since
definitions
since
onset
diagnosis),
0.8
of
of
so that
Among
percent;
percent;
actuarial
2 years,
4 years,
survival
at 1 year
52 to 58 percent;
30 to 43 percent;
is 68 to 77
Despite
the
survival
overall
ranges
up
dismal
to
10
.l
3 years,
40 to 56
and 5 years, 22 to
38 percent.TM70M
The usual mechanisms
of death
right ventricular
failure
(63 percent),
pneumonia
percent),
and sudden
death (7 percent).TM’7#{176}
prognosis,
years
or
(1)
Higher
between
studies
Vascular
the
have
0
0.3
was
Some
degree
cause
despite
resistance
.
4
5
Years
ca’e341ss
0.8
Pres-
0.7
0.6
0
for
pressure
0.4
2
a-
of 85
be that
in these
patients,
the
0.2
2
1
3
Years
caieasiesoi
0.9
finding
failed
to identify
as a predictor
of
a correlation
with
U
0.8
‘%
pulmonary
MPAP
RAP
CI
60
10
3.3
60
10
1.3
.
A
*%
response
Response
to vasodilaton
to
therapy
has long
as being predictive
ofsurvival.
components
to this predictor.
demonstrate
reduced
acute
longer,
pulmonary
:
2
a.
treatment
with
vasodilators
hance
survival.’73
Preliminary
data
randomized
survival
study
of PPH
prolonged
intravenous
prostacyclin
.
0.4
0.3
.
N
.__
0.2
tend
of
may
1
,
to
en-
from
a 12-week
patients
treated
also
N .
resis-
administration
of vasodilators
and this may be independent
treatment
status.
Second,
in addition
role of vasodilators,
there is suggestive
that
__
.N
.l05
There
First,
vascular
.N
0.6
0
Vasodilator
of the pulmonary
vasculature
to respond
to
agents
may identify
patients
in a more
(earlier)
phase ofthe
disease.
Thus, those
subsequent
the predictive
with
5
correlation
to 12 months
arterial
of Favorable
The
evidence
4
0.3
may
been recognized
are two potential
tance
with
to survive
3
!0.7
(2) Absence
who
2
of mortality.
mortality,
the ability
vasodilator
vasoreactive
2.3
abnormality
compared
studies,
however,
have
of pulmonary
hypertension
Therapy:
2.3
10
.___
I
is more advanced
or has progressed
to a more
level
relatively
rapidly
(1#{128},
by the time
of
diagnosis).
The
higher
pressure
imposes
a
workload
on the right ventricle,
contributing
from
right-sided
heart
failure,
the most
common
10
80
median
survival
for those
arterial
pressure
less than 55
pulmonary
implications
disease
severe
correct
greater
to death
and
an inverse
hemodynamic
48 months,
those
with
mean
mm Hg or more.M
The
60
A
0.2
Among
the 194 patients
in the
for the Characterization
of Primary
Pulmonary
Hypertension,
with a mean pulmonary
Hg
.
of
Isolated
Resistance
found
pulmonary
and
survival.MM87
Patient
Registry
mm
CI
survival.
Pulmonary
Most
sure:
2.3
0.5
2
(7
instances
of survival
up to 24 years
have
been
reported,
as have rare cases of apparent
regression
of
the disease.ec
A variety
of indicators
appear
to have predictive
for short
10
0.4
are
duration
more.
RAP
40
.
a
about
the rate of progression
of the disease
difficult
to establish.
patients
who
do not undergo
heart-lung
transplantation,
value
I
MPAP
support
2
3
4
5
Years
FIGURE
3. Probability
of survival
for medically
treated
patients
with PPH.
Differences
in survival
probability
are depicted
based
upon variation
ofbaseline
mean pulmonary
artery
pressure
(MPAP,
mm Hg) (upper);
right
atnal pressure
(RAP, mm Hg) (center);
and
cardiac
index
(CI, L/minlm’)
(lower).
Adapted
from
D’Alonzo
et
al.’
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
I 104 I 1 I JULY, 1993
247
this
ACKNOWLEDGMENT:
provided
by Renata
observation.
