nitric oxide gas

Nitric oxide gas is used for treating hypoxic respiratory failure in newborns caused by impaired lung function, which leads to low oxygen levels in the tissues (hypoxia).

Nitric oxide gas improves blood flow and oxygen levels in the pulmonary arteries by relaxing the smooth muscles around pulmonary blood vessels, dilating them and reducing pulmonary hypertension. Dilation of the pulmonary blood vessels redistributes the blood flow away from well ventilated lung areas to other tissues that require oxygenated blood.

Nitric oxide gas molecules bind to soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system, and activate the synthesis of a signaling molecule known as cyclic guanosine monophosphate (cGMP). Increase in cGMP concentration leads to relaxation of the pulmonary vascular smooth muscles.

Nitric oxide also combines with oxyhemoglobin and produces methemoglobin, a form of hemoglobin that does not transport oxygen to tissues, and nitrate which is excreted in the urine. Methemoglobin levels must be monitored and high blood methemoglobin levels (methemoglobinemia) must be treated appropriately.

Nitric oxide gas is administered through the ventilator using a calibrated nitric oxide delivery system and is approved by the FDA for the treatment of hypoxic respiratory failure in newborns. Nitric oxide gas is also being investigated for use in other conditions and has orphan designation for the following:

Pediatric:

• Prevention of chronic lung disease in premature newborns
• Cystic fibrosis

Adults:

• Acute respiratory distress syndrome (ARDS)
• Pulmonary arterial hypertension (PAH)
• Cystic fibrosis
• Sickle cell crises
• Diagnosis of sarcoidosis
• Idiopathic pulmonary fibrosis
• Nontuberculosis mycobacterial infections

• Do not use nitric oxide gas in newborns dependent on right-to-left shunting of blood.
• Nitrogen dioxide forms in mixtures of oxygen and nitric oxide, and can cause lung injury and airway inflammation. Monitor nitrogen dioxide levels and titrate nitric oxide dose appropriately.
• Methemoglobin levels increase with the dose of nitric oxide and it can take 8 hours or more before achieving steady-state methemoglobin levels. Monitor closely and adjust nitric oxide doses. If methemoglobin levels do not come down with decrease in dose or discontinuation of therapy, institute additional treatment as appropriate.
• Patients with left ventricular dysfunction may experience pulmonary edema when treated with nitric oxide, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia, and cardiac arrest. Discontinue nitric oxide and provide symptomatic care.
• Withdraw nitric oxide gradually, while constantly monitoring blood oxygen levels. Abrupt discontinuation of nitric oxide can cause rebound pulmonary hypertension with symptoms that include hypoxemia, systemic hypotension, bradycardia and decreased cardiac output. Reinstate nitric oxide therapy immediately if the patient develops rebound pulmonary hypertension.

Common side effects of nitric oxide gas include:

• Low blood pressure (hypotension)
• Withdrawal
• Complete or partial collapse of a lung’s lobe or an entire lung (atelectasis)
• Blood in urine (hematuria)
• High blood glucose levels (hyperglycemia)
• Whistling sound while breathing due to obstructed airway (stridor)
• Infection
• Cellulitis
• Sepsis

Less common side effects of nitric oxide gas include:

• Acute lung injury
• Fluid in the lungs (pulmonary edema)
• Pulmonary hemorrhage
• Pulmonary toxicity due to nitrogen dioxide formation
• Low oxygen levels in blood (hypoxemia)
• Shortness of breath (dyspnea)
• Methemoglobinemia
• Seizure
• Intracranial hemorrhage
• Gastrointestinal hemorrhage
• Chest discomfort
• Dizziness
• Dry throat
• Headache

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Inhalation Gas

• 100ppm
• 800ppm

Pediatric:

Hypoxic Respiratory Failure

• Indicated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension
• Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy
• Term and near-term neonates (longer than 34 weeks gestation): 20 ppm, inhaled for up to 14 days
• Decrease dose gradually at end of treatment, do not discontinue abruptly

• Nitric oxide gas overdose elevates methemoglobin levels which can reduce blood’s oxygen delivery capacity. Inhaled nitric oxide gas overdose is also associated with pulmonary toxicities from formation of nitrogen dioxide and can cause acute lung injury.
• Elevated nitric oxide gas levels higher than 3 ppm or methemoglobin levels higher than 7% may be treated by reducing nitric oxide gas dosage or discontinuing the therapy. If reduction or discontinuation of nitric oxide does not resolve methemoglobinemia, it may be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based on the clinical situation.

• Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.
• Nitric oxide gas has no listed severe, serious, moderate or mild interactions with other drugs.
• The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.
• It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Data on use of nitric oxide gas during pregnancy is limited.
• The risk of adverse outcomes is increased in pregnant patients with pulmonary arterial hypertension (PAH).
• Inhaled nitric oxide may be used to improve pulmonary blood flow and oxygenation in pregnant patients with PAH who also have cardiac decompensation.
• Inhaled nitric oxide has been used for the treatment of severe acute respiratory distress syndrome (ARDS) in pregnant or postpartum patients with or without COVID-19. Use of inhaled nitric oxide is not recommended for routine treatment of severe ARDS in patients with COVID-19, it may be considered as rescue therapy when other options have failed.
• Nitric oxide and its metabolites are naturally present in breast milk.