This document discusses inhaled nitric oxide (iNO) therapy in newborns. It describes how iNO causes potent and selective pulmonary vasodilation, improving oxygenation. iNO decreases pulmonary vascular resistance, reducing right-to-left shunting and improving ventilation-perfusion matching. The document reviews guidelines for iNO use in term infants with hypoxic respiratory failure, monitoring requirements, and different response patterns. It also discusses the use of iNO in preterm infants and clinical trials investigating its role in preventing bronchopulmonary dysplasia.

1. Inhaled Nitric Oxide (iNO)
in newborns
Dr Padmesh V
DM Neonatology

2. At birth
Vascular endothelium
Vasoactive products
Cardiopulmonary transition at birth.
Pulmonary
endothelial
NO

3. cGMP, cyclic guanosine monophosphate ; GTP, Guanosine triphosphate.
Calcium
efflux

5. • iNO therapy causes:
– Potent,
– Selective,
– Sustained
Improved Oxygenation
Pulmonary
Vasodilatation

6. • ACTIONS OF iNO:
• Decreases extrapulmonary right-to-left shunting by
reducing PVR,
• Decreases intrapulmonary shunting by redirecting
blood from poorly aerated or diseased lung regions
to better aerated distal air spaces (“microselective
effect”).

7. • Potential Beneficial Effects of Low-Dose iNO in Hypoxemic
Respiratory Failure:
• 1. Pulmonary vasodilation → decreased extrapulmonary
right-to-left shunting
• 2. Enhanced matching of alveolar ventilation with perfusion
 decreased intrapulmonary shunting
• 3. ↓ Inflammation (↓ lung neutrophil accumulation)
• 4. ↓ Vascular leak and lung edema

8. • Potential Beneficial Effects of Low-Dose iNO in Hypoxemic
Respiratory Failure:
• 5. Preservation of surfactant function
• 6. ↓ Oxidant injury (inhibition of lipid oxidation)
• 7. Diagnostic value: failure to respond to iNO  Rule out
anatomic cardiovascular or pulmonary disease.

9. • Guidelines for Use of Inhaled Nitric Oxide
Therapy:
• Patient profile: >= 34 weeks gestational age.
• When:
– In the first week of life ,
– Echocardiographic evidence of extrapulmonary right-
to-left shunting ,
– OI greater than 25 ,
– After effective lung recruitment.
• Starting dose: 20 ppm

10. • Guidelines for Use of Inhaled Nitric Oxide
Therapy:
• Duration of treatment: Typically less than 5 days.
• Discontinuation:
• FiO2 < 60% and PaO2 > 60 ,
• Without evidence of
– Rebound pulmonary hypertension
– Increase in FiO2 >15% after iNO withdrawal.
• ECMO availability: If used in a non-ECMO center,
arrangements should be in place to continue iNO
during transport.

11. • Guidelines for Use of Inhaled Nitric Oxide
Therapy: Monitoring :
• Methemoglobinemia:
• NO + Hb  Nitrosyl Hb  Oxidized to Methemoglobin
• Monitor percentage methemoglobin by co-oximetry
within 4 hours of starting iNO and at 24-hour intervals.

12. • Guidelines for Use of Inhaled Nitric Oxide
Therapy: Monitoring :
• Methemoglobinemia:
• Methemoglobinemia occurs after exposure to high
concentrations of iNO (80 ppm).
• Not reported at lower doses of iNO (< 20 ppm). However,
because methemoglobin reductase deficiency may occur
unpredictably, monitoring should be done.
• Methemoglobin: Should not exceed 5% to 7%.

13. • Guidelines for Use of Inhaled Nitric Oxide
Therapy: Monitoring :
• Other toxicities:
Nitric oxide + oxygen
Nitrogen dioxide (NO2)
Nitric acid
Pulmonary edema
Death Upper limit for NO2 –> 3ppm over 8 hours
and 5ppm over 15 minutes.

14. • 4 Patterns of response to iNO:
• Pattern 1 : Non-responders
• Pattern 2: Responders: Initial response, but no
sustained response.
• Pattern 3: Responders: Initial response + sustained
response + successfully weaned within 5 days.
• Pattern 4: Responders: Initial response, but
sustained dependence on iNO for weeks together.
Pediatrics 1996;98;706-713

15. • Ventilator Management
• Effects of iNO may be suboptimal when lung
volume is decreased in association with pulmonary
parenchymal disease.
• Recruitment of alveoli important for iNO to work.

16. • Effects of combined therapy with HFOV & iNO in
term newborns with PPHN:
HFOV
iNO
HFOV
+iNO

17. SPECIAL SITUATIONS

18. • ROLE OF INHALED NITRIC OXIDE IN NEWBORNS
WITH CONGENITAL DIAPHRAGMATIC HERNIA
• No difference in the combined endpoint of death and/or
ECMO use between iNO-treated and control infants.
• Most infants with CDH have transient improvement in
oxygenation with iNO, but this response is not sustained.

