/clinical/,/clinical/cckm-tools/,/clinical/cckm-tools/content/,/clinical/cckm-tools/content/cpg/,/clinical/cckm-tools/content/cpg/medications/,

/clinical/cckm-tools/content/cpg/medications/name-97565-en.cckm

201607203

page

100

UWHC,UWMF,

Tools,

Clinical Hub,UW Health Clinical Tool Search,UW Health Clinical Tool Search,Clinical Practice Guidelines,Medications

Epoprostenol Inhaled – Adult/Pediatric/Neonatal - Inpatient

Epoprostenol Inhaled – Adult/Pediatric/Neonatal - Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


1
Epoprostenol Inhaled – Adult/Pediatric/Neonatal
– Inpatient Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 5
METHODOLOGY ...................................................................................................................... 5
DEFINITIONS ............................................................................................................................ 5
INTRODUCTION ....................................................................................................................... 6
RECOMMENDATIONS .............................................................................................................. 7
UW HEALTH IMPLEMENTATION ............................................................................................. 9
REFERENCES .........................................................................................................................10
APPENDIX A ............................................................................................................................12
CPG Contact for Content:
Name: Cindy Gaston, PharmD, BCPS – Department of Pharmacy
Phone Number: (608) 265-8161
Email Address: cgaston@uwhealth.org
CPG Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS – Drug Policy Program Manager, Department of Pharmacy
Phone Number: (608) 263-1328
Email Address: ptrapskin@uwhealth.org
Guideline Update Author:
Cindy Gaston, PharmD, BCPS
Note: Active Table of Contents
Click to follow link
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

2
Coordinating Team Members:
Cindy Gaston, PharmD, BCPS
Review Individuals/Bodies:
J. Runo, MD, Department of Medicine – Pulmonary; J. Wells, MD, Department of Medicine – Pulmonary;
J. Limjoco, MD, Department of Pediatrics – Neonatology; Paula Breihan, RRT, Respiratory Therapy;
Kristine Ostrander, MA, RRT; Katie Willenborg, PharmD, Department of Pharmacy; Department of
Pharmacy; Rhonda Yngsdal-Krenz, RRT
Committee Approvals/Dates:
Pharmacy & Therapeutic Committee
Release Date:
July 2015
Next Review Date:
July 2018
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

3
Executive Summary
Guideline Overview
Guidance is provided for appropriate indications, dosing, titration, and tapering of inhaled epoprostenol in
adult, pediatric and neonatal patients.
Key Practice Recommendations
Adult Patients
1. Acute Respiratory Distress Syndrome
ξ Initiate at a dose of 0.05 mcg/kg/min via continuous nebulization. Doses higher than 0.05
mcg/kg/min have not been studied in ARDS. (Class IIb, Level C)
ξ The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, wean off the inhaled epoprostenol. (Class IIb, Level C)
ξ The dose of epoprostenol should be decreased by 0.01 mcg/kg/min every 2 hours as tolerated by
the patient when weaning off therapy. (Class IIb, Level C)
2. Pulmonary Hypertension, Right Heart Failure Following Pulmonary Embolism, Severe Right
Heart Failure
ξ Inhaled epoprostenol therapy may be considered for patients with refractory hypoxemia and
mean pulmonary artery pressure >30 mmHg, PaO2/FiO2 <150 mmHg, or cardiac index less than
2.2 L/min/m2. (Class IIb, Level C)
− Initiate at a dose of 0.01 mcg/kg/min. (Class IIb, Level C)
− The dose of epoprostenol may be titrated up by 0.01 mcg/kg/min every two hours to a
maximum of 0.05 mcg/kg/min. (Class IIb, Level C)
ξ The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable. (Class IIb, Level C)
− Consider decreasing the dose of epoprostenol by 0.01 mcg/kg/min every 2 hours as tolerated
until weaned off. (Class IIb, Level C)
3. Post Cardiac Surgery Patients
ξ Administer inhaled epoprostenol to intubated cardiac surgery patients or patients on continuous
BiPAP with refractory hypoxemia. For patients on BiPAP weigh the benefit of epoprostenol
therapy with the risk of rebound pulmonary hypertension if therapy is interrupted accidentally by
removal of the BiPAP mask. (Class IIb, Level C)
ξ It is reasonable to initiate dosing at 0.03 mcg/kg/min. Doses higher than 0.03 mcg/kg/min have
not been studied in this population. (Class IIb Level C)
ξ The dose of epoprostenol may be decreased by 0.01 mcg/kg/min every 2 hours as tolerated by
the patient. (Class IIb, Level C)
ξ The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable. (Class IIb, Level C)
Pediatric Patients
4. Acute Respiratory Distress Syndrome
ξ Inhaled epoprostenol therapy may be considered for patients with refractory hypoxemia
associated with ARDS. (Class IIb, Level B)
− Consider initiating doses at 0.03 mcg/kg/min via continuous nebulization. (Class IIb, Level B)
− The dose of epoprostenol can be increased to 0.05 mcg/kg/min if the patient does not
respond to the initial dose. (Class IIb, Level B)
− The dose of epoprostenol can be decreased by 0.01 mcg/kg/min every 2 hours as tolerated
by the patient. (Class IIb, Level C)
5. Primary and Secondary Pulmonary Hypertension
ξ Maximize other therapies to improve oxygenation (i.e., F
i
O2, PEEP, and hemodynamics) before
initiating inhaled epoprostenol therapy. (Class I, Level C)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

