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Nitric Oxide

Class: Nitrates and Nitrites
VA Class: CN201
Chemical Name: nitric oxide
Molecular Formula: NO
CAS Number: 10102-43-9
Brands: INOmax

Introduction

Vasodilating agent.1

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 of age) neonates with hypoxic respiratory failure and clinical or ECG evidence of pulmonary hypertension.1 2 3 9

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Most effective in patients with severe persistent pulmonary hypertension who have minimal underlying parenchymal lung disease (idiopathic persistent pulmonary hypertension).3 4 5 6 7 9 12

Least effective in neonates with pulmonary hypoplasia (e.g., congenital diaphragmatic hernia).3 4 5 6 7 9 12

Has been used with good results (i.e., decreased the incidence of severe intraventricular hemorrhage and periventricular leukomalacia) in premature neonates (<34 weeks’ gestation) who were undergoing mechanical ventilation for respiratory distress syndrome.14 15

Nitric Oxide Dosage and Administration

General

  • Precise monitoring of nitrogen dioxide, nitric oxide, and oxygen (partial pressure of arterial oxygen [PaO2]) concentrations should be performed.1 2 3 9 12 Periodic measurement of methemoglobin also recommended.1 9 12 (See Methemoglobinemia under Cautions.)

Administration

Oral Inhalation

Administer in conjunction with mechanical ventilation and other supportive therapy to maximize oxygen delivery.1 2 3 In neonates with collapsed alveoli, administer additional therapies to improve lung expansion (e.g., pulmonary surfactant replacement, high-frequency oscillatory ventilation).1 4 5 7 9 12

Administer by inhalation using a nitric oxide delivery system that provides operator-determined and constant concentrations of nitric oxide throughout the respiratory cycle,a does not cause generation of excessive nitrogen dioxide, and is equipped with appropriate alarms.1 2 3 9 12

Delivery system should include a backup battery power supply to ensure continuous administration during a power failure.1 4

Dosage

Pediatric Patients

Neonatal Hypoxic Respiratory Failure
Oral Inhalation

Term or near-term neonates (>34 weeks of age): 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.1 12

Weaning and Discontinuance of Therapy
Oral Inhalation

Following improvement in oxygenation, smaller maintenance dosages (5–6 ppm) have been used.1 3 5 8 Therapy can be discontinued after successful maintenance of oxygenation at reduced dosage (5–6 ppm).3 5 8 9

Dosage also can be reduced stepwise in increments as little as 1 ppm.4 8 11

If clinical deterioration during the weaning period occurs, the nitric oxide dosage and/or inspired oxygen concentration fraction (FiO2) may be increased transiently.4 5 8 9 11 If clinical deterioration occurs after discontinuance of therapy, temporarily reinstitute therapy at the last dosage used.9

Prescribing Limits

Pediatric Patients

Neonatal Hypoxic Respiratory Failure
Oral Inhalation

Dosages >20 ppm generally do not provide additional benefit, are associated with an increased incidence of adverse effects, and generally are not recommended.1 2 4 5 9 12

Cautions for Nitric Oxide

Contraindications

  • Neonates dependent on extrapulmonary right-to-left shunting of blood (e.g., ductal-dependent congenital heart disease).1 2 3 4

Warnings/Precautions

General Precautions

Withdrawal of Therapy

Abrupt discontinuance of nitric oxide therapy can result in oxygen desaturation and a rebound increase in pulmonary artery pressure.1 4 12 Such manifestations also can occur in neonates who do not respond to inhaled nitric oxide therapy.1

To minimize adverse effects associated with withdrawal of therapy, neonates should be weaned from therapy by a gradual reduction in dosage1 2 4 8 and should be monitored for evidence of deterioration during and after weaning.4 8 11 (See Weaning and Discontinuation of Therapy under Dosage and Administration.)

Methemoglobinemia

Possible dose-related methemoglobinemia; occurs infrequently with usual recommended dosages,1 3 but was observed in 35% of neonates receiving a higher dosage (80 ppm).1 Methemoglobin concentrations generally return to baseline within several hours following dosage adjustment or discontinuance of therapy.1

Monitor methemoglobin blood concentrations periodically1 2 3 4 5 (e.g., within 4 hours of initiating therapy and daily thereafter).4 Methemoglobinemia that does not resolve after adjustment of nitric oxide dosage may be treated with IV vitamin C, IV methylene blue, or blood transfusion as clinically appropriate.1

