Nitric Oxide

Nitric Oxide is not FDA-approved for standard use in adults; however, in critical care settings (such as for ARDS or post-cardiac surgery pulmonary hypertension), healthcare providers may utilize it off-label.

• Standard Adult Range: Doses typically start at 5 to 20 parts per million (ppm).
• Maximum Dose: Doses above 40 ppm are rarely used because they do not typically provide additional benefit and significantly increase the risk of toxicity (methemoglobinemia and nitrogen dioxide formation).
• Duration: Treatment is usually maintained for the shortest duration possible, often ranging from a few hours to several days, depending on the patient's oxygenation status.

The primary use of Nitric Oxide is in neonates (newborns).

• Neonatal Dose (Term and Near-Term): The recommended starting dose is 20 ppm.
• Maintenance: Treatment is typically maintained at 20 ppm for up to 14 days or until the underlying oxygenation issue has resolved.
• Weaning: Dosing should not be stopped abruptly. Providers typically wean the dose down (e.g., from 20 ppm to 10 ppm, then 5 ppm, then 1 ppm) before discontinuation to prevent a 'rebound' effect where pulmonary blood pressure spikes suddenly.

Renal Impairment

No specific dose adjustments are required for patients with kidney disease, as the active gas is metabolized in the blood. However, because the end-metabolite (nitrate) is excreted renally, monitoring for long-term accumulation in patients with severe renal failure may be considered by the medical team.

Hepatic Impairment

Nitric Oxide metabolism does not involve the liver or the cytochrome P450 enzyme system. Therefore, no dosage adjustments are necessary for patients with liver impairment.

Elderly Patients

Clinical studies of Nitric Oxide did not include sufficient numbers of patients aged 65 and over to determine if they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased cardiac or other organ function.

Nitric Oxide is administered via inhalation through a mechanical ventilator or a high-flow nasal cannula. It is never self-administered.

• Administration: The gas is blended into the inspiratory limb of the ventilator circuit.
• Monitoring: Continuous monitoring of the inspired concentrations of NO and NO2 is mandatory.
• Storage: Cylinders must be stored in a well-ventilated area, secured to prevent tipping, and kept away from combustible materials.

Because Nitric Oxide is administered as a continuous inhalation in a controlled hospital environment (ICU), a 'missed dose' in the traditional sense is impossible. However, if the delivery system fails or the cylinder runs out, it is considered a medical emergency. Abrupt interruption can lead to a rapid worsening of oxygenation and a dangerous rise in pulmonary artery pressure.

An overdose of Nitric Oxide is characterized by elevated levels of methemoglobin and nitrogen dioxide.

• Signs of Overdose: Bluish skin color (cyanosis), shortness of breath, rapid heart rate, and decreased oxygen saturation despite high levels of supplemental oxygen.
• Emergency Measures: If an overdose occurs, the dose of Nitric Oxide must be immediately reduced or discontinued. In severe cases of methemoglobinemia, intravenous methylene blue may be administered to convert methemoglobin back into functional hemoglobin. Supplemental oxygen and supportive care are essential.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance. Nitric Oxide therapy is managed entirely by neonatal or intensive care specialists.

In clinical trials, the most common side effects associated with Nitric Oxide therapy in neonates include:

• Hypotension (Low Blood Pressure): While Nitric Oxide is selective for the lungs, some systemic vasodilation can occur, leading to a drop in overall blood pressure. This may feel like dizziness or lethargy in older patients, but in neonates, it is monitored via arterial lines.
• Withdrawal Syndrome (Rebound Hypertension): If the gas is stopped too quickly, the body's blood vessels may constrict sharply, causing oxygen levels to plummet. This is the most common complication during the weaning phase.
• Atelectasis (Lung Collapse): Small areas of the lung may deflate, which is often a complication of the underlying respiratory failure rather than the gas itself, but it is frequently observed during treatment.

• Methemoglobinemia: This occurs when Nitric Oxide reacts with hemoglobin, changing its structure so it cannot carry oxygen. Levels between 5% and 10% are considered less common but require dose adjustment.
• Hematuria (Blood in Urine): Observed in some neonatal trials, though the direct causal link to Nitric Oxide is still debated.
• Hyperglycemia (High Blood Sugar): Temporary increases in blood glucose levels have been reported in intensive care settings.
• Sepsis: Increased risk of infection has been noted in some clinical cohorts, possibly due to the invasive nature of the ventilation required during therapy.