4
ξ Inhaled epoprostenol therapy can be considered for patients with refractory hypoxemia. (Class
IIb, Level C)
− Consider initiating dose at 0.03 mcg/kg/min via continuous nebulization. (Class IIb, Level B)
− The dose of epoprostenol can be increased to 0.05 mcg/kg/min if the patient does not
respond to the initial dose. (Class IIb, Level B)
− The dose of epoprostenol can be decreased by 0.01 mcg/kg/min every 2 hours as tolerated
by the patient. (Class IIb, Level C)
ξ The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable. (Class IIb, Level C)
Neonate Patients
6. Inhaled epoprostenol may improve oxygenation in hypoxemia neonates when all other therapies to
improve oxygenation have failed. (Class I, Level B)
ξ Initial doses of 0.03 mcg/kg/min are recommended and can be titrated up to 0.05 mcg/kg/min if
necessary. (Class I, Level C)
ξ It is reasonable to discontinue therapy by decreasing the dose 0.01 mcg/kg/min every 2 hours as
tolerated. (Class IIa, Level C)
General Recommendations for Treatment
7. Do not administer epoprostenol to patients with:
ξ Allergy or sensitivity to epoprostenol or glycine diluent (Class III, Level C)
ξ Cardiac failure secondary to left ventricular dysfunction (Class III, Level C)
8. Avoid use or use cautiously in patients with active and significant bleeding (Class IIb, Level C)
9. Epoprostenol is a pregnancy class B drug Inhaled epoprostenol should be used with caution in
pregnant women. (Class I, Level C)
10. Wean patients off epoprostenol; abrupt withdrawal can result in rebound pulmonary hypertension.
(Class IIa, Level B)
Monitoring Parameters
11. Vital signs including blood pressure, heart rate, and oxygen saturation every 15 minutes for one hour
during the first hour of treatment and after each dose change, then every hour thereafter. (Class I,
Level C)
ξ Hemodynamic monitoring may include the following based on the patients condition and
comorbidities: central venous pressure (CVP), echocardiography, ultrasound, cardiac index (CI),
peripheral vascular resistance, total pulmonary resistance, mean pulmonary artery pressure, and
stroke volume but is not required (Class I, Level C)
12. Monitor for symptoms of epoprostenol toxicity: jaw pain, headache, flushing, nausea, vomiting,
diarrhea, abdominal pain, signs of bleeding, bronchoconstriction or hypotension. (Class I, Level C)
Companion Documents
1. Epoprostenol Intravenous – Adult- Inpatient Clinical Practice Guideline
2. Order set – IP- Inhaled Epoprostenol – Procedure [2234]
Pertinent UWHC Policies & Procedures
1. UW Health Respiratory Manual Policy 3.51 Inhaled Epoprostenol
Patient Resources: none
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