(3) Worse
with
Functional
PPH
are
Nevertheless,
Classification:
symptomatic
Most
at the
symptoms
are
time
presumably
of hemodynamic
patients,
those
decompensation
dysfunction.
exhibiting
have
shorter
a late
subsequent
class
and
(4)
Right
months;
Atrial
measurable
in class
Pressure
hemodynamic
function,
mean
indices
RAP
elevation
2 Palevsky
is highly
10 mm
E,
Schloo
et
structure,
et
al.
qualitative
and
from S8patients
output
is associated
by both
high
the pulmonary
ure.
Not
correlates
less than
with
4 Wagenvoort
ventricular
sion:
of
reduced
with reduced
2.0 IJminJm2
survival.M,70,87
is associated
of 17 months;
or more
increases
cardiac
median
(6) Low
Pulmonary
Desaturation:
Low
survival
D,
nary
ation due to reduced
low cardiac
output.
in
from
the
an individual
developed:TM
registry,
patient’s
t=
the
pulmonary
septal
11
12
z
=
cardiac
The
use
13
assessing
of
Loyd
years
15
pressure
clinically
pulmo-
The
of structural
reference
1958;
pathology
Archiv
to
18:533-47
of pulmonary
(A) 1974;
364:69-79
veno-occlusive
disease
after
S. Pulmonary
for malignant
veno-occlusive
neoplasms.
1987;
Chest
veno-occlusive
study.
disease
Hum
in siblings:
Pathol
1982;
13:911-
Familial
ElemaJD.
a case
report.
Beetsra
A,
Thorax
Schultz
1978;
M,
and
veno-
32:763-66
J. Capillary
Spijker
Histopathology
pulmonary
1977;
hemangioma-
2:401-06
Michtom
Primary
RJ.
hemodynamic
study.
pulmonary
J Med
Am
1951;
Primm
Newman
RK,
clinical
Familial
JH.
patterns.
Am
primary
Rev
pulmonary
Respir
Dis
1984;
Rich
5,
BH,
Detre
Dantzker
DR.
KM.
prospective
JE, Atkinson
Loyd
Ann
Am
in
1988;
Hall
EH,
CC,
Virmani
Dis
a
1987; 107:216-23
R, Newman
Med
in familial
Respir
Brundage
hypertension:
1988;
primary
JH.
pulmo-
138:952-57
JM, Batten
AP, Wang
NS, Fitch
N,
et al. Familial
pulmonary
capillary
hemangio-
RD,
Med
Intern
lesions
Rev
Bergofsky
pulmonary
Heneghan
resulting
RJ,
study.
JB, Pietra
hypertension.
D,
SM,
Primary
of pathologic
Langleben
Barst
Ayres
al.
et
JC,
vasodilator
pulmonary
WM.
Gersony
with
children
primary
hypertension.
Ann
109:106-09
primary
agents
Factors
influencing
pulmonary
[abstract].
survival
hypertension
Circulation
treated
1988;
78(suppl
2):293
18
will
of treatment
be
important
in
Barst
different
sets
sion.
19
modalities,
three
3 for
156
120:194-97
17
are shown
hemodynamic
Figure
variables.
hyperten-
in
special
with
A, Winokur
clinical
JE,
matosis
for which
survival
data
of survival
probability
248
CA,
lung.
DT,
national
such as lung transplantation,
can be compared.
Examples
in
1989;
41:415-16
KuipersJRG,
of
and
Chest
young
1986;
Gurtner
HP
AP, ed.
The
Philadelphia:
20
induced
RJ. Pharmacologically
in children
appropriateness
1986;
morphometnic
disease:
Intern
an equation
Institute
pulmonary
Circulation
N.
L. Pulmonary
hypertension:
index
of such
CG,
Schlesinger
arterial
pressure
Blood
Circulation
of hypertensive
arteries
therapy
and
ofthe
nary
pulmonary
right atnial
vessels
11:686-705
with
mean
mean
and
of six grades
Vmrchows
Churg
P, Reid
report
Dresdale
among
=
CM,
Wagenvoort
1, 2, or 3 years
x
y
B,
a
blood
vessels
pathology
defects.
Thorax
hypertension:
16
t
J, Schloo
42:1163-84
SJ. Pulmonary
following
Voordes
tosis
an equa-
at
vasodilator
hypertension:
Lung,
lung
1970;
Wagenvoort
Capewell
occlusive
=
of survival
to
registry.
