Inhaled nitric oxide has been utilized as a pulmonary vasodilator for over 20 years and research is ongoing to uncover the usefulness of iNO in several lung diseases and disorders. 

By Bill Pruitt, MBA, RRT, CPFT, FAARC


Inhaled nitric oxide or iNO is a potent, selective vasodilator that works in the pulmonary vasculature to treat pulmonary arterial hypertension and ventilation-perfusion mismatch found in certain cardiac and pulmonary diseases. The body produces nitric oxide in vascular endothelial cells, which then diffuses into the vascular smooth muscle. It causes the vasculature to dilate in both the systemic and pulmonary circulation.1 When iNO is used, its dilating effect occurs only in the pulmonary vasculature. This article will discuss iNO and the delivery options for using this therapy.

Endogenous Production and Effects of Nitric Oxide

Endogenous (occurring naturally in the body) nitric oxide from the endothelial cells in the blood vessels activates soluble guanylyl cyclase to produce cyclic GMP. Through a process involving a few other steps, the result is a decrease in intracellular calcium and relaxation of vascular smooth muscles in the arterioles. Nitric oxide (NO) also suppresses smooth muscle proliferation and platelet aggregation and has a mild bronchodilator effect.1-2 Exogenous iNO also actives the production of cyclic GMP described above and is effective in reducing pulmonary vascular resistance with doses as low as 1 part per million (ppm).1

Nitric oxide is quickly inactivated by binding to heme moieties found in soluble guanylyl cyclase, hemoglobin, myoglobin, and thiols. In addition, nitric oxide is quickly oxidized to nitric dioxide (NO2) and nitric trioxide (NO3). The half-life of nitric oxide is very short, from 0.1 to 5 seconds. However, the vasodilating effect from iNO through the cGMP pathway has a half-life of 15 to 30 seconds with doses of 5 to 80 ppm.1 With this fast inactivation and metabolism, iNO selectively causes vasodilation in the pulmonary arterial vessels but has little effect on the systemic circulation. These characteristics make iNO “an attractive candidate as a ‘pure’ pulmonary vasodilator.”1 

Inhaled Nitric Oxide Use in Patients

In 1867, nitric oxide was first mentioned for medical use in treating angina pectoris, but the vasodilator effect was not recognized until 1987.2 In 1999, the Food and Drug Administration (FDA) approved iNO to treat persistent pulmonary hypertension with hypoxic respiratory failure in term and near-term (>34 weeks) neonates. This condition is known as persistent pulmonary hypertension of the newborn (PPHN).3 iNO use in neonates has been where the major usage has occurred. An article published in 2015 estimated that over a half-million patients had been treated with iNO worldwide.4 

Much of the research for use in adults has been related to pulmonary arterial hypertension (PAH) in both short term and long term therapeutic approaches, but other possible uses are being considered.1 Patients with PAH may have several different mechanisms causing the elevation in pulmonary pressures.

Most research is occurring in the first of five groups (defined by the 6th World Symposium on Pulmonary Hypertension):

  • Group 1 includes such diagnosis as idiopathic PAH, drug-induced PAH, PAH associated with connective tissue disease, HIV infection, portal hypertension, or congenital heart disease. PPHN is also included in the first group
  • Group 2 includes diseases that elevate pulmonary arterial pressure due to left heart
  • Group 3 includes PAH associated with lung disease
  • Group 4 includes PAH due to thromboembolic diseases, and
  • Group 5 includes miscellaneous diseases.1

Off-label use of iNO are beginning to expand research and generate a great deal of interest in many possible applications including treating pulmonary hypertension related to ARDS and in those with congenital heart disease.5 Patients with severe hypoxemia due to COVID-19 have been treated with iNO to help relieve the hypoxemia by the selective vasodilating effect. Researchers are looking into high dose administration of iNO related to its antibacterial, antifungal, and antiviral activity.3,6-7

iNO is being investigated for possible prevention of hemolysis-induced vasoconstriction, decreasing incidence of ischemia/reperfusion injury, and prevention of renal failure related to cardiopulmonary bypass.3,8 Lastly, use of iNO administered by pulsed dose is undergoing research in patients with fibrotic interstitial lung disease.2 

Adverse Effects of iNO

iNO has been shown to be safe and effective and with its short active life, adverse effects may not become an issue. However, there is a higher risk of adverse effects if iNO treatment goes on for several days, or is administered to certain patients (who may or may not be known to be high risk). 

