Inhaled pulmonary vasodilators have been a valuable adjunctive treatment for outpatient management of pulmonary arterial hypertension (PAH).¹ The potential for intrapulmonary selectivity (vasodilation of well-ventilated areas) and the possibility of avoiding percutaneous prostacyclin analog have made these medications attractive options for PAH therapy.² Inhaled nitric oxide and epoprostenol have been used for pulmonary vasodilation for vasoreactivity testing, post-cardiac surgery patients, patients with acute respiratory distress syndrome (ARDS), and those with acute cor pulmonale.^3,4 In the COVID-19 era, there are concerns about aerosol generation when using a nebulizer for inhaled pulmonary vasodilators, especially when patients get admitted to the hospital.

Procedures like airway suctioning, sputum induction, cardiopulmonary resuscitation, endotracheal intubation, bronchoscopy, and manual ventilation are associated with uncontrolled respiratory secretions and considered aerosol-generating. However, whether nebulization is an aerosol-generating procedure is less clear. In comparison to the procedures that lead to aerosolization of respiratory secretions, nebulizer causes aerosolization of medication that is being administered. That being noted, the act of inhalation of nebulized medication can provoke cough, which can generate infectious respiratory secretions. Most clinical guidelines identify nebulization as an aerosol-generating procedure that should be avoided in patients with active COVID-19 infection.^3,5

Here we discuss the use of inhaled pulmonary vasodilators in COVID-19-infected patients in the inpatient setting, including the risks, benefits, and alternatives.

Inhaled Treprostinil
Inhaled treprostinil, as combination therapy, has been shown to improve 6-minute walk test and quality of life in patients with PAH. It is a prostacyclin analog that is administered via the inhalation system Optineb-ir Model ON-100/7 (Metropolitan Medical, Inc.; Winchester, VA), which is an ultrasonic, pulsed-delivery device⁶:

• For Non-Intubated Patients: Alternatives include switching to oral treprostinil or continuing nebulization treatment when there are no health care workers in the room. At our institution, we utilize transition to an equivalent dose of oral treprostinil⁷ (54 mcg 9 breaths QID of inhaled treprostinil = 2 mg orally Q8H of oral treprostinil). For patients unable to take oral medication, we recommend a transition to inhaled nitric oxide (20-80 ppm) or intravenous treprostinil (54 mcg or 9 breaths QID of inhaled treprostinil = 10 ng/kg/min of intravenous treprostinil).^8,9
• For Intubated Patients: Options include switching to intravenous therapy, use of inhaled epoprostenol, use of inhaled nitric oxide at 20-80 ppm, or continuing use of inhaled treprostinil using vibrating mesh or jet nebulizers if available. When selecting initial dose for inhaled epoprostenol, choose 1 mg (1 mg/50 mL = 20,000 ng/mL). Use of inhaled treprostinil in intubated patients utilizing a vibrating mesh nebulizer¹⁰ (AeronebSolo [Aerogen; Galway, Ireland]) and jet nebulizer¹¹ (AeroTech II jet nebulize [Biodex Medical Systems; Shirley, NY]) has been demonstrated.

Inhaled Iloprost
Although a safe and effective pulmonary vasodilator, inhaled Iloprost is less frequently used nowadays due to the need for frequent nebulization treatment (9 times per day) due to short duration of action (30-60 min). Iloprost has a higher potency compared to epoprostenol (about 5:1)¹²:

• For Non-Intubated Patients: Options include continuing inhaled iloprost utilizing the same precautions as listed in the section on inhaled treprostinil or switching to oral treprostinil (5 mcg, 6-9 times a day of inhaled iloprost = 1 mg orally Q8H of oral treprostinil).
• For Intubated Patients: Use of inhaled iloprost has been described using a vibrating mesh nebulizer.¹³ Alternatively, inhaled epoprostenol or inhaled nitric oxide (20-80 ppm) can be used.