N. Primary
The
cardiac
Heterogeneity
chances
JS,
vascular
92:871-76
10
H(t)=[0.88-0.14t+0.01t211
A(x,y,z) =
where:
P(t) = a patient’s
Heart,
a description
disease.
DA,
disease
and
chances
K’!’, Janieki
of pulmonary
of the
JE.
CA,
8 Lombard
pre-
hypoxemia,
study
study
disease:
chemotherapy.
14
obtained
tion
to predict
survival
has been
P(t)
arterial
60:16-
15
of this factor
is probably
reflection
ofpoor
oxygen-
capacity,
Weber
pulmonary
hypertension
Edwards
changes
case
Oxygen
SVO2
1985;
hypertension:
primary
Circulation
vascular
9 Davies
to 43 months.M
%nons)
Proc
responsiveness
in the National
cases.
5 Heath
Llmin/m2
63 percent)
GC,
and
CA, Wagenvoort
diagnosed
also
survival
of 17 percent,
whereas
a mean survival
of 55 percent
at 3 years.7#{176}The
power
derived from its cumulative
on data
of 4.0
(Mixed
than
output
hypertension:
Clin
pulmonary
of
a pathologic
7 Ellis
Cardiac
index
with a median
index
Arterial
(less
a mean
3-year
SVO2 predicted
Based
cardiac
Pietra
quantitative
veno-occlusive
fixed resistance
to blood
flow through
vasculature
and right ventricular
fail-
survival
dicted
higher
Decreased
cardiac
of PPH. It is caused
unexpectedly,
pulmonary
Mayo
1989; 60:1207-21
WD, Kay JM, Rich 5, Kennis
pulmonary
6 Wagenvoort
Output:
severity
assistance
&1198-1206
Hg.TM
Cardioc
cases.
BL,
Histopathology
congenital
(5) Depressed
Primary
of8O
morphometry,
primary
predictive
WD.
Primary
al.
agents. Circulation
3 Pietra CC, Edwards
survival.
Mean
RAP greater
than 20 mm Hg corresponds
to a median
survival
of 1 month,
compared
to
46 months
survival
for patients
with mean
RAP
less
than
study
HI,
Rubin
Among
of right
the
25
in New
months;
Elevation:
Edwards
a histopathologic
IV, 6 months.
(RAP)
J,
1 Bjornsson
survival.
survival
for patients
class I or II was 58.6
31.5
appreciates
ACCP
staff.
REFERENCES
devel-
Among
symptomore
symptomatic
In the registry,
median
York Heart Association
III,
panel
and the
patients
of diagnosis.
opment
in this disease,
resulting
mainly
from endorgan
(right ventricular)
sequelae.
Level
of symptomatic deterioriation
may be considered
a global clinical
index
matic
The
Simonsen
adults
with
pulmonary
primary
vasodilatation
pulmonary
hyperten-
98:497-503
Aminorex
pulmonary
University
pulmonary
hypertension.
In:
circulation:
normal
and
ofPennsylvania
Press,
1990;
Fishman
abnormal.
397-412
JG, Munro
JF, Kitchin
AH,
Muir AL, Proudfoot
AT.
Pulmonary
hypertension
and fenfluramine.
BMJ 1981; 283:881Douglas
83
Primary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
Pulmonary
Hypertension
(Lewis
J. Rubin
eta!)
21
McMurray
J, Bloornfield
hypertension
after
P. Miller
therapy
HC.
with
Irreversible
control
pulmonary
fenfluramine.
BMJ
Dis
1986;
43
202:239-40
22
HD,
Tazelaar
Colby
induced
TV.
Russell
97:1032-36
1990;
Spehlmann
Dim
de
hypertension
25
with
female
M,
crack
prevents
pulmonary
mine
pathology
Pulmo-
CA.
[abstract].
Am
Rev
Mestre
de
Atauri
due
to
toxic
MJ, Comez-Pajuelo
C,
FJ. Pulmonary
Juan
MJ,
45
Martinez-Tello
oil
syndrome:
Gomez-Sanchez
MA,
Saene
26
McDonnell
PJ,
hypertension
Dis
27
Toye
and
1983;
de hi Calzada
C, Gomez-Pajuelo
C,
46
Coll
PA,
Cardiol
1991;
Hutchins
cirrhosis:
nary
hypertension
relation
they
MK,
Primary
related?