Nitrogen Dioxide Accumulation

Possible formation of nitrogen dioxide: Recommended dosages resulted in formation of a small amount of nitrogen dioxide (<0.5 ppm); however, a larger dosage (80 ppm) resulted in a mean peak concentration of nitrogen dioxide of 2.6 ppm.1

Nitrogen dioxide may interact with oxyhemoglobin to form methemoglobin; exposure to elevated nitrogen dioxide concentrations also can cause acute lung injury.1 7 13

The Occupational Safety and Health Administration (OSHA) has set exposure limits for nitric oxide of 25 ppm and for nitrogen dioxide of 5 ppm.a

Specific Populations

Pregnancy

Category C.1 Not intended for use in adults.1

Lactation

Not known whether nitric oxide is distributed into milk; use not indicated in nursing women.1

Pediatric Use

Manufacturer does not recommend use in neonates with chronological age of >14 days or gestational age of <34 weeks.1 12 However, in a clinical study, beneficial effects have been shown in premature neonates (<34 weeks’ gestation) with respiratory distress syndrome who received inhaled nitric oxide therapy while undergoing mechanical ventilation.14 15

ARDS

Not indicated in patients with ARDS.1

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.1 12

Interactions for Nitric Oxide

No formal drug interaction studies performed.1

Specific Drugs

Drug

Interaction

Nitric oxide donor compounds (e.g., sodium nitroprusside, nitroglycerin)

Increased risk of methemoglobinemia1

Prilocaine

Increased risk of methemoglobinemiaa

Nitric Oxide Pharmacokinetics

Absorption

Bioavailability

Absorbed systemically following inhalation.a

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.a

Elimination

Metabolism

Rapidly metabolized to methemoglobin and nitrate following inhalation.1 6 8 9 10

Elimination Route

Excreted principally in urine as nitrate.a

Stability

Storage

Oral Inhalation

25°C (may be exposed to 15–30°C).a

Actions

  • When inhaled as a gas, diffuses from the alveoli into vascular smooth muscle and causes selective pulmonary vasodilation.1 8 9 12

  • Relaxes smooth muscle by increasing intracellular levels of cyclic guanosine 3′,5′-monophosphate (cGMP), which lowers intracellular calcium concentrations and results in vasodilation.1 8 9

  • 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.1 4

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.

Nitric Oxide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Gas

100 ppm

INOmax

INO Therapeutics

800 ppm

INOmax

INO Therapeutics

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. INO Therapeutics. INOmax (nitric oxide) gas for inhalation prescribing information. Clinton, NJ; 2001 Jun.

2. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997; 336:597-604. [IDIS 380409] [PubMed 9036320]

3. Clark RH, Kueser TJ, Walker MW et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000; 342:469-74. [IDIS 440388] [PubMed 10675427]

4. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. 2000; 136:717-26. [IDIS 448456] [PubMed 10839866]

5. Kinsella JP, Truog WE, Walsh WF 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; 131:55-62. [IDIS 391097] [PubMed 9255192]

6. Finer NN, Barrington KJ. Nitric oxide therapy for the newborn infant. Semin Perinatol. 2000; 24:54-65.

7. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs. 2001; 61:27-39. [PubMed 11217869]

8. Aly H, Sahni R, Wung JT. Weaning strategy with inhaled nitric oxide treatment of persistent pulmonary hypertension of the newborn. Arch Dis Child. 1997; 76:F118-22.

9. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997; 99:838-45. [IDIS 387109] [PubMed 9190553]

10. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the Neonatal Inhaled Nitric Oxide Study Group (NINOS). J Pediatr. 2000; 136:611-7. [IDIS 450258] [PubMed 10802492]

11. Davidson D, Barefield ES, Kattwinkel J et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics. 1999; 104:231-6. [IDIS 434076] [PubMed 10429000]

12. INO Therapeutics, Clinton, NJ: Personal communication.

13. Phillips ML, Hall TA, Sekar K et al. Assessment of medical personnel exposure to nitrogen oxides during inhaled nitric oxide treatment of neonatal and pediatric patients. Pediatrics. 1999; 104:1095-100. [IDIS 440431] [PubMed 10545553]

14. Schreiber MD, Gin-Mestan K, Marks JD et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003; 349:2099-107. [IDIS 508178] [PubMed 14645637]

15. Martin RJ. Nitric oxide for preemies—not so fast. N Engl J Med. 2003; 349:2157-9. [IDIS 508180] [PubMed 14645644]

a. INO Therapeutics. INOmax (nitric oxide) gas for inhalation prescribing information. Clinton, NJ; 2003 Apr.

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