5
Scope
Disease/Condition(s):
Adults - pulmonary hypertension, acute respiratory distress syndrome (ARDS), right heart failure following
pulmonary embolism, and severe right heart dysfunction
Pediatrics/Neonates – pulmonary hypertension, ARDS
Clinical Specialty & Intended Users:
Pulmonary, Critical Care, physicians, mid-level providers, nurses, pharmacists, respiratory therapist
Major Outcomes Considered:
Safe and effective administration of inhaled epoprostenol.
Guideline Metrics:
Evaluate Adverse Drug Events in the Patient Safety Net (PSN) reporting system for errors in
administration of patient harm with inhaled epoprostenol.
Methodology
Rating Scheme for the Strength of the Recommendations:
A modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system
developed by the American Heart Association and the American College of Cardiology Foundation has
been used to assess the Quality and Strength of the evidence in this Clinical Practice Guideline.1
(Appendix A).
A PUBMED, Cochrane Library and International Pharmaceutical Abstracts were searched using the terms
inhaled or aerosolized, epoprostenol or prostacyclin, acute respiratory distress syndrome.
Cost Analysis:
The UW Health cost for epoprostenol for an 80 kg patient at a dose of 0.05 mcg/kg/min is approximately
$450 per 24 hours, whereas cost for inhaled nitric oxide is approximately $3600 per 24 hours.
A small single center trial compared safety and efficacy of inhaled epoprostenol and inhaled nitric oxide
for hypoxic respiratory failure in adult intensive care patients (ICU).2 There was no difference in duration
of therapy, mechanical ventilation, length of stay in the ICU, or duration hospitalization. However, the cost
of therapy was 4.5 to 17 times higher for inhaled nitric oxide (depending on contract pricing).
Definitions
1. Pulmonary hypertension – is characterized by increased pulmonary arterial pressure and
secondary right-sided heart failure and is defined as a mean pulmonary artery pressure ≥25
mmHg with a pulmonary capillary wedge pressure ≤15 mm Hg.3 Pulmonary hypertension is
divided in to five sub-categories:4
1.1. Primary pulmonary hypertension
1.2. Pulmonary hypertension due to left-sided heart failure
1.3. Pulmonary hypertension associated with hypoxemia
1.4. Pulmonary hypertension associated with thromboembolic disease
1.5. Pulmonary hypertension associated with disorders affecting the pulmonary vasculature
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

