What are the indications, starting dose, therapeutic range, monitoring requirements, adverse effects, weaning protocol, and alternative agents for inhaled nitric oxide (iNO) in neonates with persistent pulmonary hypertension of the newborn (PPHN) and adults with severe hypoxemic respiratory failure such as acute respiratory distress syndrome (ARDS) or right‑ventricular failure due to pulmonary hypertension?

Inhaled Nitric Oxide: Clinical Application Guide

Primary Indication and FDA Approval

Inhaled nitric oxide is FDA-approved exclusively for term and near-term neonates with persistent pulmonary hypertension of the newborn (PPHN) and hypoxemic respiratory failure, where it reduces the need for ECMO support. 1

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Neonatal PPHN: Starting Dose and Therapeutic Range

When to Initiate iNO

• Start iNO when the oxygenation index (OI) exceeds 25 in term and near-term infants with echocardiographically confirmed PPHN showing extrapulmonary right-to-left shunting 1, 2
• OI calculation: (Mean airway pressure × FiO₂ × 100) / PaO₂ 1
• The most critical criterion is echocardiographic confirmation of PPHN with right-to-left shunting, not just hypoxemia alone 1

Dosing Protocol

• Initial dose: 20 ppm 1, 3, 4
• Therapeutic range: 5-20 ppm for responders 5
• Do not exceed 20 ppm – doses above this threshold do not enhance oxygenation and increase methemoglobinemia risk 1
• Effective doses typically range from 6-20 ppm once initial response is achieved 3, 4

Disease-Specific Response Patterns

Response to iNO varies significantly by underlying etiology 5:

• Best responders (rapid, sustained improvement): Idiopathic PPHN, respiratory distress syndrome, sepsis without refractory shock 5
• Moderate responders: Meconium aspiration syndrome (less sustained improvement) 5
• Poor responders: Congenital diaphragmatic hernia (minimal improvement) 5

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Critical Optimization Strategy: Lung Recruitment First

Failure to optimize lung inflation before or during iNO administration is the most common reason for treatment failure. 2, 6

• Ensure adequate lung recruitment with appropriate ventilator settings or high-frequency oscillatory ventilation before declaring iNO ineffective 1, 5
• In parenchymal lung disease, lung recruitment strategies are mandatory to improve iNO efficacy 1, 2
• Consider exogenous surfactant administration when indicated 5

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Monitoring Requirements

Immediate Assessment (Within 30 Minutes)

• Measure OI at 30 minutes – the magnitude of OI reduction predicts survival 5
• Monitor PaO₂, SpO₂/FiO₂ ratio, and mean airway pressure 7
• Assess for systemic hypotension (iNO should NOT cause systemic blood pressure reduction) 3, 4

Ongoing Monitoring

• Methemoglobin levels: Check if using sustained high doses, though rarely problematic at therapeutic doses 6
• Serial echocardiography to assess pulmonary vascular resistance and ventricular function 1
• Continuous pulse oximetry and arterial blood gas monitoring 7

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Weaning Protocol: Avoiding Rebound Pulmonary Hypertension

Abrupt discontinuation of iNO causes life-threatening rebound pulmonary hypertension, even in non-responders. 1, 2, 6

Safe Weaning Strategy

1. Once oxygenation improves, wean relatively rapidly to 5 ppm 1
2. Wean to 1 ppm before complete discontinuation to prevent rebound 1, 2
3. Most infants can be weaned off within 5 days 1
4. If hypoxemia persists beyond 5 days, investigate underlying causes: alveolar capillary dysplasia, severe lung hypoplasia, or progressive lung injury 1

Transition Strategy for Prolonged Use

• Start or restart sildenafil before complete iNO discontinuation when prolonged therapy is needed 6
• This prevents rebound pulmonary hypertension during the transition 6

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Adjunctive Therapies for iNO-Refractory PPHN

When iNO fails to improve oxygenation (OI remains >25):

