Nitric Oxide Administration to the Term and Preterm Infant with Respiratory Failure

Last review: 21/03/2017  
Next review: 01/03/2020  
Clinical Guideline
ID: 222 
Approved By:  
Copyright© Leeds Teaching Hospitals NHS Trust 2017  


This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guideline for the Use of Inhaled Nitric Oxide


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Nitric Oxide (NO) is a naturally occurring vasodilator which is present in the vascular endothelium of all the tissues of the body. At a cellular level, it works by converting guanylyl cyclase to cyclic guanylate cyclase (cGMP) which in turn relaxes vascular smooth muscle. The half-life of NO is 3-6 seconds.  Inhaled Nitric Oxide (iNO) is a potent, selective pulmonary vasodilator and unlike systemically administered vasodilators, iNO permits improved oxygenation without accompanying systemic vasodilatation. NO is rapidly inactivated in the blood stream by binding with haemoglobin to produce methaemoglobin (MetHb).

iNO efficacy is improved by prior optimisation of an infant's clinical condition (pulmonary disease and ventilation, cardiac performance and systemic haemodynamics and physiology) and should only be considered as part of an overall clinical strategy. iNO must never be started without the involvement of the attending consultant.

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  • Term and near term babies (34 weeks and above gestation)

Hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension.

1.Hypoxemic respiratory failure:
Defined as impaired oxygenation with OI> 20 and PaO2 < 8kPa (60 mmHg) despite optimal ventilation, circulatory support and sedation

Oxygen Index (OI)=Mean airway pressure(cm of water)x FiO2(%)
                                                      PaO2(kPa)x 7.5

*Add 10 to the OI calculation if patient is already on iNO

2. Pulmonary hypertension:
ECHO- evidence of extra-pulmonary, right to left shunting at PDA or PFO level.  Clinical-difference between pre and post-ductal saturation of > 5 %,
Systemic hypoxemia defined as post-ductal PaO2 of < 8 kPa (60 mmHg).


  • Primary pulmonary hypertension
  • Secondary pulmonary hypertension resulting from:
    • Maladaptation after birth (commonest cause)
    • Meconium aspiration syndrome
    • Respiratory distress syndrome
    • Congenital diaphragmatic hernia
    • Lung hypoplasia
    • Pneumonia- Note this may cause hypoxemia without shunting

Need for iNO for more than 5 days should raise concern about nature of disease e.g. degree of hypoplasia, other rare causes such as pulmonary alveolar dysplasia etc

iNO reduces the need for extracorporeal membrane oxygenation (ECMO) but not death in term infants and infants 34 weeks and above gestational age1,2,3.

  • Preterm babies (less than 34 weeks gestation)

Rescue therapy in preterm babies who have failed to respond to surfactant and ventilation, who show clinical or echocardiographic evidence of pulmonary hypertension.

  • The use of iNO in the preterm population remains controversial. There is no supporting evidence of such practice. However in rare clinical situation (severe hypoxemic respiratory failure with ECHO evidence of pulmonary hypertension e.g. preterm infants with PPROM) where benefit is perceived to outweigh risks, a period of iNO can be tried.
  • iNO has not been consistently shown to be effective in reducing rates of chronic lung disease (CLD) or death, or survival without CLD in preterm infants with hypoxaemic respiratory failure. Sufficient data are lacking for evaluation of the possible effects of iNO on periventricular haemorrhage or on long-term neurodevelopmental outcome8.
  • iNO should not be used in infants who are 26 weeks corrected gestation or under.

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  • Coagulopathy or thrombocytopenia (iNO is an inhibitor of platelet function).
  • Congenital heart disease (iNO will increase pulmonary flow at the expense of systemic blood flow). Seek cardiology advice prior to starting iNO in patients with congenital heart disease.
  • NO combines with haemoglobin to form MetHb. MetHb levels should not exceed 2% as it cannot carry oxygen.

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Before Starting Nitric Oxide

  • Use of iNO should be discussed with the attending consultant.
  • Indications for starting iNO must be clearly documented in clinical notes.
  • Prescribe iNO on drug chart.
  • Ensure that an appropriately sized endotracheal tube is in place and there is minimal leak.
  • Record pre and post-ductal oxygen saturation (use post-ductal saturation to guide management).
  • Ideally to obtain baseline arterial PaO2 from post-ductal site (UAC or peripheral arterial line anywhere except right wrist).
  • Optimise ventilation as per clinical condition.
  • Optimise blood gas to keep pH > 7.25 (Link to neonatal metabolic acidosis guideline)
  • Optimise blood pressure. Assess cardiac dysfunction, ensure adequate circulating blood volume and correct poor contractility with inotropes.
  • Ensure adequate sedation and muscle relaxant.
  • Ideally an echocardiogram to confirm presence of pulmonary hypertension but this should not delay the start of iNO.