6
2. Acute respiratory distress syndrome –
Berlin definition of acute respiratory distress syndrome in adults5
Timing Within 1 week of known clinical insult or new or worsening respiratory
symptoms
Chest imaging Bilateral opacities – not fully explained by effusions, lobar/lung collapse, or
nodules
Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload
Oxygenation
Mild 200 mmHg Moderate 100 mmHg Severe PaO2/FIO2 ≤ 100 mmHg with PEEP ≥ 5 cm H2O
CPAP – continuous positive airway pressure; FIO2- fraction of inspired oxygen; PaO2 – partial
pressure of oxygen; PEEP – positive end-expiratory pressure
3. Prostacyclin – an endogenous prostaglandin that inhibits platelet function and is a vasodilator
4. Epoprostenol – a synthetic prostacyclin
5. Microgram to nanogram conversion: 0.01 mcg/kg/min is equal to 10 ng/kg/min
Introduction
The mortality of ARDS is approximately 30 – 40%, but can be reduced by therapeutic interventions.6-8 The
pathophysiology of ARDS includes vasoconstriction and direct administration of vasodilators via the
airway to improve pulmonary gas exchange is an accepted treatment.9, 10 Nitric oxide (NO) has been the
most studied inhaled vasodilator, but the small trials conducted have not demonstrated a decrease in
mortality .11-17 Nitric oxide activates guanylyl cyclase to increase cyclic-guanine monophosphate in
vascular smooth muscle cells producing relaxation. Nitric oxide is efficacious in improving surrogate
markers of oxygenation but, it does not improve survival near term or long term.18 Alternatives have been
explored secondary to nitric oxide’s potential side effects and its high cost. Inhaled prostacyclins are the
most widely studied alternative in adult and pediatric patients to NO. Inhaled prostacyclin produces similar
changes in oxygenation and pulmonary artery pressure as NO.19 Prostacyclins have been studied in
mechanically ventilated patients and in patients on biphasic positive airway pressure (BiPAP) therapy.20, 21
Prostacyclins cause an increased activity of the adenylate cyclase enzyme that causes a compensatory
increase in intracellular cyclic adenosine monophosphate levels. Through a series of reactions including
increased potassium conductance, blockage of calcium channels, and a decrease in cytosolic calcium,
epoprostenol causes smooth muscles to relax which leads to vasodilation. Vasodilation improves
oxygenation by allowing blood to flow into areas of the lung that are better ventilated, thus improving
oxygenation of the blood.22
Epoprostenol is administered intravenously for the treatment of pulmonary hypertension (UW Health
Epoprostenol by Intravenous Infusion Clinical Practice Guideline), but inhaled epoprostenol is an
alternative method of treatment. Intravenous epoprostenol is preferred for the longer term management of
patients with pulmonary hypertension. Inhaled epoprostenol is for the short term management of
pulmonary hypertension. Several studies demonstrate that inhaled epoprostenol is effective in the
management of acute pulmonary hypertension and produces similar decreases in pulmonary artery
pressure comparable to NO.21, 23-35 When administered by inhalation, epoprostenol has few systemic
effects. This is likely due to the low concentrations of epoprostenol found in the blood after inhalation and
the short half-life of 3-6 minutes.22
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

7
Recommendations
Adult Patients
1. Acute Respiratory Distress Syndrome
1.1. Maximize other therapies to improve oxygenation (i.e., FIO2, PEEP, hemodynamics, recruitment)
before initiating inhaled epoprostenol therapy. (Class I, Level C)
1.2. Inhaled epoprostenol therapy can be effective for patients with refractory hypoxemia associated
with ARDS. Inhaled epoprostenol therapy should be reserved for patients with the inability to
maintain adequate oxygenation despite appropriate ventilator management except in special
situations.19, 26-28, 36, 37 (Class IIa, Level C)
1.2.1. Initiate at a dose of 0.05 mcg/kg/min via continuous nebulization.19, 27 Doses higher than
0.05 mcg/kg/min have not been studied in ARDS. (Class IIb, Level C)
1.2.2. The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, wean off the inhaled epoprostenol.21, 38 (Class IIb, Level C)
1.2.3. The dose of epoprostenol should be decreased by 0.01 mcg/kg/min every 2 hours as
tolerated by the patient when weaning off therapy. (Class IIb, Level C)
2. Pulmonary Hypertension, Right Heart Failure Following Pulmonary Embolism, Severe Right
Heart Failure
2.1. Maximize other therapies to improve oxygenation (i.e., FIO2, PEEP, and hemodynamics) before
initiating inhaled epoprostenol therapy.21, 23 (Class I, Level C)
2.2. Inhaled epoprostenol therapy may be considered for patients with refractory hypoxemia and
mean pulmonary artery pressure >30 mmHg, PaO2/FiO2 <150 mmHg, or cardiac index less than
2.2 L/min/m2. (Class IIb, Level C)
2.2.1. Initiate at a dose of 0.01 mcg/kg/min.23 (Class IIb, Level C)
2.2.2. The dose of epoprostenol may be titrated up by 0.01 mcg/kg/min every two hours to a
maximum of 0.05 mcg/kg/min.23 (Class IIb, Level C)
2.3. The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable.21, 39 (Class IIb, Level C)
2.3.1. Consider decreasing the dose of epoprostenol by 0.01 mcg/kg/min every 2 hours as
tolerated by the patient until weaned off. (Class IIb, Level C)
3. Post Cardiac Surgery Patients
3.1. Maximize other therapies to improve oxygenation (i.e., FIO2, PEEP, and hemodynamics) before
initiating inhaled epoprostenol therapy.21 (Class I, Level C)
3.2. Administer inhaled epoprostenol to intubated cardiac surgery patients or patients on continuous
BiPAP with refractory hypoxemia.21, 30 For patients on BiPAP weigh the benefit of epoprostenol
therapy with the risk of rebound pulmonary hypertension if therapy is accidentally interrupted by
removal of the BiPAP mask. (Class IIb, Level C)
3.3. It is reasonable to initiate dosing at 0.03 mcg/kg/min.21 Doses higher than 0.03 mcg/kg/min have
not been studied in this population. (Class IIb Level C)
3.4. Inhaled epoprostenol can be useful to decrease mean and systolic pulmonary artery pressures.40
(Level IIa, Class B)
3.5. The dose of epoprostenol may be decreased by 0.01 mcg/kg/min every 2 hours as tolerated by
the patient.21 (Class IIb, Level C)
3.6. The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable.21, 39 (Class IIb, Level C)
Pediatric Patients
4. Acute Respiratory Distress Syndrome
4.1. Maximize other therapies to improve oxygenation (i.e., F
i
O2, PEEP, hemodynamics, recruitment)
before initiating inhaled epoprostenol therapy.34 (Class I, Level B)
4.2. Inhaled epoprostenol therapy may be considered for patients with refractory hypoxemia
associated with ARDS. Inhaled epoprostenol therapy should be reserved for patient with a
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