• Nitrogen Dioxide (NO2) Toxicity: NO2 is a toxic byproduct formed when Nitric Oxide reacts with oxygen. High levels can cause severe lung injury, pulmonary edema (fluid in the lungs), and airway inflammation.
• Platelet Inhibition: Nitric Oxide has the potential to inhibit platelet aggregation (clotting), which could theoretically increase the risk of bleeding, such as intracranial hemorrhage in premature infants.

> Warning: Stop taking Nitric Oxide and call your doctor immediately if you experience any of these.

• Severe Methemoglobinemia: If methemoglobin levels exceed 10%, the blood loses its ability to transport oxygen. This is a life-threatening condition that requires immediate intervention with methylene blue.
• Acute Rebound Pulmonary Hypertension: A sudden, severe increase in lung blood pressure following the discontinuation of the gas. This can lead to right-sided heart failure and cardiovascular collapse.
• Pulmonary Edema: The buildup of fluid in the lungs, often associated with NO2 toxicity or underlying left-sided heart failure.
• Anaphylaxis: Though extremely rare for a gas, any signs of a severe allergic reaction (hives, swelling of the face, difficulty breathing) must be treated as an emergency.

Research on the long-term effects of Nitric Oxide inhalation is ongoing. Most studies on neonates followed up to age two have shown no significant differences in neurodevelopmental, cognitive, or respiratory outcomes compared to those who did not receive the gas. However, some researchers monitor for potential changes in lung architecture or chronic airway reactivity, although these are currently considered risks of the underlying disease (PPHN) rather than the drug itself.

There are currently no FDA Black Box Warnings for Nitric Oxide. However, the FDA does provide strict 'Warnings and Precautions' regarding the risk of rebound pulmonary hypertension and methemoglobinemia, which are treated with the same level of clinical urgency as a black box warning.

Report any unusual symptoms to your healthcare provider immediately. In the ICU, this is done through continuous vital sign monitoring and frequent blood gas analysis.

Nitric Oxide is a high-alert medication that must only be used in specialized hospital environments. The most critical safety concern is the prevention of abrupt discontinuation. Because the body may reduce its own natural production of nitric oxide during therapy, stopping the supplemental gas suddenly can cause the pulmonary arteries to clamp down, leading to a life-threatening crisis. Furthermore, Nitric Oxide must never be used without a calibrated delivery system that monitors nitrogen dioxide (NO2) levels, as NO2 is a potent respiratory irritant that can cause permanent lung damage.

No FDA black box warnings for Nitric Oxide. While it lacks a black box warning, the prescribing information contains 'Contraindications' and 'Warnings' that are vital for survival, particularly regarding its use in infants with certain heart defects.

• Methemoglobinemia Risk: Patients with a deficiency in the enzyme methemoglobin reductase are at a significantly higher risk of developing toxic levels of methemoglobin. This condition prevents oxygen from being released to the tissues.
• Heart Failure (Left Ventricular Dysfunction): Nitric Oxide should be used with extreme caution in patients with pre-existing left-sided heart failure. By dilating the pulmonary vessels, it increases the amount of blood returning to the left side of the heart. If the left ventricle is weak, this can lead to 'backup' and acute pulmonary edema (fluid in the lungs).
• Nitrogen Dioxide (NO2) Formation: NO2 is formed whenever Nitric Oxide is in the presence of oxygen. High concentrations of oxygen (FiO2) and low flow rates increase NO2 production. NO2 levels must be kept below 0.5 ppm to avoid lung injury.
• Bleeding Risk: Because Nitric Oxide can interfere with how platelets stick together, it should be used cautiously in patients with active bleeding or those at high risk for internal hemorrhage.

Patients receiving Nitric Oxide require intensive monitoring, including:

• Methemoglobin Levels: Blood tests (co-oximetry) should be performed within 4-8 hours of starting therapy and at least daily thereafter.
• Nitrogen Dioxide (NO2): Continuous electronic monitoring of the gas mixture being delivered to the patient.
• Oxygenation: Continuous pulse oximetry and frequent arterial blood gas (ABG) samples to measure the partial pressure of oxygen (PaO2).
• Hemodynamics: Continuous monitoring of blood pressure and heart rate.

This section is not applicable to Nitric Oxide, as it is only administered to hospitalized, critically ill patients who are typically bedbound and often sedated or on mechanical ventilation.

There are no known direct interactions between alcohol and inhaled Nitric Oxide. However, alcohol consumption is strictly prohibited in the intensive care environments where this medication is used.

