Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.


INOmax (Delpharm)
2 and 10 litre gas cylinders containing 800 parts per million
Approved indication: neonatal respiratory failure
Australian Medicines Handbook Appendix A

Nitric oxide has a physiological role in several systems of the body. One of its actions is to cause vasodilation. When it is administered as a gas it dilates the vessels in the lung. There is little effect on the systemic circulation as nitric oxide is inactivated when it binds to oxyhaemoglobin. This has led to the study of inhaled nitric oxide in conditions where there is pulmonary vasoconstriction.

Pulmonary hypertension can cause hypoxic respiratory failure in neonates. The pulmonary vascular resistance causes deoxygenated blood to be shunted from the right to the left heart through the foramen ovale. In severe cases extracorporeal membrane oxygenation is needed, but this procedure is very specialised and mortality remains high. If nitric oxide can reduce the pulmonary hypertension it could reduce the need for extracorporeal membrane oxygenation.

The Neonatal Inhaled Nitric Oxide Study (NINOS) involved 235 babies, of at least 34 weeks gestation, who needed ventilation for hypoxic respiratory failure. In about half the cases this resulted from meconium aspiration while 16–18% of the babies had persistent pulmonary hypertension of the newborn. There was a significantly greater improvement in the oxygenation of the babies randomised to receive nitric oxide. Extracorporeal membrane oxygenation was needed by 39% compared with 55% of a control group who received 100% oxygen.1

Another study randomised 58 full-term neonates with persistent pulmonary hypertension of the newborn, confirmed by echocardiography, to receive either nitric oxide or nitrogen. Extracorporeal membrane oxygenation was needed by 12 of the 30 babies given nitric oxide and by 20 of the 28 babies in the control group.2

The Clinical Inhaled Nitric Oxide Research Group studied 248 babies, born after 34 weeks gestation, who had clinical or echocardiographic evidence of pulmonary hypertension. Extracorporeal membrane oxygenation was needed by 38% of the babies given low-dose nitric oxide and 64% of the control group. The median duration of successful treatment was 44 hours.3

Nitric oxide should not be used if the baby is dependent on a right to left shunt. It should also not be stopped suddenly as the pulmonary artery pressure may rebound, reducing oxygenation.

A complication of ventilating patients with nitric oxide is the formation of methaemoglobin. As neonates have a limited amount of methaemoglobin reductase they need to be monitored to avoid methaemoglobinaemia. Some of the toxicity of nitric oxide may be the result of oxidation to nitrogen dioxide. Monitoring is needed to ensure that nitrogen dioxide concentrations are minimised.

Adverse events are common in sick neonates. Those reported in trials of nitric oxide include hypotension, haematuria, infection and atelectasis. Hypokalaemia and thrombocytopenia occur frequently.

While nitric oxide may spare babies from extracorporeal membrane oxygenation it does not improve their survival. In NINOS 14% of the nitric oxide group and 16% of the control group died.1 With low doses the mortality in the first 30 days of life was 7% with nitric oxide and 8% in the control group.3

A Cochrane review has evaluated the evidence for giving nitric oxide for respiratory failure in infants born at or near term. It found that nitric oxide improves oxygenation in approximately 50% of cases. A combined end point including extracorporeal membrane oxygenation and death was less frequent with treatment, but this was mainly accounted for by a reduced need for extracorporeal membrane oxygenation. Babies with diaphragmatic hernias did not benefit.4

Nitric oxide is only approved for babies over 34 weeks gestation. Trials in preterm babies have not shown a clear benefit and in this group nitric oxide has been described as a therapy in search of an indication.5

manufacturer provided only the product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).

References

  1. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336:597-604.
  2. Roberts JD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997;336:605-10.
  3. Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000;342:469-74.
  4. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD000399. DOI: 10.1002/14651858.CD000399.pub2.
  5. Finer NN. Inhaled nitric oxide for preterm infants: a therapy in search of an indication? The search continues [editorial]. J Pediatr 2005;146:301-3.