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Treatment / Management

  • Start iNO at 20 ppm4, 5. (maximum dose).
  • Refer to iNO set up guideline attached to NO delivery system. (appendix 1)
  • Check MetHb levels hourly for first 4 hours followed by once daily level. Normal MetHb levels is <2%. Reduce iNO by 5ppm if >2% and discuss with consultant. MetHb levels can be measured on the blood gas analyser on neonatal unit.
  • Monitor Nitrous Oxide (NO2) level. This is analysed and displayed on the iNO machine. High level is a very rare incidence. Refer to manufacturer manual. High levels can cause pulmonary oedema.
  • Review response of iNO.

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Reviewing Response

  • The expected response is rapid, occurring in less than 30-60 minutes with a post-ductal PaO2 increase ≥ 3kPa (22.5mmHg) / >20% from baseline while maintaining the desired pre-ductal saturation range with or without changes to ventilation strategy4,5,6,8.
  • If there is no response to treatment after 4 hours8, should consider stopping iNO. The reason not to prolong iNO therapy unnecessarily is that NO synthase is down-regulated, with suppression of endogenous NO production8.
  • Consider early referral to Extra membrane corporeal oxygenation therapy (ECMO) centre if no improvement in term/near term infants with:
    • Oxygen Index (OI) > 25

Oxygen Index (OI)=Mean airway pressure(cm of water)x FiO2(%)
                                                      PaO2(kPa)x 7.5

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Weaning iNO therapy will depend upon the clinical course of the infant. A period of 24-48hours of clinical stability whilst receiving iNO should be observed before weaning is attempted. Exogenous iNO administration can suppress endogenous Nitric Oxide. iNO should always be weaned cautiously in any babies requiring iNO for more than 4 hours.

  • Weaning from iNO should be considered when an infant shows clinical improvement and when the following conditions occur:
    • iNO treatment is ≤ 20 ppm; AND
    • FiO2 ≤ 60%; AND
    • PaO2 ≥ 8kPa (60mmHg); AND
    • SpO2 ≥ 90%
  • iNO should be weaned by 5ppm decrement 1-2 hourly down to 5ppm. After that, iNO should be weaned by 1ppm every hour down to 0ppm.
  • If deterioration in oxygenation within 30 minutes of reduction of iNO (defined as increment in FiO2 > 15% or reduction of post-ductal saturation > 3%), return to previous stable iNO dose. Recheck ventilation.

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Appendix 1

Using the NOxBOXi and NOxMixer

  • Ensure both cylinders are turned on with ample supply of nitric in each
  • Check the NOx flow sensor is placed on the humidifier with the green arrow pointing downwards ensuring the blue inspiratory tubing is placed on top using connector.
  • Ensure sample line is connected as near to the baby as possible using the connector (from green bag) on the blue inspiratory line.
  • Check the water trap is emptied regularly using the luerlock syringe (in green bag).
  • Once Nitric cylinder is empty please ring Equipment Pool on extension 23492 for replacement. Make sure Equipment Pool takes the empty cylinder.
  • All green grab bags are available on the ward.
  • Once stock is below 6 bags please contact the ward clerk for future orders.

Please note NOxBoxi technical guide accompanies the system.

Any problems contact suppliers on 01622 851415 (office hours)

Out of office hours contact:
Jacopo Pavesi on 07833 252122, or
Anthony Everard on 07725 955697, or
Mohammed Waqar on 07717 455296

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Record: 222

• To improve the management neonates requiring treatment of inhaled Nitric Oxide

• To provide evidence-based recommendations for management of pulmonary hypertension with inhaled Nitric Oxide
• To provide evidence-based recommendations for starting dose and weaning regime of inhaled Nitric Oxide
• To enhance the uniformity of practice of inhaled nitric oxide for treatment of pulmonary hypertension

Clinical condition:

Use of Inhaled Nitric Oxide in Neonates

Target patient group: Neonates at the Leeds Teaching Hospitals NHS Trust (LTHT)
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

  1. Clark RH et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. NEJM 2000;342:469-74.
  2. Field D et al. Neonatal ventilation with inhaled nitric oxide vs. ventilator support without inhaled nitric oxide for infants with severe respiratory failure born at or near term: the INNOVO multicentre randomised controlled trial. Neonatology 2007;91:73-82.
  3. Konduri GG et al. A randomised trial of early versus standard inhaled nitric oxide therapy in term and near term newborn infants with hypoxic respiratory failure. Pediatr 2004;113:559-64.
  4. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006;(4):CD000399.
  5. Konduri GG, Solimano A, Sokol GM, et al; Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 2004;113:559-64.
  6. The Neonatal Inhaled Nitric Oxide Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336:597-604
  7. Women’s and Children’s Clinical Programme Group Imperial College Healthcare NHS Trust. Division of Neonatology. Use of Nitric Oxide Clinical Guidelines. July 2009.
  8. Macrae DJ, Field D, Mercier JC et al. Inhaled nitric oxide therapy in neonates and children: reaching a European consensus. Intensive Care Medicine 2004;30:372-80.

Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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Document history

LHP version 1.0

Related information

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