8
PaO2/FiO2 ≤300 mmHg after conventional therapies have been maximized.30, 34, 41 (Class IIb,
Level B)
4.2.1. Consider initiating doses at 0.03 mcg/kg/min via continuous nebulization.34 (Class IIb, Level
B)
4.2.2. The dose of epoprostenol can be increased to 0.05 mcg/kg/min if the patient does not
respond to the initial dose.34 (Class IIb, Level B)
4.2.3. The dose of epoprostenol can be decreased by 0.01 mcg/kg/min every 2 hours as tolerated
by the patient.34 (Class IIb, Level C)
4.3. The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable. (Class IIb, Level C)
5. Primary and Secondary Pulmonary Hypertension
5.1. Maximize other therapies to improve oxygenation (i.e., F
i
O2, PEEP, hemodynamics) before
initiating inhaled epoprostenol therapy.41 (Class I, Level C)
5.2. Inhaled epoprostenol therapy can be considered for patients with refractory hypoxemia for
primary and secondary pulmonary hypertension in children.41 (Class IIb, Level C)
5.2.1. Consider initiating dose at 0.03 mcg/kg/min via continuous nebulization.34 (Class IIb, Level
B)
5.2.2. The dose of epoprostenol can be increased to 0.05 mcg/kg/min if the patient does not
respond to the initial dose.34, 35, 42 (Class IIb, Level B)
5.2.3. The dose of epoprostenol can be decreased by 0.01 mcg/kg/min every 2 hours as tolerated
by the patient. (Class IIb, Level C)
5.3. The duration of therapy is dependent upon the clinical response observed. If no response is
noted in 4 hours, weaning off inhaled epoprostenol is reasonable. (Class IIb, Level C)
Neonate Patients
6. Inhaled epoprostenol may improve oxygenation in hypoxemia neonates when all other therapies to
improve oxygenation have failed.41, 43-47 (Class I, Level B)
6.1. Initial doses of 0.03 mcg/kg/min are recommended and can be titrated up to 0.05 mcg/kg/min if
necessary. (Class I, Level C)
6.2. It is reasonable to discontinue therapy by decreasing the dose 0.01 mcg/kg/min every 2 hours
as tolerated. (Class IIa, Level C)
General Recommendations for Treatment
7. Do not administer epoprostenol to patients with:
7.1. Allergy or sensitivity to epoprostenol (Class III, Level C)
7.2. Cardiac failure secondary to left ventricular dysfunction (Class III, Level C)
8. Avoid use or use cautiously in patients with active and significant bleeding (Class IIb, Level C)
9. Epoprostenol is a pregnancy class B drug.48, 49 Use inhaled epoprostenol with caution in pregnant
women. (Class I, Level C)
In animal studies epoprostenol has not been shown to cause harm to a fetus. There are no human
trials evaluating the safety of inhaled epoprostenol in pregnancy. There are case reports of the use of
intravenous epoprostenol in pregnant patients with no harm to the fetus.50, 51 Epoprostenol is not
considered a hazardous medication; pregnant care givers may handle and administer the medication.
10. Wean patients off epoprostenol; abrupt withdrawal can result in rebound pulmonary hypertension.
(Class IIa, Level B)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

