Continuing Education Activity

Nitric oxide is a medication used to manage and treat hypoxic respiratory failure or persistent pulmonary hypertension in newborns. Its administration in the clinical scenario as an inhalant (iNO) for adjunctive rescue therapy and improved oxygenation of persistent pulmonary hypertension of newborns (PPHN) and acute respiratory distress syndrome (ARDS). Off-label, it is used to treat acute bronchiolitis and as rescue therapy in patients with COVID-19 and severe ARDS after other alternatives have failed. This activity describes the indications, mechanism of action, and contraindications for nitric oxide as a valuable agent in treating PPHN. In addition, this activity will highlight the adverse effects, administration, and other key factors pertinent to interprofessional team members in treating neonatal patients with PPHN.

Objectives:

• Explain the importance of monitoring patients receiving inhaled nitric oxide therapy, including daily methemoglobin levels.
• Summarize the risks associated with initiating inhaled nitric oxide therapy.
• Identify and describe the appropriate measures needed to prevent adverse drug reactions with nitric oxide.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring nitric oxide to improve patient outcomes for patients receiving inhaled nitric oxide for persistent respiratory distress.

Indications

Nitric oxide, which exists in a gaseous state and is composed of two atoms, can be found in the natural environment and within parts of the human body. Its administration in the clinical scenario as an inhalant (iNO) for adjunctive rescue therapy and improved oxygenation of persistent pulmonary hypertension of newborns (PPHN) and acute respiratory distress syndrome (ARDS).[1][2][3]

Clinical Indications

The FDA approved a new inhaled nitric oxide product in 1999 and another in 2019 for the treatment of:

• Term and near-term infants((>34 weeks gestation) with hypoxic respiratory failure associated with clinical or echocardiographic signs of pulmonary hypertension to improve oxygenation and lower the risk of extracorporeal membrane oxygenation

Off-label Indications

• ARDS: ARDS d presents with acute-onset hypoxemia in the presence of bilateral pulmonary infiltrates of non-cardiac origin. ARDS can lead to the development of life-threatening hypoxemia. In addition, pulmonary hypertension complicates the course of neonatal respiratory failure and is reportedly present in over 10 percent of these cases. However, researchers failed to demonstrate a decrease in mortality, length of hospitalization, or an improved outcome with the use of iNO in ARDS patients; therefore, it is not recommended by the FDA for regular use.[4]

• Acute bronchiolitis: This condition is the leading cause of infant mortality and is generally treated with supportive measures. iNO has anti-viral, enhances oxygenation, and is safe in infants. In a study, high dose iNO (160 ppm) proved to be safe, well-tolerated, reduced length of stay in the hospital and displayed rapid improvement of oxygen saturation compared to the standard treatment. However, more research is needed to confirm the efficacy and safety of iNO in patients with acute bronchiolitis.[5]

• COVID-19: Exogenous nitric oxide effectively lowers systemic hyperinflammation and oxidative stress, enhances arterial oxygenation, and restores pulmonary alveolar cellular integrity to control pulmonary damage. Therapy with iNO could pave the way for better management of COVID-19 before the commencement of disease-related complications.[6][7] NIH recommends against using the routine use of inhaled nitric oxide. However, based on a meta-analysis, NIH suggests that it may be reasonable to use inhaled nitric oxide as rescue therapy in patients with COVID-19 and severe ARDS due to the transient improvement of oxygenation after other alternatives have failed. Regardless, considering iNO does not improve a patient’s oxygenation, iNO should be tapered promptly to avoid rebound pulmonary vasoconstriction, which may occur when nitric oxide is discontinued after chronic use.[8]

Mechanism of Action

Nitric oxide (NO) is produced by converting L-arginine into NO via NO synthases (NOS) in various parts of the body. Endothelial NOS produces NO that acts explicitly as an endogenous vasodilator that diffuses into vascular cells and mediates smooth muscle relaxation by binding to guanylyl cyclase. Guanylyl cyclase converts GTP into cGMP, which activates cGMP-dependent protein kinases. These protein kinases then phosphorylate various ionic channels in the endoplasmic reticulum (ER), which causes calcium sequestration and prevents calcium mobilization within the cell. As a result, smooth muscle cells relax.[3]

Endogenous Pulmonary Vasodilation

Delivery is direct to pulmonary vascular endothelial cells where vasodilation occurs and further reduces intrapulmonary shunting. The belief is that while NO causes myriad effects within the body, iNO is primarily limited to the lungs. This belief is partly because NO exposed to the bloodstream binds readily to hemoglobin, thus inactivating it and explaining why iNO causes pulmonary vasodilation with little chance of hypotension or systemic vasodilation.[9]