1. Sildenafil (phosphodiesterase-5 inhibitor): Reasonable adjunctive therapy 1, 2, 6
2. Inhaled prostacyclin analogs: May be considered as adjunctive therapy 1, 2, 6
3. Intravenous milrinone: Use specifically when left ventricular dysfunction is present 1, 2, 6
4. ECMO support: Indicated for severe PH or hypoxemia refractory to iNO and optimization of respiratory/cardiac function 1

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Preterm Infants (<34 Weeks Gestation): Evidence-Based Restrictions

The available evidence does not support routine use of iNO in preterm infants <34 weeks gestational age. 1

When iNO May Be Considered in Preterm Infants

• Selective use is reasonable when severe hypoxemia is primarily due to echocardiographically confirmed PPHN 1, 2
• Predictors of iNO effectiveness in very preterm infants with RDS: FiO₂ >0.65, confirmed PPHN diagnosis, and birth weight >750g 7
• Do not use iNO routinely for bronchopulmonary dysplasia prevention or early/late rescue in preterm infants without PPHN 1

Evidence Against Routine Preterm Use

• NIH consensus panel (2010) concluded evidence does not support early routine, early rescue, or later rescue iNO regimens in infants <34 weeks 1
• Individual-patient meta-analysis of 14 trials reached identical conclusions 1
• Off-label use escalated sixfold (2000-2008) despite lack of efficacy data 1

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Adults with Severe Hypoxemic Respiratory Failure

ARDS and Severe Hypoxemia

• Use iNO as rescue therapy in mechanically ventilated adults with severe ARDS and hypoxemia despite optimizing ventilation and other rescue strategies 6
• Typical starting dose: 20 ppm 6
• iNO improves oxygenation through enhanced ventilation-perfusion matching 6

Acute Right Ventricular Failure in PAH

• In critically ill adults with PAH who are hypotensive with acute RV failure, routinely employ iNO at 20 ppm 6
• iNO acutely decreases pulmonary vascular resistance and improves cardiac output 6
• Short half-life and rapid onset allow acute RV unloading 6

Long-Term Use in Chronic PAH

• Long-term ambulatory iNO for chronic PAH has not been formally studied and is not recommended 1
• Current use is limited to acute vasoreactivity testing during cardiac catheterization or acute stabilization during deterioration 1
• Isolated case reports exist, but extensive work is needed to determine safety, acceptability, feasibility, and effectiveness 1

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Alternative Pulmonary Vasodilators

When iNO is unavailable, contraindicated, or ineffective:

1. Sildenafil (oral/IV): Phosphodiesterase-5 inhibitor for PPHN 1, 2
2. Inhaled prostacyclin analogs (epoprostenol, iloprost): Alternative inhaled vasodilator 1, 2, 6
3. Milrinone (IV): Phosphodiesterase-3 inhibitor, particularly useful with LV dysfunction 1, 2, 6
4. L-arginine supplementation: Acute infusion (500 mg/kg over 30 min) improved oxygenation in PPHN, though long-term benefits unknown 1

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Critical Pitfalls to Avoid

• Never discontinue iNO abruptly – always wean to 1 ppm first 1, 2, 6
• Do not use iNO in congenital diaphragmatic hernia with LV dysfunction – increased pulmonary blood flow worsens pulmonary edema due to abnormal left ventricle 2
• Do not declare iNO failure without first optimizing lung recruitment 2, 6
• Do not exceed 20 ppm dosing – no additional benefit and increased toxicity risk 1
• Do not use iNO routinely in preterm infants <34 weeks without confirmed PPHN 1, 2

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Adverse Effects

• Methemoglobinemia: Usually only at sustained high doses (>20 ppm) 6
• Rebound pulmonary hypertension: Upon abrupt discontinuation 1, 2, 6
• Pulmonary edema: In CDH with LV dysfunction 2
• Nitrogen dioxide toxicity: Rare with modern delivery systems and appropriate dosing 1