9
Monitoring Parameters
11. Monitor vital signs including blood pressure, heart rate, and oxygen saturation every 15 minutes for
one hour during the first hour of treatment and after each dose change, then every hour thereafter.
(Class I, Level C)
11.1. Hemodynamic monitoring may include the following based on the patients condition and
comorbidities: central venous pressure (CVP), echocardiography, ultrasound, cardiac index
(CI), peripheral vascular resistance, total pulmonary resistance, mean pulmonary artery
pressure, and stroke volume but is not required. (Class I, Level C)
12. Toxicity
12.1. Monitor for symptoms of epoprostenol toxicity: jaw pain, headache, flushing, nausea, vomiting,
diarrhea, abdominal pain, signs of bleeding, bronchoconstriction or hypotension.23 (Class I,
Level C)
12.2. Monitor for symptoms of bleeding. (Class I, Level C) Inhibition of platelet aggregation is
demonstrated in vitro for inhaled epoprostenol, but not in vivo52
Companion/Collateral documents (as applies to CPG content)
Epoprostenol Intravenous – Adult- Inpatient Clinical Practice Guideline
UW Health Respiratory Manual Policy 3.51 Inhaled Epoprostenol
UW Health Implementation
Potential Benefits:
Describes the anticipated benefits associated with implementing the Clinical Practice Guideline’s
recommendations, as stated in the CPG text, to target populations or intended users. Where applicable,
the field includes information on the major subgroup(s) of patients within the target population most likely
to benefit from the Clinical Practice Guideline recommendations, as identified by the developer.
Potential Harms:
Describes the anticipated harms, potential risks or adverse consequences associated with the CPGs
recommendations, as stated in the guideline text, to target populations or intended users. Where
identified by the original Clinical Practice Guideline document, the major subgroup(s) of patients with the
target population most likely to suffer harm/adverse consequences associated with the guideline
recommendations will also be described.
Qualifying Statements
Only small clinical trials and case reports support the use of inhaled epoprostenol for adult, pediatric, and
neonate patients. Further large clinical trials may changes the recommendations included in this
document.
Implementation Plan/Tools
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
2. Release of the guideline will be advertised in the Clinical Knowledge Management Corner within the
Best Practice newsletter.
3. Links to this guideline will be updated and/or added in appropriate Health Link or equivalent tools,
including: epoprostenol inhaled medication order records
3. Order set – IP- Inhaled Epoprostenol – Procedure [2234] facilitates ordering, monitoring and weaning
of inhaled epoprostenol for adult, pediatric, and neonatal patients.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