Inhibition of Platelet Aggregation

NO additionally affects platelet activity. In vitro studies have revealed that NO can activate guanylate cyclase within platelets to accumulate intracellular cGMP. This cGMP subsequently activates protein kinases that reduce the binding of fibrinogen to GPIIb/IIIa and a subsequent partial reduction of platelet aggregation. Research has shown that patients with ARDS have elevated platelets and increased platelet activation within alveolar tissues. Samaha et al. conducted a study to investigate whether iNO and its anti-platelet aggregation effects would influence the platelets of ARDS patients. Their results found significant improvements in oxygenation, reduced pulmonary arterial pressure, and a decrease in ex-vivo platelet aggregation without a change in these patients' Ivy bleeding times. They concluded that the improvement in oxygenation and pulmonary circulation was attributable to the reduced platelet aggregation.[10][11]

Immunomodulation

Research has observed that NO changes the balance of T helper 1 (TH1) and T helper 2 (TH2) cells. Specifically, NO decreases the proliferation rate of TH1 cells and cytokine IL-2 synthesis but increases the production of IL-4 cytokines from TH2 cells. In this manner, NO may inhibit inflammatory responses to viral and bacterial pathogens. Additionally, the belief is that NO affects leukocyte adhesion and recruitment.[12]

Pharmacodynamics/Pharmacokinetics :

• Route of Administration: Inhalation
• The onset of Action: Rapid, dose-dependent onset within minutes
• Absorption: Nitric oxide is absorbed systemically after inhalation. Nitric oxide crosses the pulmonary capillary bed, where it combines with oxyhemoglobin.
• Metabolism: Nitric oxide combines oxygen and water, produces nitrogen dioxide and nitrite, and interacts with oxyhemoglobin to produce methemoglobin and nitrate. Consequently, the end products of nitric oxide metabolism are mainly methemoglobin and nitrate.
• Half-Life: 2 to 6 seconds
• Route of Elimination: 70% of inhaled NO metabolites undergo renal elimination. The kidney clears nitrate from the plasma at rates corresponding to the glomerular filtration rate.[13][14]

Administration

The recommended nitric oxide dosage is 20 ppm(parts per million). It is suggested to maintain treatment for up to fourteen days or until the underlying oxygen desaturation has resolved. After that, the neonate is ready to be weaned off from nitric oxide therapy. Doses higher than 20 ppm are not suggested. It is important to note that nitric oxide must be administered using precisely calibrated delivery and validated ventilator systems. To wean iNO, down titration of the dose in multiple steps is required, pausing several hours at each step to monitor for hypoxemia.[15] Newer FDA-approved delivery system cassettes deliver at least 216 liters of 800 ppm nitric oxide gas. This novel iNO delivery system must be used with antioxidant cartridges less than 12 months from manufacturing.

Specific Patient Population

Patients with Hepatic Impairment: The dose adjustment of iNO in patients with hepatic impairment is not provided in the manufacturer's product labeling.

Patients with Renal Impairment: The dose adjustment of iNO in patients with renal impairment is not provided in the manufacturer's product labeling.

Pregnancy Considerations: Nitric oxide is a maternal and fetal homeostasis regulator during pregnancy, facilitating maternal cardio-vascular changes, fetal development, and growth and adaptation to extrauterine life. Dysfunction of the NO system during pregnancy is associated with placental and vascular-related diseases such as hypertensive disorders of pregnancy and intrauterine growth restriction (IUGR). It is safe to use nitric oxide during pregnancy.[16] iNO, combined with supplemental oxygen, can reduce pulmonary arterial resistance and improve pulmonary blood flow and oxygenation and is indicated for pregnant women with the risk of cardiac decompensation.[17]

Breastfeeding Considerations: Nitric oxide has a very short half-life, so exogenously administered iNO does not reach the breast milk. Although maternal nitrate serum levels may be increased during iNO administration, it does not increase breast milk nitrate levels. Both nitric oxide and nitrate are normal components of human milk, and iNO is administered to newborns by inhalation to manage respiratory failure. Consequently, breastfeeding during maternal nitric oxide inhalation therapy is acceptable.[18]

Adverse Effects

iNO's adverse effects are primarily dose-dependent, and the recommended limit for clinical use is 20 ppm for up to 14 days in a preterm infant. However, even low doses may exert cellular toxicity. Infants who received iNO and ventilation for PPHN for 1 to 4 days showed nitrotyrosine residues within their lungs, indicating potential long-term pulmonary complications. Clinical doses of iNO have also exhibited adverse effects. Infants weaning from nitric oxide, when it was withdrawn rapidly, suffered from severe rebound pulmonary vasospasm, most likely due to the actions of exogenous nitric oxide downregulating nitric oxide synthase activity.[19]

NO can also rapidly interact with other atoms or anions to facilitate damage. It can combine with oxygen in the lungs to form nitrogen dioxide, a potent pulmonary irritant. Additionally, it can interact with a superoxide anion to form peroxynitrite. Peroxynitrite is cytogenic and can disrupt surfactant functioning within the lungs.[20]

Clinical adverse effects of iNO include the following: [21]