Lebrec
D,
splanchnic
Rev
Respir
47
Benhamou
JR
hypertension:
Pulmo-
prevalence
GH, Baily RG, Brettler
JO, Driscol
TE, et al. Primary
DB, Davidson
pulmonary
hemophilia.
Ann
48
WRJ,
Ballard
hypertension
Intern
Med
Speich
R, Jenni R, Opravil
M, Pfab M,
pulmonary
hypertension
in HIV infection.
1988;
tension:
31
Yamald
Edwards
three
pathologic
32
Reeves
J1
Russi
EW.
Chest
Respir
Rich
5,
Dis
49
108:797-
Primary
1991; 100:
50
Rich
5,
35
36
37
Heath
E,
Whitaker
ease.
Circulation
Rich
5,
BH.
Antinuclear
J Am
Barst
RJ, Flaster
the
1992;
with
ER,
52
53
channel
blocking
evidence
for long-
and
regression
effect
of
high
primary
in
doses
of
54
PF.
pulmonary
vascular
Notes
Physiol
Guazzi
MD,
Hypersensitivity
BM,
Stodo
in primary
and
Miura
JD,
Stone
D,
pulmonary
1991;
338:
HC,
reactivity
in
pulmonary
A, Fotino
56
hyperten-
pulmonary
JH.
pulmonary
Cor
M, Suzuki
Y, Ishizawa
in secundum
atrial
Chest
do vascular
endothelial
Sci 1989; 4:22-5
Alimeato
M, Fiorentini
vessels
1986;
57
Vasa
E, Takahashi
septal defect
respond
Pepi
to catecholamines
M,
Rabinovitch
H,
Trusler
endothelial
do-
in pul-
CA,
factor
Williams
VIII
and congenital
associ-
heart
defects.
LW, Reid LM. von Willebrand
pulmonary
hypertension.
M. Endothelial
monocrotaline
injury
pulmonary
L,
progressive
Johnson
Am
and
vascular
hypertension.
DJ,
elastin
pulmonary
a biochemical
Smith
P, Heath
Banger
and collagen
J
Am
P
Keeley
synthesis
hypertension
and
study.
FW,
associated
induced
ultrastructural
Pathol
1990;
US.
Proc
1986;
by monocro-
Lab
Invest
1988;
M,
Madden
J,
A, Gosney
pulmonary
arteriopathy.
endothelial
surface
and
responses
to injury.
Fed
E,
BE,
AS,
45:101-08
PR, Lucore
C,
Kaufmann
5, et al. ibrinopeptide
A levels
throm’bosis
in patients
tension.
Circulation
1990;
D’Alonzo
GG,
Detre
Barst
KM.
Ann
with
RJ, Ayres
et
Intern
al
SM,
EK,
Rich
Med
5,
1991;
J Am
J, Harrison
ofprimary
pulmonary
hyper-
EH,
patients
from
a
Brundage
with
natural
primary
prospective
115:343-49
in primary
Brundage
BH.
left
pressure
Goodman
pulmonary
pulmonary
hyper-
1980; 12:181-93
of impaired
ventricular
Jaffe
of pulmonary
Bergofsky
in
results
J Cardiol
primary
Survival
N. Electrocardiogram
Eur
Sobel
indicative
82:841-47
hypertension:
Kanemoto
Louie
B, Caslin
of plexogenic
vascular
Coll
Doppler
ventricular
overload
Cardiol
DC,
due
RL.
echocardiographic
filling
in patients
to primary
1986;
Popp
with
pulmonary
8:1307-11
Echocardiographic
hypertension.
J
Am
Shimada
R, Takeshita
A, Nakamura
of
ventricular
systolic
right
1984;
A.
in systemic
BMJ 1986; 293:291-94
Barst RJ, Stalcup
SA, Steeg
CN, Hall JC, Frosolono
MF, Cato
AE, et al. Relation
of arachinodate
metabolites
to abnormal
Yacoub
160:111-21
The
Eisenberg
septum
to flow?
