Understanding Inhaled Nitric Oxide (iNO)
Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that works by relaxing the smooth muscles in the blood vessels of the lungs [1.8.4]. After inhalation, it diffuses across the alveolar-capillary membrane, activating soluble guanylate cyclase, which increases levels of cGMP and leads to vasodilation [1.8.2]. This effect is largely confined to the lungs because iNO is rapidly inactivated by hemoglobin in the bloodstream [1.8.2]. This targeted action improves ventilation-perfusion (V/Q) matching by increasing blood flow to well-ventilated areas of the lungs, which helps to improve arterial oxygen levels [1.8.2, 1.8.6]. It is a primary treatment for term and near-term neonates with hypoxic respiratory failure associated with persistent pulmonary hypertension of the newborn (PPHN) [1.8.5].
Readiness Criteria for Weaning
Before attempting to wean a patient from iNO, clinicians must assess their readiness to ensure a high probability of success and minimize risks. The decision to wean is typically made after a period of stability and marked improvement in the patient's underlying condition.
Key criteria include [1.6.1, 1.6.5, 1.6.6]:
- Improved Oxygenation: The patient's need for supplemental oxygen should be significantly reduced. A common target is a fraction of inspired oxygen (FiO2) of ≤ 60% (0.60) [1.2.4, 1.3.3, 1.6.2].
- Hemodynamic Stability: The patient should be hemodynamically stable for a sustained period, often defined as at least 4 to 6 hours, without requiring significant vasoactive drug support [1.6.1, 1.6.5].
- Resolution of Underlying Pathology: The primary reason for initiating iNO, such as PPHN or severe ARDS, should show signs of improvement.
- Oxygenation Index (OI): In neonatal care, an OI of ≤10 is often used as a benchmark to begin the weaning process [1.6.1].
- Echocardiogram Findings: For some patients, particularly infants with severe PPHN or congenital diaphragmatic hernia, an echocardiogram may be used to evaluate right ventricular function and pressure before discontinuing iNO [1.7.1].
Step-by-Step Weaning Protocols
Weaning protocols can vary by institution and patient population (neonate vs. adult), but they all share a common principle: a gradual, stepwise reduction of the iNO dose to avoid abrupt withdrawal.
Neonatal Weaning Protocol
A typical approach for neonates starts after the FiO2 has been successfully lowered to ≤ 0.60. The initial iNO dose is usually 20 parts per million (ppm) [1.3.1, 1.3.2].
- Initial Reduction: Wean iNO from 20 ppm down to 10 ppm, and then to 5 ppm. These decrements of 5 ppm can often be made every 1 to 4 hours, provided the infant remains stable [1.2.1, 1.2.4, 1.3.3].
- Slower Titration: Once the dose reaches 5 ppm, the weaning process slows considerably. The dose is then reduced by 1 ppm every 1 to 4 hours [1.2.1, 1.2.2].
- Final Step: The final step, from 1 ppm to 0 ppm, is the most critical due to the high risk of rebound pulmonary hypertension. Some protocols recommend increasing the FiO2 by 10% just before discontinuing the iNO to help mitigate any rebound effects [1.2.3, 1.4.1].
- Monitoring and Failure: Throughout the process, the infant's oxygen saturation (SpO2) and arterial oxygen partial pressure (PaO2) must be closely monitored [1.7.1]. A wean is considered a failure if there's a significant drop in oxygenation (e.g., >10% decrease in SpO2) or evidence of hemodynamic instability [1.6.4, 1.7.2]. If failure occurs, the dose should be returned to the previous stable level, and another attempt can be made after a period of stabilization, typically 4 to 12 hours [1.2.4, 1.3.6].
Adult (ARDS) Weaning Protocol
Weaning in adults with conditions like Acute Respiratory Distress Syndrome (ARDS) follows a similar cautious, stepwise approach. The criteria for starting the wean often include a PaO2/FiO2 ratio > 200 mmHg for over 24 hours and stable hemodynamics [1.4.7].
- Initial Wean: From a starting dose of 20 ppm, the dose can be weaned to 10 ppm and then to 5 ppm, often with a 4- to 6-hour observation period at each step [1.4.2].
- Low-Dose Wean: From 5 ppm, the dose may be weaned more slowly, for example, to 2.5 ppm and then held for another 6 hours before discontinuation [1.4.2].
- Discontinuation: As with neonates, a precautionary increase in FiO2 may be employed just before stopping the gas [1.4.1].
- Failure Criteria: Weaning failure in adults is defined by criteria such as a >10% drop in SpO2, a significant increase in pulmonary artery pressure (PAP), or hypotension [1.6.4]. If the patient fails a weaning attempt, the dose is increased to the prior concentration [1.4.7].
| Feature | Neonatal Protocol (PPHN) | Adult Protocol (ARDS) |
|---|---|---|
| Initiation Criteria | FiO2 ≤ 0.60, OI ≤ 10, hemodynamic stability [1.6.1, 1.3.3] | FiO2 < 0.50, PaO2/FiO2 > 200 mmHg, hemodynamic stability [1.4.3, 1.4.7] |
| Initial Dose Reduction | 20 ppm to 10 ppm, then to 5 ppm, often in 5 ppm steps every 1-4 hours [1.2.4, 1.3.3] | 20 ppm to 10 ppm, then to 5 ppm, often with 4-6 hour intervals [1.4.2, 1.4.3] |
| Low Dose Reduction | From 5 ppm, wean by 1 ppm every 1-4 hours [1.2.2] | From 5 ppm, may wean to 2.5 ppm before stopping [1.4.2] |
| Key Monitoring | Pre-ductal and post-ductal SpO2, PaO2, MetHb levels daily [1.7.1, 1.7.2] | SpO2, PaO2, mean arterial pressure (MAP), pulmonary artery pressure (PAP) [1.6.4, 1.4.7] |
| Failure Management | Return to previous dose; re-attempt after 4-12 hours [1.2.4, 1.3.2] | Increase to prior concentration; may consider sildenafil [1.4.7, 1.4.2] |
Complications: Rebound Pulmonary Hypertension
Sudden discontinuation of iNO can lead to a dangerous phenomenon known as rebound pulmonary hypertension [1.5.1, 1.8.2]. This occurs because exogenous iNO administration can suppress the body's own production of endogenous nitric oxide [1.5.3]. When the external source is abruptly removed, the pulmonary vasculature can constrict powerfully, leading to a rapid increase in pulmonary artery pressure, worsening oxygenation (hypoxemia), systemic hypotension, and decreased cardiac output [1.5.1]. In severe cases, this can be life-threatening [1.5.5]. This is why a slow, methodical weaning process is essential. If rebound occurs, iNO therapy should be immediately reinstated at the last effective dose [1.5.1]. Studies have also explored using phosphodiesterase-5 inhibitors like sildenafil to prevent rebound PHT, as it helps maintain levels of cGMP, the molecule responsible for vasodilation [1.5.2, 1.5.6].
Conclusion
The process of how to wean iNO is a delicate and critical step in managing patients with severe hypoxic respiratory failure. Success hinges on careful patient selection based on clear readiness criteria, adherence to a gradual, stepwise dose reduction protocol, and vigilant monitoring for any signs of deterioration. Understanding the risk of rebound pulmonary hypertension and managing it appropriately are paramount to ensuring a safe transition off this potent therapy. Institutional guidelines and a multidisciplinary team approach are crucial for optimizing outcomes.
For further reading, see guidelines from the American Academy of Pediatrics on the use of iNO:
https://publications.aap.org/pediatrics/article/106/2/344/62822/Use-of-Inhaled-Nitric-Oxide