Upon initiation of therapy there may be a sudden decrease in systemic vascular resistance and decreased systemic blood pressure, an increased in heart rate, and/or development of pulmonary edema, and worsening hypoxemia. Should any of these occur, iNO administration should be stopped immediately and the patient evaluated for possible pulmonary veno-occlusive disease.1

Although rare, methemoglobin (MetHb) may develop, particularly when iNO is administered in higher doses (ie, >40 ppm), in patients who are predisposed to developing MetHb, or when administered for prolong periods. MetHb should be monitored during administration of iNO (usually by a multiple wavelength CO-oximeter).1 Treatment options includes stopping the cause (which may not be easily done in iNO therapy) and providing support such as mechanical ventilation and vasopressors (which may already be in place). Methylene Blue (MB) is the primary treatment for decreasing MetHb levels and will bring MetHb levels down fairly quickly (within an hour or so).9

Abruptly stopping iNO therapy can bring on a rapid increase in ventilation-perfusion mismatch and/or pulmonary hypertension (reflected in worsening hypoxemia and/or hemodynamic compromise). With this in mind, iNO therapy should be weaned over several days.1

Mentioned earlier, NO oxidizes to NO2, which is toxic to alveolar and vascular tissue. The formation of NO2 increases exponentially with the concentration of oxygen used. Due to this issue, levels of NO2 need to be monitored, especially when FiO2 is being delivered at higher concentrations. Many of the commercially available delivery systems offer this monitoring as part of the system but an external monitoring device may be required if the system does not include the NO2 monitoring capability.1 A limit of 3 ppm of NO2 in an 8-hour time weighted average and 5 ppm in a short-term exposure has been set by the American Conference of Governmental Industrial Hygienists. The National Institute for Occupational Safety and Health has taken a more conservative stand with the limit 1 ppm for short-term exposure.3

Administration of iNO

iNO is delivered by nasal cannula, face mask, or through the ventilator circuit for patients on mechanical ventilation. NO is mixed in with the delivered gas and the amount of nitric oxide is adjusted by bleeder valves.1 The major source for NO delivery has been by compressed gas cylinders but newer NO generators are being introduced that allow for the avoidance of the problems related to cylinders—namely the need for a reliable supply chain, cylinder storage requirements, and cost. NO can be produced by an electric generator that uses a high-voltage electrical discharge to ionize air and leads to the production of NO, NO2, and ozone (NO3). The toxic byproducts (NO2, NO3) are separated out using a scavenger system. NO can also be produced by the reduction of NO2 using ascorbic acid (a chemical NO generator).3 There are some seven cylinder-based and one chemical-based delivery systems available worldwide for commercial use (excluding research-only systems), according to a review published in 2021 of delivery systems for mechanically ventilated and non-intubated patients. There are other systems either under development or currently being used in research.3 According to a worldwide analysis of the NO market, there are at least some fifteen companies involved with production and/or administration of this gas.

One system of interest that is undergoing evaluation is the INOpulse (Bellerophon Therapeutics, Warren, NJ). This is a portable system that uses a 0.16 L mini-cylinder as the NO source. The device delivers a pulsed column of NO at the beginning of each breath through a special nasal cannula. With this system a constant dose of NO is given over time and provides three advantages; the nasal cannula delivery eliminates the need for a tight-fitting mask (more comfortable for the patient), by using a pulse dose less drug is used from the cylinder, and the pulse dose reduces the amount of NO being released into the environment. If the evaluations are successful, the portability, use of a small NO cylinder, patient comfort, and environmental protection will make this a system attractive for home use.3 

iNO Administration in Neonates

The majority of iNO use has been in neonates and there is a large number of published peer-reviewed research articles related to iNO in neonatal patients. Approximately 2% of neonates born in the US need mechanical ventilation each year, and the reason is hypoxic respiratory failure due to PPHN in approximately 35,000 term and near-term neonates.10 As stated earlier, iNO was approved by the FDA for use in neonates >34 weeks gestational age who have the diagnosis of persistent pulmonary hypertension of the newborn (PPHN). The indication given for application in neonates is to improve oxygenation and reduce the need for extracorporeal membrane oxygenation.11 To accomplish this the recommended dose is 20 ppm for up to 14 days or until the issue of oxygen desaturation is resolved (doses >20 ppm are not recommended when treating PPHN). 