Polese
D,
ultrastructure
Ryan
analysis
59
C,
heart
features
Cardiol
1974;
33:438-
43
89:694-98
cells
congenital
with
1987; 135:294-99
M. Altered
hypertension.
in
Circulation
hypertension.
M,
in patients
of endothelin
Thom
hypertension
Todorovich-Hunter
right
Evidence
hypertension
complex.
Y, Matsumura
1988; 255:H1484-91
assessment
M, Morse
K, Sarto
1991; 84:2280-85
M,
in primary
Dis
Rosenberg
tension.
Brundage
8:1307-11
disease
of lung
AT,
Lancet
with
1987; 76:1043-52
RL, Carvalho
CA, Hoyer
registry.
dis55
Groves
hypertension.
How
Ber-
pulmonary
ofselective
production
et al. Abnormal
pulmonary
pulmonary
327:76-81
58
pulmonary
in
concentrations
associated
Andrew
RD.
Respir
BH,
pulmonary
27:160-71
Davies
GA,
the excretion
Dinh-Xuan
K, Nakao
endothein
abnormalities
Rich
1987; 76:135-41
histocompatibility
HP Aminorex
hypertension.
42
with
Geggel
J
of
Am
88:249-58
Yama.ki 5, HoriuchiT,
T. Pulmonary
vascular
41
1992;
of unexplained
39
with
The
survival
1986;
the major
Gurtner
40
K,
Menom
38
1985;
PS.
Hypertensive
Cardiol
between
as a cause
Circulation
M,
et al. The
for treatment
pressure
Circulation
antibodies
Coil
51
84:428-34
25:323-43
Hart
King
58:184-95
hypertension.
calcium
arterial
Med
W.
K,
association
children
dose
on
J
EM,
blockade
82:1765-77
JH,
hypertension.
Nishioka
circulation.
taline:
plexogenic
1985;
case
hypertension:
Levy
1956;
Kieras
sion.
for
High
blockers
N Engl
D,
D. The
hypertrophy.
Kaufmann
hypertension.
J
hyper-
56:884-88
of primary
Br Heart
pulmonary
in pulmonary
calcium-channel
1977;
Comparison
children.
pulmonary
ventricular
Green
heparmn-prota-
metabolites
oxide
for increased
Babinovitch
134:342-46
BH.
reduction
pulmonary
Circulation
primary
1986;
for primary
ofright
34
with
Brundage
therapy
term
CA.
and
primary
BM , Turkevich
Groves
patients
Rev
Clinical
types.
in adults
selected
33
JE.
5, Wagenvoort
arteriopathy
Respir
327:70-5
TW,
nitric
hypertension
Rowe
Rev
in
M,
Rabinovitch
with
WD,
prostacyclin
Higgenboftam
evidence
Physiol
Edwards
by
1990;
Newman
J Med 1992;
T, et al. Plasma
Circulation
Castroenterology
1268-71
30
ML,
An imbalance
in pulmonary
Yoshibayashi
ated
99
29
J,
factor
classic
and
Inhaled
monary
pulmonary
Am
hemodynamics.
Goldsmith
with
Rev
receptor
Circulation
CD,
etal.
N EngI
Pepke-Zaba
fects:
100:520-28
patients
BM,
WallworkJ.
Ogletree
induced
sheep.
McPherson
Groves
pulmonary
18:1539-45
GM.
are
complicatingportal
to
E,
hypertension
thromboxane
WG,
A, Behayoun
and
GR,
Ueda
127:43741
Hadengue
1991;
28
J Am
oil syndrome.
Am
1173-74
Martinez-Tello
FJ, Mestre
de Juan MJ, James
TN. Clinical
and
pathologic
manifestation
of pulmonary
vascular
disease
in the
toxic
BW,
vasodilatation
a clinicopathologic
in a child.
K, et al. Thromboxane
in awake
hypertension.
1989; 95:325-31
Chest
Christman
of
Hartl
reactions
nard
circulation
Lowenstein
and
Lillington
users
G,
L-tryptophan-
5,
44
Clarke
Montalevscot
DR.