19. • ROLE OF INHALED NITRIC OXIDE IN NEWBORNS
WITH CONGENITAL DIAPHRAGMATIC HERNIA
• iNO therapy should not be routinely used in patients with
CDH; rather, its use should be limited to patients with:
– Suprasystemic PVR
– After establishing optimal lung inflation and
– After demonstrating adequate LV performance
• However, there is clearly a role for iNO therapy in the
treatment of late pulmonary hypertension (PH) in
patients with CDH.

20. • THE PREMATURE NEWBORN:
• In preterm infants, iNO can be used for:
– Acute treatment of severe PPHN (as in term infants),
– Management of chronic PH in evolving or established
BPD, and
– For prevention of BPD.

21. • THE PREMATURE NEWBORN:
• Effects of iNO in preterms may depend on:
– Timing,
– Dose, of therapy
– Duration,
– Nature of underlying disease.
• Low-dose iNO may be safe and effective in
reducing risk of death/BPD for infants with birth
weights >1000 g.
• Treatment between 7 and 14 days after birth
appears to be safe and effective in reducing BPD.

22. • THE PREMATURE NEWBORN:
• A consensus conference by NICHD:
• Insufficient data to support use of iNO therapy for
the prevention of BPD.

23. EVIDENCES / TRIALS

24. • THE PREMATURE NEWBORN:
• INNOVO trial:
• 108 premature infants with severe hypoxemic
respiratory failure were randomized to receive or
not receive iNO.
• Primary outcome: Death or severe disability at 1
year corrected age.
• No difference between the iNO and the control
group in the main outcome and no difference in
adverse events.

25. • THE PREMATURE NEWBORN:
• NO CLD trial:
• Prolonged inhaled nitric oxide therapy that is
initiated between 7 and 21 days of age in preterm
infants undergoing mechanical ventilation
– significantly improved survival without
bronchopulmonary dysplasia
– without short-term adverse effects.
• However, no long term benefits demonstrated.

26. • THE PREMATURE NEWBORN:
• Schreiber et al.
• 207 infants randomized to treatment with iNO or
placebo.
• Reduction in incidence of BPD and death by 24%
in iNO group.
• 47% decrease in the incidence of severe ICH and
periventricular leukomalacia (PVL)  improved
neurodevelopmental outcome on follow-up
examinations.

27. • Inhaled nitric oxide for respiratory failure in
preterm infants
• iNO does not appear to be effective as
rescue therapy for the very ill preterm infant.
• Early routine use of iNO in preterm infants with
respiratory disease does not prevent serious brain
injury or improve survival without BPD.
• Later use of iNO to prevent BPD could be effective,
but current 95% confidence intervals include no
effect; the effect size is likely small (RR 0.92) and
requires further study.

28. • Neonatal Inhaled Nitric Oxide Study (NINOS) trial:
(NICHD)
• 235 infants >34 weeks’ gestation with hypoxic
respiratory failure were randomized to:
–iNO 20-80 ppm with 91-96% FiO2 versus
–Standard ventilator management with 100%
oxygen.
• Primary end point was death or ECMO.

29. • Neonatal Inhaled Nitric Oxide Study (NINOS) trial:
(NICHD)
• There was 40% reduction in need for ECMO among babies
treated with iNO.
• However, mortality rate was not different in either
treatment arm.
• Follow-up of survivors at 2 years showed no difference in
neurodevelopmental outcome between treated and control
patients.

30. • Neonatal Inhaled Nitric Oxide Study (NINOS) trial:
(NICHD)
Initial dose in NINOS: 20 ppm
If improvement in PaO2< 20 torr.
Dose increased to 80 ppm
• Only 3 (6%) of 53 infants who had little response to 20 ppm
had an increase in PaO2 greater than 20 torr when treated
with 80 ppm iNO.
• At 80 ppm: Methemoglobinemia (> 7%) occurred 35% of
patients.

31. • Neonatal Inhaled Nitric Oxide Study (NINOS) trial:
(NICHD):
• iNO in CDH
• Immediate short-term improvements in oxygenation seen
in some treated infants may be of benefit in stabilizing
responding infants for transport and initiation of ECMO.
• Conclusion: For term and near-term infants with CDH and
hypoxemic respiratory failure unresponsive to conventional
therapy, inhaled NO therapy did not reduce the need for
ECMO or death.

32. • Nitric oxide for respiratory failure in infants
born at or near term:
Inhaled nitric oxide is effective at an initial
concentration of 20 ppm for term and near-
term infants with hypoxic respiratory failure
who do not have a diaphragmatic hernia.

33. THANK YOU!!!