Nitric Oxide (Monograph)

Brand names: Genosyl, INOmax
Drug class: Vasodilating Agents, Miscellaneous

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Vasodilating agent.

Uses for Nitric Oxide

Neonatal Hypoxic Respiratory Failure

Used in conjunction with ventilatory support and other appropriate therapy to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) in term or near-term (>34 weeks’ gestation) neonates with hypoxic respiratory failure and clinical or ECG evidence of pulmonary hypertension.

Most effective in patients with severe persistent pulmonary hypertension who have minimal underlying parenchymal lung disease (idiopathic persistent pulmonary hypertension).

Least effective in neonates with pulmonary hypoplasia (e.g., congenital diaphragmatic hernia).

Has been used with good results (i.e., decreased the incidence of severe intraventricular hemorrhage and periventricular leukomalacia) in premature neonates^{† [off-label]} (<34 weeks’ gestation) undergoing mechanical ventilation for respiratory distress syndrome.

Prevention of Bronchopulmonary Dysplasia

Not recommended for prevention of bronchopulmonary dysplasia^{† [off-label]} in preterm neonates ≤34 weeks’ gestational age requiring respiratory support; has not been shown to provide a meaningful difference with regard to mortality reduction and need for supplemental oxygen.

Acute Respiratory Distress Syndrome

Manufacturers state that inhaled nitric oxide is not indicated for use in acute respiratory distress syndrome (ARDS)^{† [off-label]}. However, has been used in adults and children with ARDS, generally as rescue therapy for refractory hypoxemia.

Treatment of ARDS is largely supportive; mechanical ventilation is the only intervention proven to reduce mortality. Inhaled nitric oxide may be used adjunctively to improve oxygenation; localized effects in the lung may improve ventilation-perfusion mismatch.

May temporarily improve oxygenation, but no effect on mortality and possible harm (e.g., renal impairment) demonstrated. Routine use of inhaled nitric oxide not recommended for treatment of ARDS; however, may be considered in selected patients with severe hypoxemia not responsive to conventional ventilation strategies, documented pulmonary hypertension, or severe right ventricular dysfunction.

Risk of renal toxicity appears to be increased with higher concentrations and/or prolonged use; therefore, use minimum effective concentration necessary to improve the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) and minimize duration of exposure.

Related/similar drugs

INOmax, Ulspira, caffeine / sodium benzoate

Nitric Oxide Dosage and Administration

General

• Use only under supervision of a clinician experienced in the use, administration, and hazards of gas mixtures.

• Monitor inspired nitrogen dioxide and PaO₂ concentrations during administration. Periodic measurement of methemoglobin also recommended. (See Methemoglobinemia and also see Elevated Nitrogen Dioxide under Cautions.)

Administration

Oral Inhalation

Administer in conjunction with mechanical ventilation and other supportive therapy to maximize oxygen delivery. In neonates with collapsed alveoli, administer additional therapies to improve lung expansion (e.g., pulmonary surfactant replacement, high-frequency oscillatory ventilation).

Administer by inhalation using a calibrated FDA-cleared nitric oxide delivery system. The Genosyl preparation of nitric oxide must be used with the Genosyl delivery system, which is designed to deliver a controlled level of nitric oxide mixed with air (breathing air or oxygen-enriched breathing air).

Delivery systems should include a backup battery power supply to ensure continuous administration during a power failure.

Dosage

Pediatric Patients

Neonatal Hypoxic Respiratory Failure

Oral Inhalation

Term or near-term neonates (>34 weeks’ gestation): 20 ppm given continuously for up to 14 days or until the underlying oxygen desaturation has resolved and the patient is ready to be weaned from therapy. (See Prescribing Limits under Dosage and Administration.)

Following improvement in oxygenation, smaller maintenance dosages (5–6 ppm) have been used. In some studies, therapy was discontinued after successful maintenance of oxygenation at reduced dosage (5–6 ppm). Avoid abrupt discontinuance of therapy; manufacturers state to titrate dosage downward in several steps when withdrawing therapy, pausing several hours at each step to monitor for hypoxemia. In some studies, dosage was reduced stepwise in increments as little as 1 ppm.

If clinical deterioration during the weaning period occurs, may transiently increase nitric oxide dosage and/or FiO₂. If clinical deterioration occurs after discontinuance of therapy, temporarily reinstitute therapy at the last dosage used.

Acute Respiratory Distress Syndrome† [off-label]

Oral Inhalation

Various dosages in the range of 5–10 ppm have been used in clinical studies; evidence suggests that concentrations <5 ppm are likely to improve oxygenation, while doses >10 ppm may worsen PaO₂/FiO₂ ratio. In clinical studies, inhaled nitric oxide was given in fixed doses or titrated to response. Duration of therapy has ranged from <24 hours to 4 weeks (median of 7 days).