10
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.
References
1. Jacobs AK, Kushner FG, Ettinger SM, et al. ACCF/AHA clinical practice guideline methodology summit
report: a report of the American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines. Journal of the American College of Cardiology 2013;61:213-265.
2. Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S, Weinhouse G. Inhaled epoprostenol vs inhaled
nitric oxide for refractory hypoxemia in critically ill patients. Journal of critical care 2013;28:844-848.
3. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial
hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. Vol 131. United
States2007:1917-1928.
4. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol.
Vol 43. United States2004:5S-12S.
5. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition.
JAMA 2012;307:2526-2533.
6. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome.
The New England journal of medicine 2013;368:2159-2168.
7. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress
syndrome. The New England journal of medicine 2010;363:1107-1116.
8. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. The New England
journal of medicine 2000;342:1301-1308.
9. Kemming G, Habler O, Kleen M, Kisch-Wedel H, Welte M, Zwissler B. Searching the ideal inhaled
vasodilator: from nitric oxide to prostacyclin. Eur Surg Res 2002;34:196-202.
10. Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V, Velissaris D. Acute respiratory distress syndrome:
pathophysiology and therapeutic options. J Clin Med Res 2012;4:7-16.
11. Michael JR, Barton RG, Saffle JR, et al. Inhaled nitric oxide versus conventional therapy: effect on
oxygenation in ARDS. Am J Respir Crit Care Med 1998;157:1372-1380.
12. Troncy E, Collet JP, Shapiro S, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot
randomized controlled study. Am J Respir Crit Care Med 1998;157:1483-1488.
13. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute
respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study
Group. Crit Care Med 1998;26:15-23.
14. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results
of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med.
Vol 25. United States1999:911-919.
15. Gerlach H, Keh D, Semmerow A, et al. Dose-response characteristics during long-term inhalation of nitric
oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled
study. Am J Respir Crit Care Med. Vol 167. United States2003:1008-1015.
16. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung
injury: a randomized controlled trial. JAMA. Vol 291. United States2004:1603-1609.
17. Afshari A, Brok J, Moller AM, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome
(ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010:CD002787.
18. Angus DC, Clermont G, Linde-Zwirble WT, et al. Healthcare costs and long-term outcomes after acute
respiratory distress syndrome: A phase III trial of inhaled nitric oxide. Crit Care Med 2006;34:2883-2890.
19. Van Heerden PV, Blythe D, Webb SA. Inhaled aerosolized prostacyclin and nitric oxide as selective
pulmonary vasodilators in ARDS--a pilot study. Anaesth Intensive Care 1996;24:564-568.
20. Brown AT, Gillespie JV, Miquel-Verges F, et al. Inhaled epoprostenol therapy for pulmonary hypertension:
Improves oxygenation. Pulm Circ 2012;2:61-66.
21. De Wet CJ, Affleck DG, Jacobsohn E, et al. Inhaled prostacyclin is safe, effective, and affordable in patients
with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery.
J Thorac Cardiovasc Surg. Vol 127. United States2004:1058-1067.
22. Lowson SM. Inhaled alternatives to nitric oxide. Crit Care Med 2005;33:S188-195.
23. Mikhail G, Gibbs J, Richardson M, et al. An evaluation of nebulized prostacyclin in patients with primary and
secondary. Eur Heart J 1997;18:1499-1504.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

