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CRITICAL CARE EXTRA
Inhaled Epoprostenol
An approach to the treatment of pulmonary hypertension in patients with ARDS.
By Paula Lusardi, PhD, RN, CCRN, CCNS, and Virginia Brown, BSN, RN, CCRN
T
he care of patients
with acute respiratory distress syndrome (ARDS) is a
challenge to even the
most seasoned critical care
nurse. The patient mortality rate
associated with the syndrome
remains high at 40% to 60%,
and care is complex.1-3 Despite
30 years of clinical trials focused
on improving patient outcomes,
no therapeutic interventions
have convincingly altered the
treatment of the underlying
pathophysiology of ARDS,4
which, consequently, remains
supportive. The search for supportive therapies has recently
focused on the severe hypoxemia
and pulmonary hypertension of
ARDS, and has led to renewed
interest in the use of the prostacyclin epoprostenol (Flolan), a
naturally occurring prostaglandin and pulmonary vasodilator.5
This article discusses the use of
the medication, especially the
inhaled route of administration,
in the treatment of pulmonary
hypertension in patients with
ARDS, and its implications for
the critical care nurse.
ACUTE RESPIRATORY DISTRESS
SYNDROME
ARDS, a severe form of acute
lung injury caused by a direct or
Paula Lusardi is a critical care clinical nurse
specialist and Virginia Brown, her fellow, is a
clinical nurse III on the intensive care unit at
Baystate Medical Center, Springfield, MA. The
authors developed this article as part of the
AACN/AJN Nursing Fellows Program, a professional development program of the
American Association of Critical-Care Nurses
in collaboration with AJN.
[email protected]
The Pathogenesis and Pathophysiology of ARDS
Direct or indirect insult
⇓
Inflammatory response and release of chemical mediators
⇓
Increased pulmonary capillary permeability with decreased surfactant activity
Possible formation of microemboli
⇓
Pulmonary interstitial alveolar edema
Progressive alveolar collapse
Decreased compliance
⇓
Low ventilation–perfusion units and right-to-left intrapulmonary shunting
⇓
Severe hypoxemia
Progressive fibrosis and pulmonary hypertension
systemic insult, such as pulmonary contusion or sepsis, is
characterized by the acute onset
of inflammatory lung injury. The
resultant increased alveolar capillary permeability causes noncardiogenic pulmonary edema, left
atrial hypertension that is not evident (pulmonary artery wedge
pressure 18 mmHg or lower),
bilateral pulmonary infiltrates
seen on chest X-ray, and severe
hypoxemia,6, 7 in which the ratio
of arterial partial pressure of oxygen (PaO2) to fraction of inspired
oxygen (FIO2) is 200 mmHg or
lower (the normal range is 300 to
400 mmHg). Without adequate
pulmonary oxygen uptake and
delivery to cells, ARDS patients
quickly die.
Pathophysiology. Central to the
pathophysiology of ARDS is the
activation of the inflammatory
response leading to ventilation–
perfusion (V/Q) mismatch, intrapulmonary shunting of blood,
microemboli, severe hypoxemia,
and pulmonary hypertension3, 8
(see The Pathogenesis and Pathophysiology of ARDS, above).
V/Q mismatch occurs when
some alveoli fill with protein
exudates and are not ventilated.
