Inhaled nitric oxide (iNO) is a form of therapy utilized by respiratory care practitioners in the treatment of a variety of pulmonary conditions, such as acute respiratory distress syndrome, pulmonary thromboembolism, status post cardiopulmonary bypass, and lung transplantation.1 Prior to the initiation of iNO therapy, practitioners should be well versed in current recommendations for the administration of iNO. Incorrect administration of iNO therapy may potentially cause a wide array of side effects RCPs should be aware of and recognize.

The use of iNO is currently approved by the Food and Drug Administration (FDA) for the treatment of term and near-term neonates with hypoxic respiratory failure and documented pulmonary hypertension.2 Inhaled nitric oxide is largely used for persistent pulmonary hypertension of the newborn (PPHN) with a gestational age greater than 34 weeks and has been shown to decrease the need for extracorporeal membrane oxygenation (ECMO).3-6 The use of iNO for other neonatal medical conditions and for treatment in the adult patient population is considered “off label” usage.6,7

PPHN is a life-threatening condition characterized by persistent pulmonary hypertension and severe hypoxia resulting from a right-to-left shunting of blood through a patent ductus arteriosus and/or foramen ovale.8,9 It occurs in approximately 0.43 to 6.8 per 1,000 neonates and is the leading cause of death in neonatal intensive care units.8,9 A patent ductus arteriosus and foramen ovale is normally present during fetal circulation and will close following birth. In PPHN, these fetal shunts fail to constrict and close, which results in hypoxia and increased pulmonary vascular resistance.8 Pulmonary hypertension is confirmed by observing a right-to-left shunt on an echocardiogram and by measuring mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR).8,10 Pulmonary hypertension is described as having a MPAP ≥25 mm Hg, PCWP ≤15 mm Hg, and PVR ≥3 mm Hg/L/min.8

What Is Nitric Oxide?

Nitric oxide is a colorless, almost odorless gas that is naturally formed in endothelial cells and is known to contribute to homeostasis control, vasomotor tone, and neurotransmission.4,6,10 It is further produced in the environment by lightning and combustion of fossil fuels and is also found in tobacco smoke.4,10 Nitric oxide is present in the atmosphere at concentrations between 10 and 500 parts per billion but can exceed 1.5 parts per million (ppm) around heavy automobile traffic.10

Inhaled NO acts as a selective pulmonary vasodilator. It can rapidly diffuse across the alveolar capillary membrane of ventilated alveoli, producing vasodilation without a concomitant effect on systemic vascular resistance.4,6,11,12 Inhaled NO produces vascular smooth muscle relaxation due to a cascade of events. Following diffusion across the alveolar capillary membrane of ventilated alveoli, it activates soluble guanylate cyclase in the vascular smooth muscle.10 Soluble guanylate cyclase further catalyzes the production of cyclic guanosine monophosphate (cGMP), which increases the intracellular concentration of cGMP, producing vascular smooth muscle relaxation.10 As a result, pulmonary blood flow is increased to ventilated lung units, which improves ventilation-perfusion matching, decreases pulmonary vascular resistance, and reduces the right-to-left shunting of blood through a patent ductus arteriosus and/or foramen ovale.4,11 Upon administration of iNO therapy, the patient will ideally experience a decrease in mean pulmonary artery pressure and an improvement in oxygenation.

Inhaled NO must be continuously administered, because the vasodilation effect remains for only a few seconds in vivo.10 Inhaled NO is absorbed during inhalation and will be eliminated by the body as nitrate in the urine, nitrite in oral secretions, and nitrogen gas in the stomach. Some is eventually converted to urea and is excreted by the kidneys.10

Adverse Effects of iNO Therapy

In addition to the benefits of iNO therapy, there are harmful side effects that may occur as a result of its use. When oxygen and iNO mix together, the gases chemically react to form nitrogen dioxide (NO2), which is a toxic particle to the lungs.10 Nitrogen dioxide can form in the circuit of ventilators that have low bias flow or no bias flow because these situations increase the contact time between iNO and O2. Higher concentrations of NO2 formation are associated with administration of higher concentrations of iNO and O2.13 Nitrogen dioxide concentrations of greater than 10 ppm have been known to induce pulmonary edema, alveolar hemorrhage, changes in the surface tension properties of surfactant, and death.10 Due to this, NO2 concentrations should be maintained below 3 ppm by decreasing the iNO concentration if the NO2 concentration increases.13 Methemoglobinemia, an abnormal amount of methemoglobin, is another harmful side effect that may occur as a result of iNO therapy. Methemoglobin (MetHb) is formed by iNO binding to intracellular iron and heme-containing proteins within hemoglobin.4,10,13,14 This impairs the ability of the hemoglobin molecule to bind with oxygen.4 MetHb formation is directly related to the increase/decrease in dosage of iNO.3 Increased MetHb levels (>10%) may cause side effects such as cyanosis, headaches, muscle weakness, and tissue hypoxia.14

Indications and Administration of iNO Therapy

Inhaled nitric oxide therapy is indicated for the treatment of term or near-term infants (34 weeks gestation or within 14 days of birth) who have been diagnosed with hypoxic respiratory failure, confirmed pulmonary hypertension (either by visualization on echocardiography or by the presence of a pre-ductal/post-ductal Spo2 gradient), and an oxygen index (OI) greater than or equal to 25.13,14 Inhaled NO should be delivered using only an FDA-approved delivery system that is capable of monitoring the concentration of NO, NO2, and Fio2 from a sample port and alerting a clinician when concentrations are outside the normal range.4,15 The delivery systems for iNO therapy are composed of an iNO injector module that continuously provides a steady iNO concentration based on gas flow rate through the module.4 The administration of iNO can be given inline with mechanical ventilators, high-frequency oscillation ventilators (HFOV), anesthesia ventilators, nasal cannulas, and face masks.15 The delivery modality also must reduce the contact time of iNO with oxygen, thereby reducing the risk of NO2 formation.4

