Usage
- Inhaled nitric oxide (iNO) is prescribed for term and near-term neonates with hypoxic respiratory failure associated with pulmonary hypertension. It is used in conjunction with ventilatory support and other appropriate agents to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO). It is also used in adults with Acute Respiratory Distress Syndrome (ARDS) associated with COVID-19, as it also reduces viral load.
- Pharmacological Classification: Pulmonary vasodilator, inhaled gas, antimicrobial
- Mechanism of Action: Nitric oxide relaxes vascular smooth muscle in the pulmonary vasculature, leading to selective vasodilation. It has minimal effect on systemic circulation due to its rapid inactivation by hemoglobin in the blood. At higher concentrations, nitric oxide demonstrates antimicrobial properties.
Alternate Names
- NO
- iNO (inhaled nitric oxide)
- Brand Names: INOmax, Noxivent, Genosyl
How It Works
- Pharmacodynamics: Inhaled nitric oxide selectively dilates pulmonary arterioles, reducing pulmonary vascular resistance and improving blood flow to ventilated lung regions. This results in enhanced oxygenation and decreased pulmonary artery pressure.
- Pharmacokinetics: Inhaled nitric oxide is absorbed through the lungs. It rapidly binds to hemoglobin in the blood, forming methemoglobin and nitrate. Nitrate is primarily eliminated through renal excretion. Methemoglobin spontaneously reduces to hemoglobin. Exogenously administered nitric oxide has a half-life of only a few seconds and thus cannot reach the breastmilk.
- Mode of Action: Nitric oxide activates guanylate cyclase within pulmonary vascular smooth muscle cells. This activation increases cyclic guanosine monophosphate (cGMP) levels, which leads to smooth muscle relaxation and vasodilation.
- Receptor Binding/Enzyme Inhibition: Activates guanylate cyclase.
- Elimination Pathways: Rapidly converted to methemoglobin and nitrate; nitrate is renally excreted.
Dosage
Standard Dosage
Adults:
High-dose (160-200 ppm) inhaled NO by mask for 30 to 60 minutes twice a day is used for severe COVID-19.
Children (Neonates):
- Term and Near-Term Neonates: Initial dose: 20 ppm via inhalation. Maintenance dose: titrate down to lowest effective dose (e.g. 5ppm), usually less than 4 days. Maximum dose 20 ppm. Do not give doses above 20ppm. Duration: Up to 14 days or until the underlying oxygen desaturation has resolved. Monitor NO2 levels. If NO2 exceeds 1 ppm, the nitric oxide dose should immediately be reduced.
Special Cases:
- Preterm Infants: Use with caution, starting dose may be 5-10 ppm. SMO decision only due to limited evidence.
Clinical Use Cases
- Intubation: Administered via mechanical ventilation following intubation.
- Mechanical Ventilation: Used in conjunction with mechanical ventilation.
- Intensive Care Unit (ICU) Use: Commonly used in neonatal and adult ICUs for respiratory failure.
- Emergency Situations: May be used in acute respiratory distress syndrome (ARDS).
Dosage Adjustments
- Based on oxygenation response and methemoglobin levels.
- Preterm Infants: Lower starting doses (5-10 ppm) are recommended due to limited evidence and increased risk of adverse effects.
Side Effects
Common Side Effects:
Generally, inhaled nitric oxide is well-tolerated, especially at recommended doses. Potential common side effects include methemoglobinemia (usually mild), hypotension.
Rare but Serious Side Effects:
Rare but serious side effects include worsening heart failure, pulmonary edema, and rebound pulmonary hypertension upon withdrawal.
Long-Term Effects:
Chronic complications from prolonged use are rare, but may include developmental issues in preterm infants with prolonged exposure.
Adverse Drug Reactions (ADR): Methemoglobinemia, hypotension, rebound pulmonary hypertension
Contraindications
- Neonates dependent on right-to-left shunting of blood.