Adults

Acute Respiratory Distress Syndrome† [off-label]

Oral Inhalation

Various dosages in the range of 5–10 ppm have been used in clinical studies; evidence suggests that concentrations <5 ppm are likely to improve oxygenation, while doses >10 ppm may worsen PaO₂/FiO₂ ratio. In clinical studies, inhaled nitric oxide was given in fixed doses or titrated to response. Duration of therapy has ranged from <24 hours to 4 weeks (median of 7 days).

Avoid abrupt discontinuance of therapy; slowly titrate dosage downward when withdrawing therapy. (See Discontinuance of Therapy under Cautions.)

Prescribing Limits

Pediatric Patients

Neonatal Hypoxic Respiratory Failure

Oral Inhalation

Dosages >20 ppm not recommended; such dosages provide no additional benefit and are associated with increased incidence of adverse effects.

Cautions for Nitric Oxide

Contraindications

• Neonates dependent on extrapulmonary right-to-left shunting of blood (e.g., ductal-dependent congenital heart disease).

Warnings/Precautions

General Precautions

Discontinuance of Therapy

Abrupt discontinuance of nitric oxide therapy can result in oxygen desaturation and a rebound increase in pulmonary artery pressure.

To minimize this risk, avoid abrupt discontinuance; gradually reduce dosage when withdrawing therapy. Monitor patients for evidence of deterioration during and after weaning. (See Dosage under Dosage and Administration.)

Methemoglobinemia

Possible dose-related methemoglobinemia due to nitric oxide combining with hemoglobin; reported to occur with dosages ≥40 ppm. May take ≥8 hours for steady-state methemoglobin concentrations to be attained. Generally resolves within several hours following dosage reduction or drug discontinuance.

Monitor methemoglobin blood concentrations 4–8 hours after initiating therapy and periodically during treatment. If methemoglobinemia does not resolve after adjustment of nitric oxide dosage or discontinuance of therapy, may consider treatment with IV ascorbic acid, IV methylene blue, or blood transfusion as clinically appropriate.

Elevated Nitrogen Dioxide

Possible formation of nitrogen dioxide, which can cause airway inflammation and damage lung tissue.

Monitor inspired nitrogen dioxide concentrations. If there is an unexpected change in nitrogen dioxide concentration or if the concentration reaches 3 ppm (or 0.5 ppm if using the Genosyl delivery system) when measured in the breathing circuit, assess and recalibrate the delivery system; adjust dosage of inhaled nitric oxide and/or FiO₂ as appropriate.

The Occupational Safety and Health Administration (OSHA) has set exposure limits for nitrogen dioxide of 5 ppm.

Heart Failure

In patients with preexisting left ventricular dysfunction, inhaled nitric oxide may increase pulmonary capillary wedge pressure resulting in pulmonary edema. If such effects occur, discontinue drug and provide symptomatic treatment.

Specific Populations

Pediatric Use

Manufacturers state efficacy and safety established in term or near-term neonates with hypoxic respiratory failure and evidence of pulmonary hypertension; no information regarding efficacy in other pediatric age groups. However, beneficial effects have been observed in premature neonates (<34 weeks’ gestation) with respiratory distress syndrome undergoing mechanical ventilation. There is also evidence demonstrating potential use in children with ARDS^†.

Efficacy not established for prevention of bronchopulmonary dysplasia in preterm neonates ≤34 weeks’ gestational age.

Common Adverse Effects

Hypotension, withdrawal manifestations (e.g., increased pulmonary artery pressure, decreased PaO₂), increase in or return to right-to-left shunting of blood, atelectasis, hematuria, hyperglycemia, sepsis, infection, stridor, cellulitis.

Drug Interactions

Specific Drugs

Nitric Oxide Pharmacokinetics

Absorption

Bioavailability

Absorbed systemically following inhalation.

Distribution

Extent

Rapidly distributes into the pulmonary system; combines with hemoglobin in the pulmonary capillary bed to produce methemoglobin and nitrate which distribute into the systemic circulation.

Elimination

Metabolism

Rapidly metabolized to methemoglobin and nitrate following inhalation.

Elimination Route

Excreted principally in urine as nitrate.

Stability

Storage

Oral Inhalation

20–25°C (may be exposed to 15–30°C).

Follow all regulations concerning handling of pressure vessels.

Actions

• When inhaled as a gas, diffuses from the alveoli into vascular smooth muscle and causes selective pulmonary vasodilation.

• Relaxes smooth muscle by increasing intracellular levels of cyclic guanosine 3′,5′-monophosphate (cGMP), which lowers intracellular calcium concentrations and results in vasodilation.

• Appears to increase PaO₂ by dilating pulmonary vessels in better ventilated areas of the lung, thereby redistributing pulmonary blood flow away from regions with poor gas exchange (as indicated by ventilation/perfusion ratios) toward regions with better gas exchange.

Advice to Patients

• Importance of informing caregiver of important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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