Right-to-left intrapulmonary
shunting occurs when blood is
shunted past these fluid-filled or
collapsed alveoli, resulting in
substantial amounts of unoxygenated blood, sometimes as
much as to 50%, being returned
to the central circulation.8 Poor
V/Q and occlusion of pulmonary
capillaries from microemboli
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Studies of the Use of Inhaled Epoprostenol (PGI2)
Method and
rate of administration
Study
Patients
Results regarding PGI2
Walmarth, et al. (1993)
3 medical
prospective, case reports
17–50 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP, PVR, and shunt
no change in CI or PCWP
Van Heerden, et al. (1996)
2 medical
case reports
20–50 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP and shunt
no change in MAP
Van Heerden, et al. (1996)
5 medical
descriptive, PGI2 and NO
50 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ shunt
no change in MAP or PCWP
Walmarth, et al. (1996)22
16 medical–surgical
prospective, randomized PGI2 vs. NO
1.5–34 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP and shunt
Zwissler, et al. (1996)
8 medical–surgical
prospective, randomized PGI2 vs. NO
1, 10, or 25 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP and shunt
Van Heerden, et al. (1997)
1 medical
prospective, case report
10–50 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP and PVR
no change in MAP
platelet aggregation defect
Domenighetti, et al. (2001)
15 medical–surgical
prospective, unrandomized (patients
with intra- and extrapulmonary causes
of ARDS)
2–40 ng/kg/min
Responders (8 extrapulmonary causes
of ARDS)
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP and PVR
Nonresponders (6 intrapulmonary causes
and 1 extrapulmonary causes)
↓ PaO2, ↓ PaO2–FIO2 ratio
↓ PAP and PVR
Miesen, et al. (2001)
1 medical
prospective, case report
16–32 ng/kg/min
↑ PaO2, ↑ PaO2–FIO2 ratio
↓ PAP
PaO2 = arterial partial pressure of oxygen; PaO2–FIO2 ratio = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PAP = pulmonary
arterial pressure; PVR = pulmonary vascular resistance; CI = cardiac index; PCWP = pulmonary capillary wedge pressure; MAP = mean arterial pressure;
epoprostenol (PGI2) = Flolan; NO = nitric oxide.
result in severe hypoxemia
(PaO2–FIO2 ratio lower than
200 mmHg) that is progressive
and refractory.3, 8 As a consequence of progressive hypoxemia, the pulmonary circulation,
unlike the systemic circulation,
becomes constricted through a
poorly understood reflex mechanism, causing an increase in pulmonary vascular resistance and
pulmonary hypertension.8-10
Pulmonary hypertension (PH)
can be classified as either primary
or secondary. Primary PH, a disease with an unexplained cause,11
is uncommon, but the causes
of secondary PH are known
(PH secondary to ARDS, for
example). Whether primary or
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secondary, PH is defined as
having a mean pulmonary arterial pressure (PAP) greater than
30 mmHg (the normal mean
range is 20 to 30 mmHg at rest
or greater than 30 mmHg with
exercise), and when secondary to
ARDS, it is associated with poor
clinical outcomes.
PH causes changes in the
smooth muscle of the arterial
wall, leading to muscle hypertrophy, thrombosis formation, and
small vessel occlusion.12 The elevation of PAP increases right
ventricular afterload (pulmonary
vascular resistance) and right
ventricular dysfunction, leading
to reduced right ventricular output, decreased blood flow to the
lungs, and a worsening of
already severe hypoxemia.9
Progressive, refractory, severe
hypoxemia coupled with PH are
hallmark clinical manifestations
of ARDS.4, 13, 14
EPOPROSTENOL
Epoprostenol is a prostacyclin, a
metabolite of arachidonic acid,
and one of several naturally
occurring prostaglandins—
prostaglandin I2 (PGI2)4, 8, 14––
that is produced in all vascular
tissues, particularly in endothelial cells and smooth muscle
cells. This agent produces important effects in patients with
ARDS. Epoprostenol causes
vasodilation of pulmonary and
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systemic vasculature in a dosedependent manner,15 and by this
action can reduce postcapillary
vasoconstriction in the lungs and
thereby decrease microvascular
pressure, reducing the formation
of lung edema.14 In addition, it
has an inhibitory effect on
platelet aggregation, thereby preventing adhesion of platelets to
the vascular endothelium.16
Finally, it can inhibit the activation of leukocytes and monocytes during the inflammatory
reaction and reduce the release
of lysosomal enzymes. In other
words, epoprostenol can play a
role in reducing the inflammation that occurs in ARDS.14, 17
Epoprostenol was discovered
in 1976 during studies of thromboxane production.18 Its use
leads to potent relaxation of
smooth muscle cells induced by
a receptor-mediated increase in
intracellular adenosine 3, 5
cyclic monophosphate cAMP.