- Congenital or acquired methemoglobin reductase deficiency.
Drug Interactions
- Nitroglycerin and Sodium Nitroprusside: May potentiate hypotension and risk of methemoglobinemia.
- Prilocaine: Increased risk of methemoglobinemia.
- PDE5 Inhibitors (e.g., sildenafil): Additive hypotensive effects.
- Consult a comprehensive drug interaction resource for a complete list of potential interactions.
Pregnancy and Breastfeeding
- Pregnancy: Nitric oxide is not indicated for use in adults, including pregnant women. In cases of COVID-19 treatment with inhaled NO, benefits must be weighed against potential risks. However, inhaled nitric oxide has been shown to reduce hospital stay and improve oxygenation in pregnant patients with COVID-19 pneumonia without observed adverse effects to mother or fetus.
- Breastfeeding: Maternal nitrate serum levels may elevate during NO administration, but breastmilk levels remain unaffected. Breastfeeding is considered acceptable during maternal nitric oxide therapy as nitric oxide has a short half-life and cannot reach breast milk.
Drug Profile Summary
- Mechanism of Action: Pulmonary vasodilator.
- Side Effects: Methemoglobinemia, hypotension, rebound pulmonary hypertension.
- Contraindications: Right-to-left shunting, methemoglobin reductase deficiency.
- Drug Interactions: Nitroglycerin, sodium nitroprusside, prilocaine, PDE5 inhibitors.
- Pregnancy & Breastfeeding: Generally avoided in pregnancy, breastfeeding considered acceptable.
- Dosage: Neonates: 20 ppm initially, titrated to effect. Adults: 160-200 ppm, twice daily for COVID-19
- Monitoring Parameters: Oxygen saturation, methemoglobin levels, nitrogen dioxide levels, blood pressure.
Popular Combinations
- Inhaled nitric oxide is often used in combination with surfactant, mechanical ventilation, and other supportive therapies in the treatment of neonatal respiratory failure.
Precautions
- General Precautions: Methemoglobin levels and nitrogen dioxide levels must be closely monitored during therapy.
- Specific Populations: Use with caution in preterm infants.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Nitric oxide in neonates?
A: The initial recommended dose is 20 ppm. The dose is then titrated down to the lowest effective dose based on oxygenation, typically within 4 days, for a maximum of 14 days or until respiratory failure is resolved.
Q2: What are the contraindications for inhaled nitric oxide?
A: Absolute contraindications include neonates with right-to-left shunting of blood and congenital or acquired methemoglobin reductase deficiency.
Q3: How is inhaled nitric oxide administered?
A: It is administered via a calibrated nitric oxide delivery system as part of the ventilator circuit.
Q4: What are the common side effects of iNO?
A: Common side effects include methemoglobinemia (usually mild) and hypotension.
Q5: What are the serious side effects of iNO?
A: Serious side effects include worsening of heart failure, pulmonary edema, and rebound pulmonary hypertension upon withdrawal.
Q6: Can nitric oxide be used in preterm infants?
A: It can be used cautiously in preterm infants, starting at lower doses (5-10 ppm) under close monitoring. Benefits and risks should be carefully considered due to the limited evidence in this population.
Q7: What are the important drug interactions with iNO?
A: Important interactions include nitroglycerin, sodium nitroprusside (increased risk of hypotension and methemoglobinemia), and prilocaine (increased risk of methemoglobinemia). Co-administration with PDE5 inhibitors can also potentiate hypotensive effects.
Q8: Can iNO be used during pregnancy?
A: iNO is generally avoided during pregnancy except in specific cases like COVID-19 where high-dose inhaled NO may improve outcomes.
Q9: Can breastfeeding continue during iNO therapy?
A: Yes, breastfeeding can generally continue during maternal iNO therapy, as the drug does not reach clinically significant levels in breast milk. It is important to monitor the infant and ensure adequate nutritional intake.
