Introduction to Inhaled Nitric Oxide (INO)
In the landscape of critical care medicine, particularly in the neonatal intensive care unit (NICU), certain treatments stand out for their targeted efficacy. Inhaled Nitric Oxide, commonly referred to as iNO, is one such cornerstone therapy. While the term "INO" can also refer to Internuclear Ophthalmoplegia, a neurological disorder affecting eye movement, in the context of pharmacology and respiratory medication, it signifies Inhaled Nitric Oxide [1.2.1, 1.2.3]. This therapeutic gas is administered to patients, primarily newborns, who are connected to a ventilator [1.2.1]. Its discovery as a key endothelial-derived vasodilator molecule has revolutionized the treatment of specific cardiopulmonary conditions [1.4.2].
Mechanism of Action: How Does INO Work?
The primary function of iNO is to induce selective pulmonary vasodilation, meaning it specifically widens the blood vessels within the lungs without significantly affecting the blood vessels in the rest of the body [1.4.2, 1.4.5]. This selectivity is its key advantage over intravenous vasodilators, which can cause systemic hypotension (low blood pressure) [1.4.2].
When inhaled, nitric oxide gas diffuses across the alveolar-capillary membrane and into the smooth muscle cells of the pulmonary vessels [1.4.2]. There, it activates an enzyme called soluble guanylate cyclase (sGC) [1.4.1]. This activation increases the intracellular levels of cyclic guanosine monophosphate (cGMP), which in turn leads to the relaxation of the vascular smooth muscle [1.3.2, 1.4.1]. This relaxation of the lung's blood vessels reduces pulmonary vascular resistance, allowing more blood to flow through well-ventilated areas of the lungs. This process improves the matching of ventilation (airflow) and perfusion (blood flow), leading to better oxygenation of the blood [1.4.6, 1.4.5]. Once the nitric oxide enters the bloodstream, it is rapidly inactivated by binding to hemoglobin, which prevents it from causing widespread vasodilation throughout the body [1.4.2].
Primary Approved Use: PPHN
The U.S. Food and Drug Administration (FDA) has approved iNO for the treatment of term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension [1.4.2, 1.3.7]. This condition is often called Persistent Pulmonary Hypertension of the Newborn (PPHN). In PPHN, the infant's circulatory system fails to adapt to breathing air after birth, and high pressure in the lung's arteries (pulmonary hypertension) causes deoxygenated blood to bypass the lungs through fetal circulatory pathways. iNO helps to relax these arteries, improve blood flow to the lungs, and thereby increase oxygen levels in the blood, reducing the need for more invasive treatments like extracorporeal membrane oxygenation (ECMO) [1.4.2, 1.8.6]. The typical starting dose is 20 parts per million (ppm), which is weaned down as the patient's condition improves [1.7.1].
Off-Label and Investigational Uses
While its primary indication is for neonatal PPHN, iNO has been explored for several off-label uses in both pediatric and adult patients, though evidence for many of these applications is still developing.
- Acute Respiratory Distress Syndrome (ARDS): In patients with ARDS, iNO can transiently improve oxygenation by enhancing ventilation-perfusion matching [1.4.5]. However, studies have not shown a benefit in terms of overall survival or duration of ventilation [1.4.6].
- Pediatric Cardiac Surgery: iNO is sometimes used to manage and prevent pulmonary hypertensive crises following surgery for congenital heart defects in children [1.6.5].
- Pulmonary Vasoreactivity Testing: In adults with pulmonary arterial hypertension (PAH), iNO is used during right heart catheterization to test whether the pulmonary arteries are still capable of dilating. This helps determine potential responsiveness to other long-term vasodilator therapies [1.3.5].
- Other Uses: It has been investigated for conditions like acute bronchiolitis, sickle cell crisis, and even as a potential therapy for COVID-19-related ARDS, though its routine use is not recommended for these conditions [1.6.1, 1.4.4].
Administration and Safety
INO is a gas delivered through a specialized, calibrated system that is integrated into a patient's ventilator circuit [1.7.2]. Continuous monitoring is critical.
Key Monitoring Parameters:
- Methemoglobin (MetHb): When nitric oxide binds to hemoglobin, it can form methemoglobin, which cannot carry oxygen. High levels can be toxic, so blood levels of MetHb are checked regularly [1.7.2, 1.7.5]. Doses are generally kept at or below 20 ppm to minimize this risk [1.6.6].
- Nitrogen Dioxide (NO2): Nitric oxide can react with oxygen to form nitrogen dioxide, a toxic gas that can cause lung injury. The delivery system is designed to minimize NO2 formation, and levels in the breathing circuit are continuously monitored [1.4.2, 1.7.4].
- Oxygenation and Hemodynamics: Healthcare providers closely watch the patient's oxygen saturation levels and blood pressure [1.7.2].
- Weaning: Abruptly stopping iNO can cause severe rebound pulmonary hypertension. Therefore, the dose must be weaned down slowly and carefully [1.7.2, 1.4.2].
Comparison of Pulmonary Vasodilators for PPHN
While iNO is a first-line therapy, other vasodilators may be used, especially in cases of iNO resistance or when iNO is unavailable [1.8.2].
| Medication | Mechanism of Action | Route | Key Considerations |
|---|---|---|---|
| Inhaled Nitric Oxide (iNO) | Increases cGMP, leading to selective pulmonary vasodilation [1.3.2]. | Inhaled | Selective to the lungs; risk of methemoglobinemia and rebound hypertension [1.8.4]. First-line FDA-approved therapy for neonatal PPHN [1.8.6]. |
| Sildenafil | Phosphodiesterase-5 (PDE5) inhibitor; prevents the breakdown of cGMP, potentiating the NO pathway [1.8.1]. | IV, Oral | Systemic administration can cause hypotension. Can be used as an adjunct or alternative to iNO [1.8.4]. |
| Milrinone | Phosphodiesterase-3 (PDE3) inhibitor; increases cAMP, causing vasodilation and improved cardiac contractility (inodilator) [1.8.1, 1.8.2]. | IV | Useful in PPHN with associated left ventricular dysfunction, but carries a risk of systemic hypotension [1.8.6]. |
| Prostacyclins (e.g., Iloprost, Epoprostenol) | Activate adenylate cyclase to increase cAMP, producing vasodilation [1.8.1, 1.8.2]. | Inhaled, IV | Inhaled forms offer more lung selectivity. IV forms have a higher risk of systemic hypotension. Can be used when iNO is ineffective or unavailable [1.8.5, 1.8.2]. |
Conclusion
In summary, Inhaled Nitric Oxide (iNO) is a critical, life-saving medication primarily used to treat term and near-term newborn infants with hypoxic respiratory failure and persistent pulmonary hypertension [1.6.4, 1.4.2]. Its ability to selectively dilate the pulmonary arteries without causing systemic side effects makes it uniquely effective for improving oxygenation in this vulnerable population and reducing the need for ECMO [1.8.6]. While its use has been explored in other conditions, its foundational role remains firmly in the NICU. Careful administration and diligent monitoring are essential to ensure its benefits are realized while minimizing potential risks like methemoglobinemia and rebound hypertension [1.7.2].
For further reading, you may consult authoritative resources such as the Mayo Clinic.