11
24. Webb SA, Stott S, van Heerden PV. The use of inhaled aerosolized prostacyclin (IAP) in the treatment of
pulmonary. Intensive Care Med 1996;22:353-355.
25. Schroeder RA, Rafii AA, Plotkin JS, Johnson LB, Rustgi VK, Kuo PC. Use of aerosolized inhaled
epoprostenol in the treatment of portopulmonary. Transplantation 2000;70:548-550.
26. Walmrath D, Schneider T, Pilch J, Grimminger F, Seeger W. Aerosolised prostacyclin in adult respiratory
distress syndrome. Lancet 1993;342:961-962.
27. van Heerden PV, Barden A, Michalopoulos N, Bulsara MK, Roberts BL. Dose-response to inhaled
aerosolized prostacyclin for hypoxemia due to ARDS. Chest 2000;117:819-827.
28. Zwissler B, Kemming G, Habler O, et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult
respiratory. Am J Respir Crit Care Med 1996;154:1671-1677.
29. Della Rocca G, Coccia C, Costa MG, et al. Inhaled areosolized prostacyclin and pulmonary hypertension
during anesthesia for. Transplant Proc 2001;33:1634-1636.
30. Fattouch K, Sbraga F, Sampognaro R, et al. Treatment of pulmonary hypertension in patients undergoing
cardiac surgery with. J Cardiovasc Med (Hagerstown) 2006;7:119-123.
31. Fiser SM, Cope JT, Kron IL, et al. Aerosolized prostacyclin (epoprostenol) as an alternative to inhaled nitric
oxide. J Thorac Cardiovasc Surg 2001;121:981-982.
32. Lowson SM, Doctor A, Walsh BK, Doorley PA. Inhaled prostacyclin for the treatment of pulmonary
hypertension after cardiac. Crit Care Med 2002;30:2762-2764.
33. Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of
inhaled nitric oxide and aerosolized prostacyclin in acute. Am J Respir Crit Care Med 1996;153:991-996.
34. Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos AP. Randomized controlled trial of aerosolized
prostacyclin therapy in children with. Crit Care Med 2004;32:1055-1060.
35. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with
persistent pulmonary hypertension. J Pediatr 2002;141:830-832.
36. Tabrizi MB, Schinco MA, Tepas JJ, 3rd, Hwang J, Spiwak E, Kerwin AJ. Inhaled epoprostenol improves
oxygenation in severe hypoxemia. J Trauma Acute Care Surg 2012;73:503-506.
37. Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress
syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas
exchange response. Crit Care Med 2001;29:57-62.
38. McMillen JC, Burke CF, Dhingra A, Dudney TM, Faircloth BE. Use of inhaled epoprostenol in patients with
H1N1 influenza-associated acute. Ann Pharmacother 2011;45:e26.
39. Camamo JM, McCoy RH, Erstad BL. Retrospective evaluation of inhaled prostaglandins in patients with
acute respiratory distress syndrome. Pharmacotherapy 2005;25:184-190.
40. Groves DS, Blum FE, Huffmyer JL, et al. Effects of early inhaled epoprostenol therapy on pulmonary artery
pressure and blood loss during LVAD placement. Journal of cardiothoracic and vascular anesthesia
2014;28:652-660.
41. Kovach J, Ibsen L, Womack M, Steusse D, Law YM. Treatment of refractory pulmonary arterial hypertension
with inhaled epoprostenol in an infant with congenital heart disease. Congenit Heart Dis 2007;2:194-198.
42. Carroll CL, Backer CL, Mavroudis C, Cook K, Goodman DM. Inhaled prostacyclin following surgical repair of
congenital heart disease--a. J Card Surg 2005;20:436-439.
43. Gupta M, Guertin S, Martin S, Omar S. Inhaled prostacyclin and high-frequency oscillatory ventilation in a
premature infant with respiratory syncytial virus-associated respiratory failure. Pediatrics 2012;130:e442-
445.
44. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with
persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002;141:830-832.
45. Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed
2012;97:F223-228.
46. Zwissler B, Rank N, Jaenicke U, et al. Selective pulmonary vasodilation by inhaled prostacyclin in a newborn
with congenital heart disease and cardiopulmonary bypass. Anesthesiology 1995;82:1512-1516.
47. Bindl L, Fahnenstich H, Peukert U. Aerosolised prostacyclin for pulmonary hypertension in neonates. Arch
Dis Child Fetal Neonatal Ed 1994;71:F214-216.
48. Veletri [package insert]. San Francisco , CA: Actelion Pharmaceuticals US, Inc; 2012. .
49. Flolan (intavenous epoprostenol) [Package Insert]. GSK. March 2011.
50. Garabedian MJ, Hansen WF, Gianferrari EA, et al. Epoprostenol treatment for idiopathic pulmonary arterial
hypertension in pregnancy. J Perinatol. Vol 30. United States2010:628-631.
51. Goland S, Tsai F, Habib M, Janmohamed M, Goodwin TM, Elkayam U. Favorable outcome of pregnancy
with an elective use of epoprostenol and sildenafil in women with severe pulmonary hypertension.
Cardiology. Vol 115. Switzerland2010:205-208.
52. Haraldsson A, Kieler-Jensen N, Wadenvik H, Ricksten SE. Inhaled prostacyclin and platelet function after
cardiac surgery and. Intensive Care Med 2000;26:188-194.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

12
Appendix A
American Heart Association Grades of Recommendation1
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org