Discontinuation must be a gradual process (weaning). The healthcare team will slowly lower the concentration of the gas while monitoring the patient's oxygen levels. If oxygen levels drop by more than a certain percentage (usually 5-10%), the dose is increased back to the previous level before attempting to wean again.

> Important: Discuss all your medical conditions with your healthcare provider before starting Nitric Oxide. Ensure the medical team is aware of any known enzyme deficiencies or heart defects.

There are no drugs that are strictly contraindicated (forbidden) for use with Nitric Oxide; however, certain combinations are avoided due to extreme risk.

• Prilocaine and Nitric Oxide: Prilocaine (a local anesthetic) is known to induce methemoglobinemia. Using it alongside Nitric Oxide can cause a synergistic rise in methemoglobin levels, leading to severe hypoxia (lack of oxygen in tissues). This combination should be avoided whenever possible.

• Sildenafil (Viagra) and other PDE-5 Inhibitors: Sildenafil works by preventing the breakdown of cGMP, the same molecule that Nitric Oxide increases. Using these together can lead to profound, unpredictable vasodilation and dangerous drops in systemic blood pressure. While sometimes used together intentionally in specialized pediatric cardiology, this requires expert supervision.
• Nitroglycerin and Sodium Nitroprusside: These are 'nitric oxide donors.' Using them with inhaled Nitric Oxide can increase the risk of additive systemic hypotension and methemoglobinemia.

• Sympathomimetics (e.g., Dopamine, Epinephrine): These drugs increase blood pressure and are often used in the ICU. Nitric Oxide may counteract some of the vasoconstrictive effects of these drugs in the pulmonary circuit, which is usually the desired clinical goal, but blood pressure must be monitored closely.
• Anticoagulants (e.g., Heparin): Due to the potential for Nitric Oxide to inhibit platelet function, there is a theoretical increased risk of bleeding when used with blood thinners.

There are no known interactions between inhaled Nitric Oxide and food. Patients receiving this medication are typically on intravenous fluids or enteral (tube) feeding due to the severity of their illness.

• Nitrate-rich Supplements: Supplements containing high levels of nitrates (like beetroot extract) could theoretically contribute to higher nitrate/nitrite levels in the blood, though this is clinically insignificant for an inhaled gas.
• St. John's Wort: While St. John's Wort affects many drugs via the liver (CYP450), it does not interact with Nitric Oxide because Nitric Oxide is not metabolized by the liver.

• Pulse Oximetry: High levels of methemoglobin can cause inaccurate pulse oximetry readings (the 'finger clip' oxygen sensor). In the presence of methemoglobinemia, the pulse oximeter may show a reading of approximately 85% regardless of the actual oxygen level.
• Co-oximetry: This is the only reliable way to measure oxygen saturation and methemoglobin levels in patients receiving Nitric Oxide.

For each major interaction, the mechanism involves either the enhancement of the cGMP pathway (pharmacodynamic) or the additive stress on the hemoglobin molecule (methemoglobin formation). The management strategy always involves increased frequency of blood monitoring and potential dose reduction of one or both agents.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, even though this drug is used in emergency settings.

Nitric Oxide must NEVER be used in the following situations:

1. 1Neonates with Dependent Right-to-Left Shunts: This refers to certain congenital heart defects (like interrupted aortic arch or severe coarctation of the aorta) where the baby relies on blood flowing from the right side of the heart to the left side through a 'shunt' to stay alive. Nitric Oxide can cause these shunts to close or reverse, leading to a sudden stop in blood flow to the body and death.
2. 2Known Hypersensitivity: Although extremely rare, a known severe allergy to Nitric Oxide gas or any component of the delivery system is a contraindication.

Conditions requiring careful risk-benefit analysis include:

• Left Ventricular Dysfunction: As mentioned, increasing pulmonary blood flow can overwhelm a failing left heart, leading to pulmonary edema.
• Methemoglobin Reductase Deficiency: A rare genetic condition that makes a patient unable to process the byproducts of Nitric Oxide, leading to rapid toxicity.
• Severe Bleeding Diathesis: Patients with active brain bleeds (intracranial hemorrhage) or severe clotting disorders, as Nitric Oxide may slightly worsen bleeding times.

There is no known cross-sensitivity between Nitric Oxide gas and other nitrate medications (like nitroglycerin tablets). However, patients who have had severe adverse reactions to other inhaled gases should be monitored with extra caution.