• Worsening heart failure
• Hypotension
• Pulmonary vasospasm
• Methemoglobinemia: The risk of methemoglobinemia increases with the simultaneous use of the eutectic mixture of local anesthetics. (EMLA-Lidocaine/Prilocaine)[22][23]

Contraindications

Contraindications of iNO include severe left ventricular dysfunction and congenital heart disease involving a right to left shunt. Echocardiogram findings should rule out congenital cyanotic heart disease before initiating iNO, as this drug can further exacerbate heart failure in systems dependent on ductal systemic blood flow.[24] Abrupt discontinuation of iNO can worsen oxygenation and increase pulmonary artery pressure, resulting in rebound pulmonary hypertension syndrome.[25]

Monitoring

Therapeutic Effects 

Administration as an inhalant provides a rapid and smooth onset with a predictable duration of effect in hypoxic respiratory failure. In addition, with most of its immediate effects confined to the lungs, there is relatively low organ toxicity.

Respiratory Effects

Low-dose iNO therapy for PPHN could decrease the need for ECMO therapy, as evidenced by the study performed in 2000 by the Clinical Inhaled Nitric Oxide Research Group (CINRGI). Neonates who received low dose iNO therapy had less need (38%) for ECMO therapy and less chronic lung disease than the control group (48%).[21] Schreiber et al. confirmed this finding and revealed that preterm infants treated with iNO for respiratory distress had a decreased incidence of chronic lung disease and death.[26]

Cardiovascular Effects

Current recommendations are limited to 20 ppm as higher doses may be associated with methemoglobinemia and nitric dioxide formation. The Neonatal Inhaled Nitric Oxide Research Group (NiNOS) observed the peak level of methemoglobin to be 2.4% +/- 1.85% in the iNO-treated group compared to controls. Once initiated, daily methemoglobin and nitrogen dioxide levels require close vigilance.[14][27] In the CINRGI study, hypotension was the only observed adverse effect between control and iNO-treated groups.[21]

Oxygen Saturation

Preductal and postductal oxygen saturation/PaO2 measurements can differentiate PPHN from structural heart disease. Saturation differences of > 5-10% or PaO2 differences of 10 to 20 mmHg between the right upper and lower limbs are significant. In neonates with PPHN and atrial-level right-to-left shunting without a significant ductal shunt, the right arm and right leg saturations will be low. Contrariwise, infants with PDA and coarctation of the aorta may have differential cyanosis.[28] However, echocardiography is the gold standard for diagnosing PPHN and monitoring the efficacy of specific therapeutic interventions such as iNO.[29]

Toxicity

In animal primary neuronal cell cultures, excess nitric oxide is partially responsible for glutamate neurotoxicity. These glutamate derangements affect neurodegenerative disorders, including stroke, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. However, it is more likely that these neurotoxic mechanisms are subject to mediation through peroxynitrite, the product of an NO and superoxide anion reaction. Peroxynitrite and excess oxygen free radicals can be generated from severe cellular damage and cross the blood-brain barrier as lipid-soluble products accumulate within neuronal tissue.[30] The newer FDA-approved iNO delivery system limits the toxicity of nitric oxide by delivering a controlled level of nitric oxide with oxygen.

Enhancing Healthcare Team Outcomes

FDA approval limits iNO for persistent hypoxic respiratory distress in preterm infants. Its use requires experienced staff in tertiary level neonatal intensive care units (NICU) with advanced modes of ventilatory support. Ideally, diagnostic findings such as an echocardiogram performed by a radiologist should rule out cyanotic heart disease before initiating iNO therapy, as the drug can exacerbate heart failure in these patients.[24] [Level 3]

Clinical and diagnostic findings should confirm PPHN in preterm infants before administration, and SaO2 and pulse oximetry readings should be followed closely by the dedicated nurse to ensure adequate administration and alleviation of symptomatic findings. In addition, clinicians need to counsel pregnant women to need counseling regarding the use of NSAIDs like ibuprofen, aspirin, and naproxen, which increase the risk of persistent pulmonary hypertension.[31] [Level 3] Close collaboration between healthcare providers and interprofessional teamwork is crucial for patients receiving iNO therapy to optimize patient outcomes and prevent adverse events. [Level 5]

Sedation may often be necessary with the administration to prevent agitation in the infant. Therefore, the anesthesiologist must be alert and attentive to any rapid change resulting from drug-drug interactions. Once initiated, iNO requires gradual weaning to prevent pulmonary vasospasm and blood levels of methemoglobin should be kept under 2.5% and closely followed.[14][27] [Level 1] Additionally, while adjunctive use for adult ARDS patients may provide relief, it is important to note that iNO failed to reduce mortality, length of hospitalization, or improve outcomes in these patients.[1][3] [Level 3]

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Disclosure: Jennifer Witek declares no relevant financial relationships with ineligible companies.

Disclosure: Anand Lakhkar declares no relevant financial relationships with ineligible companies.