Prior research has shown an increase in therapeutic benefits of iNO therapy when used following lung recruitment maneuvers and lung recruitment ventilator strategies due to improved alveolar ventilation.13,16 HFOV have been shown to facilitate an improved response to iNO due to the alveolar recruitment associated with HFOV in patients with atelectasis and parenchymal lung disease.4,16

Dosage recommendations for iNO therapy range between an initial iNO dose of 20 ppm and the maximum dosage of 80 ppm.13 An increase in dosage of higher than the recommended 80 ppm has been shown to increase the risk of adverse effects, such as methemoglobinemia and increased NO2 production.4,13 A therapeutic response to the administration of iNO therapy will reveal an immediate increase in oxygenation and a reduced difference between pre- and post-ductal Spo2.13 If an improvement of oxygenation is not observed with the initial dose of 20 ppm, the practitioner may increase the dosage to 40 ppm in an attempt to increase oxygenation.13 A poor response to iNO could be a result of poorly ventilated alveoli, and it should be discontinued after 30 minutes if no response has been observed.7

Practitioners administering iNO therapy via mechanical ventilator will have additional considerations when iNO therapy is administered to patients requiring high Fio2 concentrations. The addition of iNO to a ventilator circuit will cause the Fio2 to decrease by 2.5% for every increase in 20 ppm of iNO due to dilution.4,13 For example, a maximum iNO concentration of 80 ppm will decrease the Fio2 concentration by as much as 10% of the actual ventilator set amount. Therefore, the practitioner may need to increase the set Fio2 in order to compensate for this effect. In addition, the practitioner should monitor the downstream Fio2 displayed on the iNO system versus the upstream Fio2 displayed on the ventilator. The administration of iNO may also cause the tidal volume a patient receives to increase by 10% when given volume-controlled mechanical ventilation breaths, due to the increased volume being added to the ventilator circuit from the iNO delivery system injector module.15 This effect is, however, minimized by the removal of volume from the sample line.15 This removal of volume may also cause a ventilator to auto-trigger if the RCP is using a low flow-sensitivity setting.15 The sensitivity may need to be adjusted to prevent auto-triggering.

The administration of iNO in patients with PPHN causes vasodilation of pulmonary blood vessels, which reduces PVR. As PVR decreases, pulmonary blood flow increases and reduces the left to right shunting of blood through the patent ductus arteriosus and/or foramen ovale. This significantly increases ventilation to perfusion matching and increases systemic oxygenation.

Weaning of iNO

Once the patient’s oxygenation and hemodynamic status has been improved, the practitioner should attempt to wean the iNO concentration every 12 to 24 hours.7 Evidence of improved oxygenation status includes an OI of <10 and Fio2 requirements ≤0.6.4,13 Weaning is performed by decreasing the iNO dosage in 50% increments every 30 minutes until a dosage of 5 ppm is reached.4,13 At that point, the iNO dosage can be decreased to 1 ppm. If the patient’s oxygen saturation declines >5% and is <90% with an increased oxygen demand, the iNO dosage should be increased to the previous dosage, and the weaning of the iNO dosage should be discontinued for a few hours before weaning can be initiated again.13 Once the dosage of 1 ppm has been reached, iNO can be discontinued, although this can cause the largest drop in Spo2 due to a rebound effect of pulmonary hypertension and hypoxia.4,13 This is evidenced by a sudden decrease in oxygenation and a greater difference between pre- and post-ductal Spo2.4,13 An increase in Fio2 of 0.20 prior to iNO discontinuation can prevent a rebound decrease in Pao2.4

Practitioner ExposureThere has been previous concern that practitioners providing care to patients receiving high concentrations of iNO were potentially at risk of becoming exposed to NO and NO2 in exhaled gases.15,17 Prior literature has shown that practitioners are not at risk of becoming exposed to these gases and that any detectable exposure is brief and infrequent.15,17 The Occupational Safety and Health Administration has further set the permissible exposure limit of iNO to 25 ppm over an 8-hour shift as a way to prevent methemoglobinemia and other adverse effects to health care practitioners.15,17 Analysis of the exhaled gas from patients receiving iNO is not necessary.15

Conclusion

Inhaled NO therapy is a selective pulmonary vasodilator that has been shown to be a safe and effective treatment for PPHN, while posing little risk to health care practitioners. Prior medical research has shown the use of iNO therapy can improve a patient’s oxygenation status while reducing pulmonary vascular resistance. Despite its benefits, however, iNO therapy can potentially lead to harmful side effects; and proper monitoring of NO, NO2, and Fio2 should be performed during iNO administration to reduce the possibility of these adverse effects. With the knowledge of proper use and benefits of iNO therapy, an RCP can drastically improve the outcome in a hypoxic newborn.

Nicholas R. Henry, MS, RRT-NPS, AE-C, is assistant professor for the respiratory care department at Texas State University-San Marcos and an organ recovery coordinator for the Texas Organ Sharing Alliance; Joshua Gonzales, MHA, RRT-NPS, is assistant professor, department of respiratory care; and Christopher J. Russian, MEd, RRT-NPS, RPSGT, , is associate professor in the department of respiratory care, Texas State University-San Marcos. For further information, contact [email protected].

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