Jr. Aguayo
clinical
pulmonary
131:171-77
Robinson
TE
145:A717
MA,
JI,
King
syndrome:
JE,
in
1992;
Gomez-Sanchez
study.
associated
Chest
hypertension
Lopez
disease
myalgia
Bespmr Dis
24
CW,
Pulmonary
LA,
nary
JL, Drage
eosinophilic
features.
23
Myers
of the
1985;
the
end-systolic
by
two-dimensional
Noninvasive
in
atrial
configuration
of
echocardiography.
assessment
septal
the
defect:
ventricular
J
Am
Cardiol
53:1117-23
Berger
M,
Haimowitz
Quan
titative
with
tricuspid
ultrasound.
60
of
M.
pressure
Masuyama
A, Van Tosh
assessment
of pulmonary
regurgitation
J Am
CoU
T, Kodama
M. Continuous-wave
Cardiol
using
1985;
K, Kitabatake
Doppler
Goldberg
hypertension
continuous
E.
in patients
wave
Doppler
6:359-65
A, Sato
H, Nanto
5, Inoue
echocardiographic
detection
I 104
1993
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
A, BerdoffRL,
1 1 I JULY.
of
249
pulmonary
regurgitation
and
estimation
of
artery
pulmonary
its
application
to
pressure.
noninvasive
Circulation
74
1986;
74:484-94
61
J,
elevated
Torres
A,
M, Trugeda
et al.
pulmonary
at cardiac
DG,
arterial
pulmonary
echocardiographic
Chen
WJ,
ovale
by contrast
Kuan
76
77
Chest
1992;
Moser
KM,
scans
provide
GT,
Ashburn
a guide
pulmonary
WL,
to which
hypertension
Fedullo
patients
merit
PF.
with
Perfusion
lung
apparent
angiography.
Med
Posteraro
Am
66
J
Sostman
HD,
Spritzer
CE,
MR imaging
of central
RH,
Roentgen
Debatin
AJ,
et
comparing
67
79
MR
K,
ger,
Hansen
and
JM,
Morgan
Mathur
PN,
blood
Imaging
DY,
80
RE,
pool
BJ.
Principles
1991;
99:551-56
Powles
RCP,
Pugsley
of digoxin
on
airflow
obstruction.
PM,
RL.
Primary
importance
Wagenvoort
72
Weir
of
Detre
KM.
The
pulmonary
PPH.
Am
U,
tinuous
Rev
Treatment
intravenous
Intern
and
SM,
1989;
Hood
of primary
prostacyclin
M,
83
1981;
95:283-88
BJ,
1984;
85
and
86
the
registry
1993
on
(pros-
of treatment
survival
in PPH
[ab-
(in press)
P. Oaldey
88
on
Fate
C.
Factors
that
hypertension.
of
the
1971;
influence
the
J
Br Heart
1986;
patient
Wallwork
Oyer
PE,
et al. Heart-lung
patients
with
306:557-64
Pasque
MK,
SA,
vascular
Circulation
CM,
JL,
Billingham
JD.
J
Med
Single
three
lung
he-
month
84:2275-79
J,
ED.
Robin
of survival
Chest
ME,
therapy
N Engl
Cooper
Theodore
idiopathic
145:A717
successful
1991;
length
pulmonary
1992;
disease.
LD,
pulmo-
RJ. Efficacy
Dis
hypertension:
transplantation.
1973;
Respir
balloon
cor
Barst
Pennock
Kaiser
and
advanced
transplantation:
ER
Burke
Benign
in
Rev
for pulmonary
hypertension:
Burdillon
HardofAJ,
pulmonary
Trulock
AR,
E.
DT,
Hunt
follow-up.
Glanville
Trell
JL,
Blade
60(suppl):1
Am
BA,
Eisenmenger’s
for terminal
septostomy
Reitz
1982;
CE.
1987;
lIP, Hsu
[abstract].
with
65:655.69
J Cardiol
atnial
disease
Primary
in patients
referred
1987; 91:675-81
pulmonary
hypertension.
Med
Acta
193:137-43
PD,
CM.
Oakley
J
Br Heart
Kanemoto
mary
BH,
in primary
NIH
Dis
H.
balloon
hypertension.