Administration. Epoprostenol
is administered both intravenously and by inhalation but
is approved by the FDA for IV
use only. It is indicated for longterm IV treatment of primary PH
and secondary PH resulting from
intrinsic precapillary pulmonary
vascular disease or PH associated with scleroderma in New
York Heart Association Class III
and Class IV patients who don’t
respond adequately to conventional therapy.16, 19
The IV route, however, has
limited utility in critically ill
patients with ARDS because of
its side effects––systemic
hypotension and increased rightto-left shunting in the lung, the
first of which, caused by arterial
vasodilation, can lead to a
reduction in coronary perfusion
and compromised ventricular
performance, and the second of
which, resulting in less oxygenated blood being supplied to
the left side of the heart, can
worsen hypoxemia.20 In contrast,
inhaled epoprostenol reaches
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Criteria for Use in Adults
A protocol of Baystate Medical Center.
General criteria
• Inhaled epoprostenol is used for salvage therapy in acute respiratory distress
syndrome (ARDS) with hypoxemia and pulmonary hypertension (PH).
• Inhalation of epoprostenol aerosol is an alternative route of delivery that may
improve ventilation–perfusion matching in secondary PH.
• Aerosolized epoprostenol should NOT be used in the treatment of PH.
• Orders for inhaled epoprostenol administration must be either written or
approved by a qualified attending physician.
• Use the established respiratory therapy protocol for continuous delivery of
inhaled epoprostenol from the Miniheart nebulizer into the mechanical
ventilator circuit.
Specific criteria*
Yes No
___ ___
___ ___
___ ___
___ ___
___ ___
___ ___
___ ___
___ ___
PVRI > 250 or mean PA > 25.
PaO2–FIO2 ratio < 150.
No clinical evidence of left atrial hypertension. PAWP < 18 mmHg or
PAD–PAWP difference is > 5 mmHg.
The patient is ventilated, and you plan to provide all necessary life support
measures.
Exclusive of ARDS or pulmonary hypertension, there is a reasonable
expectation of survival.
If the patient is hypoxemic, you have optimized mechanical ventilator
support.
A pulmonary artery catheter is in place.
Treatment with epoprostenol will be guided by an intensivist or physician
experienced in the treatment of PH and in the use of vasoactive infusion
agents.
*All should be checked “yes” for use of epoprostenol.
PVRI = pulmonary vascular resistance index; PA = pulmonary arterial pressure; PaO2–FIO2 ratio = ratio of
arterial partial pressure of oxygen to fraction of inspired oxygen; PAWP = pulmonary artery wedge
pressure; PAD = pulmonary artery diastolic pressure.
Used with permission of Baystate Medical Center, Springfield, MA.
