1 Epoprostenol Inhaled – Neonatal/Pediatric/Adult – 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 • 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) • 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) • 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 • 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) • 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 • 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) • 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) • 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) • 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 • 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 • Maximize other therapies to improve oxygenation (i.e., FiO2, PEEP, and hemodynamics) before initiating inhaled epoprostenol therapy. (Class I, Level C) Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 4 • 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) • 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) • 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) • 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: • Allergy or sensitivity to epoprostenol or glycine diluent (Class III, Level C) • 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) • 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 Healthcare Event Reporting Online (HERO) 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 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., FiO2, 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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., FiO2, 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 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 © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 12 Appendix A American Heart Association Grades of Recommendation1 Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 01/2022 Scope Methodology Definitions Introduction Recommendations UW Health Implementation References Appendix A