NEODOSE

INDICATIONS

• Bronchopulmonary dysplasia, prevention (premature newborn): Inhaled nitric oxide is not recommended for premature newborns for the prevention of bronchopulmonary dysplasia. No differences were demonstrated in mortality, incidence of bronchopulmonary dysplasia, or respiratory or neurodevelopmental outcomes in very preterm infants (younger than 30 weeks’ gestation and less than 1250 g) at 36 weeks through 24 months’ postmenstrual age in a randomized trial (n=451) comparing inhaled nitric oxide and placebo initiated on postnatal days 5 to 14 and continued for 24 days.
• Persistent pulmonary hypertension (PPHN)
  • Full-term newborn: Inhaled nitric oxide in term and near-term infants with PPHN or hypoxemic respiratory failure and an oxygenation index of greater than 25 reduces the need for extracorporeal membrane oxygenation.
  • Preterm newborn:Based on the established safety profile with short and long follow-up durations, inhaled nitric oxide can be beneficial for preterm infants with severe hypoxemia, which is primarily due to PPHN rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohydramnios. A subgroup analysis of preterm infants with pulmonary hypertension did not support the use of inhaled nitric oxide during a meta-analysis of preterm infants (less than 34 weeks gestational age) on respiratory support
• Respiratory Failure: Available evidence does not support the use in preterm infants less than 34 weeks GA . This was confirmed in a multicenter, randomized, double-blind study of preterm infants born at less than 29 weeks gestation with moderate respiratory failure. Treatment was initiated within 24 hours of life with inhaled nitric oxide (5 ppm) or placebo and continued for 7 to 21 days. The survival (without bronchopulmonary dysplasia) rate at 36 weeks postmenstrual age was 65% vs 66%, respectively. At 2 years follow-up, there was no difference in growth, neurologic development, including cerebral palsy, or respiratory outcomes between the nitric oxide group and placebo group. The use of iNO in this population should be done under the auspices of a research protocol. Low-dose inhaled nitric oxide (adjusted to 5 to 20 parts per million (ppm)) significantly reduced the use of extracorporeal membrane oxygenation (ECMO) compared with 100% nitrogen (38% vs 64%) in infants with persistent pulmonary hypertension and hypoxic respiratory failure in the randomized CINRGI trial (N=248). Overall, there was no significant difference in mortality (10 vs 13 infants), ventilator settings, heart rate, mean blood pressure, or level of dopamine support during the first 4 hours. After 1 hour of therapy, the ratio of arterial to alveolar oxygen was significantly increased in the nitric oxide group (0.1 vs 0.05). Among surviving infants, the incidence of chronic lung disease at 30 days was significantly lower in the nitric oxide group (7% vs 20%). The study gas was initiated at 20 ppm and continued for 4 hours then subsequently decreased to 5 ppm based on clinical stability within the first 24 hours, or after 24 hours of treatment in all infants. In a retrospective analysis of the CINRGI study, among the 66 responders in the nitric oxide group (those who did not need ECMO), 48 patients responded within 30 minutes of therapy initiation, 6 patients within 1 hour, 8 within 24 hours, and 4 after 24 hours. Among the 48 nonresponders in the nitric oxide group (those who went on to need ECMO), 40 initially responded to therapy (22 within 30 minutes, 7 within 1 hour, 1 within 24 hours, and 10 after 24 hours) by having a 10% or more increase in PaO(2) or a 10% or greater decrease in oxygenation index, which was similar to the responding group, even though nonresponders went on to need ECMO. Of the 29 nonresponders who initially showed a response to nitric oxide therapy, PaO(2) levels at baseline were significantly lower than responders (46 vs 88 mm Hg). Among patients in the control group who responded (n=38), 20 responded within 30 minutes, 6 within 1 hour, and 11 within 24 hours, and 1 after 24 hours. Overall, disease severity at baseline did not correspond to time to improvement in oxygenation.

FDA APPROVED INDICATION

Treatment of term and near-term infants (greater than 34 weeks gestation) with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support or other appropriate agents.

CONTRAINDICATION

• Contraindicated in infants dependent on right-to-left cardiac blood flow.

PRECAUTIONS:

• Cardiovascular :
  • Pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia, and cardiac arrest may occur in patients with left ventricular dysfunction; discontinue if occurs
• Hematologic :
  • Dose-related methemoglobinemia may occur and lead to hypoxemia; monitoring recommended and dosage adjustment may be necessary.
• Respiratory:
  • Abrupt discontinuation may worsen oxygenation and increase pulmonary artery pressure (rebound pulmonary hypertension syndrome); carefully taper dose during weaning; monitoring recommended; restart treatment immediately if rebound pulmonary hypertension occurs.
  • The risks of methemoglobinemia and elevated NO2 levels increase significantly at doses greater than 20 ppm. Methemoglobin has very high affinity for oxygen and has a profound effect on oxygen content. Small increases in methemoglobin cause significant decreases in available oxygen content. Normal methemoglobin levels are less than 1%. In most neonatal studies, methemoglobinemia was defined as levels of 5% to 7%. Cyanosis develops at levels of 10%, although the patients generally remain asymptomatic. At methemoglobin levels approaching 30%, patients begin to experience respiratory distress, and cardiac, gastrointestinal, and neurologic symptoms. A methemoglobin level greater than 50% is usually lethal. Avoid concomitant use of acetaminophen, metoclopramide, sulfa drugs, topical anesthetics (EMLA, benzocaine, lidocaine, prilocaine). Congenital deficiencies in the methemoglobin reductase enzyme system occur but are rare. The environmental exposure limit set by the Occupational Safety and Health Administration is 25 ppm for NO and 5 ppm for NO2.
  • Airway injury from elevated nitrogen dioxide levels may occur; monitoring recommended and dosage adjustment may be necessary

ADVERSE EFFECTS

No adverse effects have been reported in neonates (small numbers). Hypotension andtachycardia are dose-dependent in adults. Headache, nausea, and vomiting were the other common effects reported.

ADMINISTRATION

• Genosyl®:
  • Administer using a calibrated Genosyl® Delivery System.
  • Only validated ventilator systems should be used. Keep available a backup power supply to address power failures.
  • The delivery system consists of a primary system and a fully functional second system that can be used as backup. The delivery system monitors the concentration of nitric oxide, nitrogen dioxide and air; system will shutdown if nitrogen dioxide reaches 3 parts per million (ppm).
  • The delivery system must be used with antioxidant cartridges not older than 12 months from the manufacturing date.

• INOmax®:
  • Must be administered using a calibrated FDA-cleared nitric oxide delivery system (NODS); refer to NODS labeling to determine which NODS to use. When using a NODS specifically cleared for use in the MRI suite, only use INOmax MR Conditional cylinders at 100 gauss or less.
  • Keep backup battery power supply and independent reserve nitric oxide delivery system on standby.

• Noxivent 102:
  • Use equipment rated for cylinder pressure.

MONITORING

• Measure blood methemoglobin concentration 4 to 8 hours after initiation of therapy and periodically thereafter.
• Monitor inspired PaO2 and nitrogen dioxide (NO2) throughout administration of therapy.
• Assess delivery system if there is an unexpected change in NO2 concentration or if the NO2 concentration reaches 0.5 ppm (Glenosyl®) or 3 ppm (Inomax®) when measured in the breathing circuit.
• During weaning and discontinuation from therapy, monitor for hypoxemia .
• Continuous monitoring of oxygenation, blood pressure and heart rate are mandatory