From the package insert for INOMax (Mallinckrodt Pharmaceuticals, Bedminster, NJ) iNO “appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.” In addition, “PPHN occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, INOmax improves oxygenation (as indicated by significant increases in PaO2.”11 

Treatment using iNO for PPHN brings about a rapid response (within the first hour) in patients who respond to the therapy.10,12 Enhancing lung recruitment using high-frequency oscillatory ventilation (HFOV) prior to and during iNO therapy appears to be the best approach for significant improvement according to published studies.13-14 Once a patient has reached acceptable improvements in oxygenation, the iNO dose is reduced to 5 ppm, and eventually weaned completely. Moving to ECMO is often the next step if treatment with iNO has failed to achieve adequate oxygenation.10 

Conclusion

iNO has been utilized for over 20 years and research is ongoing to uncover the usefulness of this therapy in several lung diseases and disorders. iNO appears to be safe and often very effective in improving oxygenation and V/Q, and as newer means of NO production gain approval, iNO therapy may be moving into the home environment. However, iNO has some distinct adverse effects (particularly in formation of methemoglobin and NO2) and careful monitoring is needed to avoid doing harm. Respiratory therapists are key players in the administration and management of iNO and need to have a solid understanding of all aspects of this therapy to provide the best care and help achieve the best outcomes for their patients needing iNO.


RT

Bill Pruitt, MBA, RRT, CPFT, FAARC, is a writer, lecturer, and consultant. He has over 40 years of experience in respiratory care, and has over 20 years teaching at the University of South Alabama in Cardiorespiratory Care. Now retired from teaching, he continues to provide guest lectures and write. For more info, contact [email protected]



References

  1. From UpToDate: Inhaled Nitric Oxide in Adults: Biology and indications.
  2. Khor YH, Adegunsoye A. Inhaled Nitric Oxide for Fibrotic Interstitial Lung Disease: A Step Forward. Annals of the American Thoracic Society. 2022 Apr;19(4):536-8.
  3. Gianni S, Carroll RW, Kacmarek RM, Berra L. Inhaled nitric oxide delivery systems for mechanically ventilated and nonintubated patients: a review. Respir Care. 2021 Jun 1;66(6):1021-8. 
  4. Todd Tzanetos DR, Housley JJ, Barr FE, May WL, Landers CD. Implementation of an inhaled nitric oxide protocol decreases direct cost associated with its use. Respir Care 2015;60(5):644-650.
  5. Ranallo CD, et al. Effect of Nitric Oxide Delivery Device on Tidal Volume Accuracy During Mechanical Ventilation at Small Tidal Volumes. Respir Care. 2020 Nov 1;65(11):1641-7.
  6. Eedara BB, et al. Inhalation delivery for the treatment and prevention of COVID-19 infection. Pharmaceutics. 2021 Jul 14;13(7):1077.
  7. Gianni S, et al. High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air. Respiratory Care. 2022 Feb 1;67(2):201-8.
  8. Redaelli S, et al. Nitric oxide: clinical applications in critically ill patients. Nitric Oxide. 2022 Feb 2.
  9. Iolascon A, et al. Recommendations for diagnosis and treatment of methemoglobinemia. American Journal of Hematology. 2021 Dec;96(12):1666-78.
  10. Nelin LD, Potenziano JL. Inhaled nitric oxide for neonates with persistent pulmonary hypertension of the newborn in the CINRGI study: time to treatment response. BMC pediatrics. 2019 Dec;19(1):1-7.
  11. INOMAX. Package insert. Mallinckrodt Pharmaceuticals. Accessed 9/5/2022.
  12. Hwang SJ, Lee KH, Hwang JH, Choi CW, Shim JW, et al. Factors affecting the response to inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn infants. Yonsei medical journal. 2004 Feb 1;45(1):49-55.
  13. Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr. 1997;131(1 Pt 1):55–62.
  14. Dobyns EL, Anas NG, Fortenberry JD, Deshpande J, Cornfield DN, Tasker RC, et al. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. Crit Care Med. 2002;30:2425–9.