Inhaled Epoprostenol
Inhaled epoprostenol is not used in the outpatient setting. However, its use in patients with COVID-19 may be required for management of ARDS^3,14 or to transition from other therapies for ease of use and hospital familiarity:

• For Non-Intubated Patients: Inhaled epoprostenol for patients using heated high-flow nasal cannula or venti mask should be avoided to avoid potential aerosol generation. Alternatives such as oral treprostinil or intravenous epoprostenol or treprostinil can be used.
• For Intubated Patients: Inhaled epoprostenol can be used as an alternative to inhaled treprostinil as described above or for hypoxia due to ARDS. For the latter indication, epoprostenol can be started at 0.01-0.05 mcg/kg/min and increased in a stepwise fashion. Because inhaled epoprostenol is an alkaline solution, the ventilator filter needs to be changed every 2 hours due to glycine buffer diluent. This is critical because epoprostenol has a short half-life, and interruption due to ventilator clogging can cause rebound pulmonary hypertension.^15,16

Inhaled Nitric Oxide
Inhaled nitric oxide can be used in non-intubated patients as a replacement for other PAH medication as described above or as treatment of hypoxemia in patients with ARDS^3,17:

• For Non-Intubated Patients: Because it can be delivered via face mask or nasal prongs, inhaled nitric oxide can be safely used at a dose of 20-80 ppm as a replacement for inhaled treprostinil, which needs nebulization in patients with COVID-19.
• For Intubated Patients: Inhaled nitric oxide can be used as an alternative to other pulmonary vasodilators like treprostinil as described above or it can be used for hypoxia as a management protocol for ARDS in patients with COVID-19. Because it is known to have antiviral properties, use of inhaled nitric oxide is being investigated as a possible therapeutic option for patients with COVID-19.

Although nitric oxide is quite safe, adverse effects include hypotension, methemoglobinemia, and pulmonary hypertension.¹⁸ Inhaled nitric oxide can be administered only by trained personnel using a calibrated delivery system with validated ventilators. In addition to adverse effects, inhaled nitric oxide exposure in health care staff can result in chest discomfort, dizziness, dyspnea, and headache.

References

1. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019;53:1801889.
2. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9.
3. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med 2020;46:854-87.
4. Konstam MA, Kiernan MS, Bernstein D, et al. Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association. Circulation 2018;137:e578-e622.
5. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One 2012;7:e35797.
6. Prescribing Information for Tyvaso (treprostinil) (Tyvaso website). 2017. Available at https://www.tyvaso.com/hcp/pdf/Tyvaso-PI.pdf. Accessed April 28, 2020.
7. Prescribing Information for ORENITRAM (treprostinil) (ORENITRAM website). 2017. Available at https://www.orenitram.com/pdf/Orenitram_Full_Prescribing_Information.pdf. Accessed April 28, 2020.
8. Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet 2016;55:1495-505.
9. Smith ZR, Kelly B, Awdish RL, Hegab S. Transitioning Parenteral or Inhaled Treprostinil to Oral Treprostinil Diolamine: Case Series and Review of the Literature. J Pharm Pract 2019;32:599-604.
10. Patel RB, Smaldone GC, Cuccia AD, Strachan P. In vitro delivery of aerosolized treprostinil via modern mechanical ventilation. J Aerosol Med Pulm Drug Deliv 2013;26:200-7.
11. Parker DK, Shen S, Zheng J, et al. Inhaled Treprostinil Drug Delivery During Mechanical Ventilation and Spontaneous Breathing Using Two Different Nebulizers. Pediatr Crit Care Med 2017;18:e253-e260.
12. Olschewski H. Inhaled Iloprost for Treatment of Pulmonary Arterial Hypertension. Adv Pulm Hypertens 2002;1:16-21.
13. DiBlasi RM, Crotwell DN, Shen S, Zheng J, Fink JB, Yung D. Iloprost drug delivery during infant conventional and high-frequency oscillatory ventilation. Pulm Circ 2016;6:63-9.
14. Searcy RJ, Morales JR, Ferreira JA, Johnson DW. The role of inhaled prostacyclin in treating acute respiratory distress syndrome. Ther Adv Respir Dis 2015;9:302-12.
15. 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 2004;127:1058-67.
16. Dzierba AL, Abel EE, Buckley MS, Lat I. A review of inhaled nitric oxide and aerosolized epoprostenol in acute lung injury or acute respiratory distress syndrome. Pharmacotherapy 2014;34:279-90.
17. Griffiths MJD, McAuley DF, Perkins GD, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res 2019;6:e000420.
18. Prescribing Information for INOMAX (nitric oxide) (INOMAX website). 2019. Available at https://www.inomax.com/wp-content/themes/inomax-website/dist/downloads/Inomax-PI.pdf. Accessed April 28, 2020.

Clinical Topics: COVID-19 Hub, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Lipid Metabolism, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, Epoprostenol, Iloprost, Respiratory Distress Syndrome, Vasodilator Agents, Nitric Oxide, Cough, Dizziness, Vasodilation, Bronchoscopy, Outpatients, Inpatients, Quality of Life, COVID-19

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