> Important: Your healthcare provider will evaluate your complete medical history, including an echocardiogram (ultrasound of the heart), before prescribing Nitric Oxide to ensure no dangerous heart defects are present.

Nitric Oxide is classified as FDA Pregnancy Category C. There are no adequate and well-controlled studies of inhaled Nitric Oxide in pregnant women. Animal reproduction studies have not been conducted. It is unknown whether Nitric Oxide can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. In clinical practice, it is only used in pregnant women if the potential benefit to the mother (e.g., in severe pulmonary hypertension or ARDS) clearly outweighs the potential risk to the fetus.

It is not known whether Nitric Oxide is excreted in human milk. However, because Nitric Oxide is a gas that is rapidly inactivated in the maternal bloodstream by binding to hemoglobin, it is highly unlikely that any active drug would reach the breast milk or be absorbed by a nursing infant. Most mothers whose infants are receiving Nitric Oxide are in the neonatal intensive care unit (NICU) and may be pumping milk for their infants; the use of the gas in the infant is not a contraindication to breastfeeding.

Nitric Oxide is specifically indicated for neonates (newborns) born at more than 34 weeks of gestation.

• Premature Infants (<34 weeks): The use of Nitric Oxide in premature infants is controversial. While it can improve oxygenation, large clinical trials have not consistently shown that it prevents chronic lung disease or improves survival in this specific population. Some studies have even suggested a slightly higher risk of brain bleeds in very premature infants.
• Older Children: It is used off-label in older children for pulmonary hypertension, particularly following heart surgery.

There is limited data on the use of Nitric Oxide in patients over 65. In older adults, the risk of underlying left-sided heart failure is much higher. Therefore, the risk of developing pulmonary edema (fluid in the lungs) when starting Nitric Oxide is significantly increased. Doctors will typically perform a thorough heart evaluation before starting the gas in an elderly patient.

In patients with renal impairment, the primary concern is the accumulation of nitrate, the end-metabolite. While nitrate itself is not highly toxic, its levels can rise in the blood if the kidneys cannot clear it. No specific dose adjustment is usually required, but the duration of therapy should be kept to a minimum.

Nitric Oxide does not undergo hepatic metabolism. Therefore, no dosage adjustments are necessary for patients with liver disease (Child-Pugh Class A, B, or C). The safety profile remains the same as in patients with normal liver function.

> Important: Special populations, particularly neonates and the elderly, require individualized medical assessment and continuous monitoring during Nitric Oxide therapy.

Nitric Oxide (NO) is an endogenous (naturally produced) gas that relaxes vascular smooth muscle. It works by binding to the heme moiety of cytosolic soluble guanylate cyclase (sGC). This binding activates the enzyme, which catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP then activates protein kinase G, which leads to the dephosphorylation of myosin light chains and the sequestration of intracellular calcium. The result is a profound relaxation of the smooth muscle cells that wrap around blood vessels. When inhaled, this effect is restricted to the pulmonary vascular bed because the gas is neutralized by hemoglobin before it can reach the rest of the body.

• Onset of Action: Nearly instantaneous. Improvements in oxygenation (PaO2) are typically seen within minutes of starting the inhalation.
• Duration of Effect: Very short. Because the half-life is seconds, the vasodilatory effect disappears almost immediately once the gas is stopped. This is why continuous administration is required.
• Tolerance: There is little evidence of pharmacological tolerance (where the drug stops working) over short-term use (up to 14 days). However, the body may downregulate its own natural nitric oxide production, leading to the 'rebound' effect upon withdrawal.

| Parameter | Value |

|---|---|

| Bioavailability | High (Pulmonary) / Low (Systemic) |

| Protein Binding | 0% (Binds to Hemoglobin instead) |

| Half-life | < 6 seconds |

| Tmax | Minutes (for oxygenation effect) |

| Metabolism | Conversion to Methemoglobin and Nitrate |

| Excretion | Renal (>70% as Nitrate) |

• Molecular Formula: NO
• Molecular Weight: 30.01 g/mol
• Solubility: Slightly soluble in water; highly diffusible gas.
• Structure: A simple diatomic molecule consisting of one nitrogen atom and one oxygen atom with an unpaired electron (making it a free radical).

Nitric Oxide is a 'Nitrate Vasodilator'. It is related to other nitrates like Nitroglycerin and Sodium Nitroprusside, but it differs because it is administered in its active gaseous form rather than requiring chemical conversion by the body's tissues.