INHALED NITRIC OXIDE
Nitric Oxide, iNO
Reviewed by Clinical Practice Committee
Nitric oxide (iNO) is a potent vasodilator used to treat pulmonary
hypertension. It is a gas that is given into the ventilator circuit; it is
inactivated instantly in blood, by reacting with haemoglobin. Therefore, it
produces rapid and localized effects on the pulmonary vasculature but no action
on the systemic vasculature or systemic blood pressure.
- Persistent Pulmonary Hypertension of the Newborn (PPHN)- proven
clinically (i.e. 20% differential in pre/postductal saturations) or by point
of care ultrasound/Echocardiography
- Severe respiratory failure (i.e. oxygenation index>25, PaO2 <60 mmHg
despite 100% FiO2)
Contraindications and Precautions
- Cyanotic congenital heart disease, i.e. systemic perfusion dependent on
right-to-left shunting. An echocardiogram is not always needed before
starting iNO, but in many cases congenital heart disease needs to be
eliminated soon after. Total or Partial Anomalous Pulmonary Venous Drainage
is difficult to diagnose and should be considered in pure Right to Left
shunting at the Ductus and PFO. It is also wise to check for Coarctation and
abnormal heart structure.
- Caution in preterm infants. Benefit has not been proven by randomised
studies but may be indicated in case-by-case basis.
- Caution if known or suspected major haemorrhage (ICH, GI, pulmonary).
Risk of platelet dysfunction secondary to iNO.
- Caution if Congenital Diaphragmatic Hernia as there is limited evidence
to support use. It should not be started routinely however, should be tried
if there is difficulty maintaining preductal saturations ≥85%, an Oxygen
Index >20 or pre-post ductal saturation difference >10%.
Dose and Administration
- Start on 20 ppm. Doses above 20 ppm are not indicated as there would be
little if any additional benefit plus risk of toxicity increases.
- Evaluate for response to treatment in 30-60 minutes. Examples of
complete (and partial) responses to iNO include:
- Increase in PaO2 > 20 mmHg (or 10-20)
- Increase in saturations >10% (or 5-10%)
- Ability to wean FiO2 by 0.2 (or 0.05-0.2)
Weaning iNO and FiO2
There is little evidence to guide the best method of weaning iNO. If a
positive response is seen after iNO initiation, then iNO dose should continue at
20 ppm while the bedside nurse weans FiO2.
- Goal saturations are ≥95%. (In Congenital Diaphragmatic Hernia the
target saturations may be lower when initiating weaning of iNO.)
- Weaning FiO2 should be gradual with a maximum wean rate of ~0.10 FiO2
- Weaning iNO occurs step-wise every 1-2 hours.
- If, after 4-6 hours of iNO, the FiO2 is down to 0.60, then begin to wean
- If no response to iNO is found after 60 minutes, then the iNO may be
discontinued with caution – see weaning flow diagram.
“Rebound” pulmonary hypertension occurs when FiO2 must be increased by 0.20
or more to maintain sSaturations>95%, following an iNO wean. If this occurs,
halt weaning or return to the previous therapeutic iNO dose.
- Cylinder has 880 parts per million (ppm) in nitrogen
- Add to ventilator circuit between humidifier and baby.
- Click here to open the nitric oxide calculator
- 100 ml/min added to 10 litres/min ventilator gas flow = 8.7 ppm
- 200 ml/min added to 10 litres/min ventilator gas flow = 17.4 ppm
Nitric oxide is endothelial derived
relaxing factor (EDRF). It is produced in the endothelium of blood vessels and
diffuses out of the cells. It then enters vascular smooth muscle cells and
activates guanalate cyclase which forms cyclic guanosine monophosphate (cGMP).
This is a smooth muscle relaxer. cGMP is inactivated by cGMP phosphodiesterase.
The half life of NO is 3-6 seconds.
iNO is bound to haemoglobin and
inactivated to nitosylhaemoglobins and methaemoglobin.
Possible Adverse Effects
- Methaemoglobinaemia when nitric combines with haemoglobin to form
methaemoglobin. At clinically used doses (i.e. 20 ppm or less), high
methaemoglobin levels have not been reported. In overdose, it may be fatal.
If methaemoglobinaemia (>5%) occurs, check the ventilator circuit,
particularly the delivery and measuring points of iNO.
- iNO is a free radical and causes tissue damage. iNO is used by
macrophages to kill bacteria. It can theoretically damage the lung through
lipid peroxidation. The precise importance of this has not been elucidated.
Biproducts called peroxynitrates can be toxic to tissue.
- iNO converts to nitrogen dioxide NO2 spontaneously when mixed with
oxygen. High concentration of iNO in O2 lasts 6 seconds! At clinical doses
(<20 ppm), the half-life is much longer. NO2 is toxic.
- iNO is an inhibitor of platelet function. Caution when
or bleeding problem
Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory
failure in preterm infants. Cochrane Database of Systematic Reviews 2017, Issue
1. Art. No.: CD000509. DOI: 10.1002/14651858.CD000509.pub5
Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory
failure in infants born at or near term. Cochrane Database of Systematic Reviews
2017, Issue 1. Art. No.: CD000399. DOI: 10.1002/14651858.CD000399.pub3
Baczynski M, Ginty S, Weisz DE, et al. Short-term and long-term outcomes of
preterm neonates with acute severe pulmonary hypertension following rescue
treatment with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed
2017;102:F508-F514. Doi:10.1136/ archdischild-2016-312409.