87
Brundage
of primary
epoprostenol
M. Influence
prostacyclin
D, Garofano
blade
Scand
in
22:535-46
EH,
from
history
in primary
J. Treatment
RJ, McGoon
J Cardiol
Am
for heart-lung
MD,
hypertrophy
ofvasodilators
N,
Sasamoto
pulmonary
Regression
1976;
H.
Pulmonary
hypertension.
Roskovic
A, Montanes
outcome
of primary
of primary
pulmonary
38:264-70
Jpn
P. Oakley
hemodynamics
J
Heart
CM.
Factors
pulmonary
hypertension.
BH,
PS.
in pri-
20:395-405
1979;
that
influence
Br Heart
the
J
1986;
55:449-58
140:1623-30
McCoon
pulmonary
Kerstein
pulmonary
70:580-87
medial
1960;
84
severe
McGoon
Comparable
110:1200-04
intravenous
pulmonary
Mark
Am
transplantation
Campbell
in
natural
Bergofsky
experience
Dis
J,
MP,
function
Med
Gersh
Circulation
administration
Respir
Mendoza
McEwan
Circulation
acute
pulmonary
hypertension:
Ayres
hypertension:
Rubin
WB.
D,
modynamic
WD,
Vasoconstriction
U,
pulmonary
primary
Barst
Respir
[abstractj.
for
Febi-
Hypoxic
and
SO,
Ann
ofthrombosis.
Rubin
KM.
ventricular
Edwards
hypertension.
EK,
right
pulmonary
CA.
pulmonary
Bois
Wallwork
with
A, Montanes
vascular
82
and
TW,
1985;
Nihill MR. O’Laughlin
MP, Muffins
atnial septostomy
is effective
palliation
of
imaging,
2:135-42
Lea
81
study
1992;
Whipp
sclerosis
Chest
V, Steele
71
250
Coleman
phantom
Philadelphia:
M, du
Fuster
1990;
Sue
systemic
chronic
Frye
73
Reson
interpretation.
in
EJ. Effect
the
HD,
fraction:
radionucide
JE,
Grilliths
hypertension.
70
emboli.
1987
vasoconstriction
69
imaging,
J Magn
testing
RJ. Cine-
JF, Sostman
ejection
Heart
infusion
ofprimary
Young
nale
Paolini
Cardiac
ventriculography.
Wasserman
Herikens
pulmonary
152:465-68
SN,
al.
cine
exercise
68
1989;
JF, Nadel
Evans
and
Rozkovec
syndrome.
gradient-refocused
U,
Rev
J
Am
MF.
hydralazmne
J 1987; 57:270-78
Br Heart
Am
and
primary
66:334-38
Frosolono
ofprostacycin
hypertension
continuous
1982;
JT,
F, Cato
in
55:449-58
1988;
148:167-70
65
Reeves
M, Handel
vasodilation
Circulation
U,
effects
outcome
primary
J
West
Rubin
Long W, Rubin
JT, Frosolono
pulmonary
hypertension.
stract].
78
Page
Reeves
DK, Higgenbottam
Jones
with
foramen
echocardiography.
BM,
tacyclin).
85:1414-22
ofpatent
BM,
hypertension.
Groves
pul monary
in severe
transesoph-
1992;
FY. Detection
transesophageal
75
pulmonary
101:1515-20
64
Groves
hemodynamic
57:859-63
adaptation
Circulation
W, Un
JA,
measured
an intraoperative
study.
P. Lien
pressure
1986;
Pericardial
hypertension:
ageal
with
J Cardiol
HC.
de Prada
of Doppler-determined
pressure
Am
Dittrich
A, Vazquez
Comparison
catheterization.
Blanchard
chronic
63
U,
Prostacycin-induced
pulmonary
R, Larman
Martin-Duran
Ruane
62
Rubin
AE.
M,
Barst
hypertension
(epoprostenol).
Ann
R, Williams
with
Intern
89
Rich
5,
con-
therapy
Med
pulmonary
Brundage
on
the
clinical
hypertension.
Levy
outcome
Circulation
The
of
effect
patients
of
vasodilator
with
primary
1985; 71:1191-96
112:485-91
Primary
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21673/ on 05/02/2017
Pulmonary
Hypertension
(Lewis
J. Rubin
et a!)