only the well-ventilated areas of
the lungs, causing greater vasodilation in these regions than the
IV route does, while not causing
systemic hypotension.5
INHALED (AEROSOLIZED)
EPOPROSTENOL
Case reports and descriptive and
randomized trial research in the
last six years suggest that administration of epoprostenol by
inhalation decreases shunting
while improving oxygenation
and decreasing PH1, 5, 13, 17, 21-24 (see
Studies of the Use of Inhaled
Epoprostenol, page 64CC). In
addition to its direct vasodilative
properties, inhaled epoprostenol
can modulate vascular growth or
vascular remodeling and modify
platelet function, thereby
improving oxygenation and
reducing PAP.9, 23
Inhaled epoprostenol’s role as
an inhibitor of platelet aggregation was noted in early trials.25
Max and Roissant suggest that
IV-administered epoprostenol
may induce a platelet aggregation defect with subsequent
bleeding,9 an effect that has not
been associated with the use of
inhaled epoprostenol.17 The literature suggests that individually
titrated doses of nitric oxide
(NO) and inhaled epoprostenol
have identical efficacy profiles in
terms of selective pulmonary
vasodilation and redistribution
of blood flow in the lungs.1, 5, 22, 24
However, the potential side
effects of NO include direct lung
injury, inhibition of platelet
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aggregation, methemoglobinemia, and possibly mutagenesis or
carcinogenesis.24 In contrast,
epoprostenol produces none of
the adverse effects of toxic
metabolites and its potential side
effects are uncommon, transient,
and negligible in sedated, ventilated patients.24
INHALED EPOPROSTENOL AT
BAYSTATE MEDICAL CENTER
In August 2002 the Pharmacy
and Therapeutic Committee at
Baystate Medical Center in
Springfield, Massachusetts,
approved the use of inhaled
epoprostenol for salvage therapy
in patients with the hypoxemia
and PH of ARDS and developed
guidelines for its administration
and patient selection (see Criteria for Use in Adults, page 64EE,
and Cautions in the Use of
Inhaled Epoprostenol in Adults,
above). The information is not
intended to supersede informed
medical judgment applied to specific patient cases.
Dosage. Recent data indicate
that a broad range in dosage of
inhaled epoprostenol has been
found to be effective. One study
found that dosages ranged from
2 ng/kg/min to a maximal dosage
of 40 ng/kg/min.23 Another, in a
single dosage response curve for
a patient with ARDS, demonstrated that a dosage of 20 to
30ng/kg/min is as effective as
50ng/kg/min.5 Baystate’s pharmacy mixes an epoprostenol
solution of 1.5 mg/100 mL,
which results in a dose based on
ng/kg/min. The center’s dosage
guidelines are still in development in accordance with the
trend toward administering lesser
amounts of the agent, given adequate patient response.
Actions. Inhaled epoprostenol’s action is site-specific to
ventilated areas of the lung.9
Coupled with its short half-life
and selective vasodilation, the
drug’s actions result in redistribution of blood flow from [email protected]
Cautions in the Use of Inhaled Epoprostenol in Adults
• The bedside nurse and respiratory therapist must understand set-up, maintenance,
and the need for continuous refilling of the nebulizer; the clinical end points of
therapy; and that monitoring for possible side effects is critical.
• The half-life of epoprostenol is one to five minutes. Abrupt withdrawal or interruption
of drug delivery will result in hypoxemia and pulmonary arterial pressure increasing
to pretreatment levels, and rebound might occur. For this reason, transporting
patients during aerosol administration is difficult.
• Cardiac arrhythmias may occur.
• Because of epoprostenol’s inhibition of platelet aggregation, there is a potential for
an increased risk of bleeding if platelet inhibitors are given concurrently.
• The effects of epoprostenol on preexisting subacute or chronic lung disease are
unknown.
• The administration of epoprostenol to patients with pulmonary veno-occlusive disease has been associated with the development of pulmonary edema.
• Although there are no data on short-term inhalation of epoprostenol in patients with
severe left-ventricular systolic dysfunction (New York Heart Association III or IV),
chronic IV use has been associated with increased mortality.
• There are no adequate studies of epoprostenol use in pregnant women.
• There are no data on the safety of epoprostenol in children younger than 18 years
or in adults older than 65 years.
Used with permission of Baystate Medical Center, Springfield, MA.
tilated to ventilated areas, leading to a decrease in the V/Q mismatch and improved hypoxemia
without lowered systemic blood
pressure.21
CASE STUDY
Darryl Brightman, a 49-year-old
with a history of high triglyceride levels and hypertension,
presents to a local hospital with
abdominal pain. Laboratory
testing reveals a markedly elevated lipase level of 21,330 U/L
and a triglyceride level higher
than 2,000 mg/dL. Because Mr.
