What are the indications for inhaled nitric oxide (iNO) therapy?

Indications for Inhaled Nitric Oxide (iNO) Therapy

Inhaled nitric oxide (iNO) is primarily indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension. 1

FDA-Approved Indication

• Term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with:
  • Clinical or echocardiographic evidence of pulmonary hypertension
  • In conjunction with ventilatory support and other appropriate agents 1

Specific Clinical Scenarios with Strong Evidence

Persistent Pulmonary Hypertension of the Newborn (PPHN)

• Indicated when oxygenation index exceeds 25 in term and near-term infants 2
• Reduces the need for ECMO support 2, 3
• Improves oxygenation in 60-70% of patients 4
• Standard initial dose: 20 ppm 5, 1
• Maximum treatment duration: up to 14 days or until underlying oxygen desaturation resolves 1

Congenital Diaphragmatic Hernia (CDH)

• May be used as part of management strategy for severe pulmonary hypertension associated with CDH 2
• Often used in conjunction with high-frequency oscillatory ventilation when conventional ventilation fails 2

Off-Label Uses with Limited Evidence

Preterm Infants

• Not recommended for routine use in preterm infants <34 weeks gestation 2
• The American Academy of Pediatrics Committee on Fetus and Newborn concluded that available evidence does not support use in early routine, early rescue, or later rescue regimens in infants <34 weeks gestation 2
• May be considered in select cases of severe hypoxemia primarily due to PPHN in preterm infants, but evidence is limited 2

Chronic Lung Disease of Infancy (CLDI)

• Limited evidence for use in children with CLDI who have severe hypoxemic respiratory failure 2
• Should be considered experimental and limited to research protocols 2

Administration and Monitoring Requirements

• Delivered through the inspiratory limb of the ventilator circuit 5
• Continuous monitoring required:
  • Methemoglobin levels (can increase with dose) 1
  • Nitrogen dioxide (NO₂) levels 1
  • Electrocardiographic monitoring 5

Response Assessment and Weaning

• Positive response defined as:

  • Reduction in mean pulmonary artery pressure 5
  • Improvement in oxygenation 2, 3

• Weaning protocol:

  • Gradual weaning essential to prevent rebound pulmonary hypertension 5
  • Consider weaning to 1 ppm before discontinuation to avoid rebound effects 2
  • Consider starting phosphodiesterase inhibitor before weaning 5

Potential Complications

• Rebound pulmonary hypertension upon abrupt discontinuation 2, 5, 1
• Methemoglobinemia (dose-dependent) 1
• Elevated NO₂ levels 1
• Pulmonary edema in patients with pre-existing left ventricular dysfunction 1

Important Contraindications

• Neonates dependent on right-to-left shunting of blood 1
• Doses greater than 20 ppm are not recommended 1

Adjunctive Therapies to Consider

• Lung recruitment strategies to improve efficacy in PPHN associated with parenchymal lung disease 2
• Sildenafil for infants with PPHN refractory to iNO (especially with oxygenation index >25) 2
• Inhaled prostacyclin analogs may be considered as adjunctive therapy for iNO-refractory PPHN 2
• Intravenous milrinone in infants with PPHN and signs of left ventricular dysfunction 2

While iNO has shown promise in various clinical scenarios, it's important to recognize that it does not improve outcomes in all conditions. For example, in alveolar capillary dysplasia (ACD), iNO may initially enhance oxygenation but does not improve survival 6. Additionally, the evidence does not support routine use in preterm infants despite the increasing off-label use in this population 2.