Brightman is in shock and experiencing ARDS secondary to
severe necrotizing pancreatitis,
he is placed on mechanical ventilation (MV). Over the next two
days the state of shock persists,
the ARDS becomes more severe,
and the patient develops anuric
renal failure. He is transferred to
Baystate Medical Center.
On admission, Mr. Brightman
is afebrile (at 98.4°F), with a
heart rate of 85 beats per minute.
A phenylephrine infusion is necessary to maintain a mean arterial pressure of 69 mmHg, and
the patient is pharmacologically
sedated and paralyzed to facili-
tate optimal MV. There is generalized edema and mottling of the
extremities, and a chest X-ray
shows bilateral lung edema.
Despite 100% oxygen and a
positive end expiratory pressure
of 18 mmHg, arterial PaO2 is
61 mmHg.
A solution of epoprostenol
(1.5 mg/100 mL) is administered
by continuous aerosol, and PaO2
rapidly increases to 83 mmHg.
The FIO2 decreases to 85%
within 24 hours and to 50%
after 48 hours, indicating an
improvement in PaO2–FIO2
ratio. The patient’s cardiac
index increases from 1.8 to
2.3 L/min/m2 immediately, and
to 4.2 L after 24 hours. The PAP
does not change substantially. At
the same time, Mr. Brightman is
supported with continuous venovenous hemofiltration and
eventually taken to the operating
room for debridement of a
necrotic pancreas.
Epoprostenol is administered
by continuous aerosol for 10
days, during which period the
need for treatment is determined
by the level of oxygenation and
the hemodynamic response to
withdrawal of the medication for
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short intervals. Eventually, the
patient no longer needs administration. After an ICU stay of
about six weeks and an additional three weeks’ hospitalization for the healing of abdominal
wounds, Mr. Brightman, ambulatory and no longer in need of
MV, is discharged to a rehabilitation center.
NURSING IMPLICATIONS
The nursing care of patients
receiving aerosolized epoprostenol for ARDS focuses on the
end points of therapy, proper
administration, and the monitoring of side effects. Hypoxemia
should decrease, PaO2–FIO2
ratio should increase, and PAP
should decrease without a
decrease in the mean arterial
pressure. Abrupt withdrawal or
interruption of drug delivery will
result in the return of hypoxemia
and PAP to pretreatment levels.
The nurse, pharmacist, intensivist, and respiratory therapist
should collaborate in the attainment of end points.
The proper administration is
crucial. While institutions may
maintain constant inhalation in
a variety of ways, as determined
by the type of nebulizer used, it
is important that the bedside
nurse and respiratory therapist
set up, maintain, and continuously refill the nebulizer to
ensure constant inhalation.
Finally, observation for side
effects is critical to the safety of
the patient. While the side effects
of IV-administered epoprostenol
vary and can be severe (bleeding,
chills, tachycardia, nausea and
vomiting, jaw pain, and dizziness),16 inhaled epoprostenol
produces few side effects.
Although cardiac arrhythmias
may occur and bleeding related
to the inhibition of platelet
aggregation are of possible concern, research indicates otherwise.21 Baystate Medical Center’s
guidelines underscore several
cautions to be considered in the
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use of inhaled epoprostenol.
Cost containment. In 1996
inhaled epoprostenol cost about
$2,000 a day at 20 ng/kg/min in
a 70-kg adult,1, 26 but in October
2002 Baystate ICU pharmacist
Gary Tereso reported that the
cost of the same treatment had
decreased to as little as $70 a day.
The nursing care of patients
receiving epoprostenol for the
treatment of ARDS is crucial to
the improvement of outcomes in
critically ill patients, among
whom there is a high mortality
rate. The use of inhaled
epoprostenol is a promising
therapy for the severe hypoxemia and PH of ARDS, and the
pursuit of its use requires the
collaborative effort of nurses,
physicians, pharmacists, and respiratory therapists. ▼
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