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Nitric Oxide - inhaled

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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.

Indications

  • Persistent Pulmonary Hypertension of the Newborn (PPHN) - proven clinically (i.e. 20% differential in pre/postductal saturations) or by point of care ultrasound/echocardiography

OR

  • 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 per hour.
  • 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 iNO.
  • If no response to iNO is found after 60 minutes, then the iNO may be discontinued with caution - see weaning flow diagram.

Weaning NO

"Rebound" pulmonary hypertension occurs when FiO2 must be increased by 0.20 or more to maintain saturations>95%, following an iNO wean. If this occurs, halt weaning or return to the previous therapeutic iNO dose.

Equipment

  • 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

Clinical pharmacology

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 thrombocytopenia or bleeding problem

Management of Nitric Oxide administration

Description

  • Colourless, odourless, toxic, nonflammable gas.
  • The cylinder has 6200 litres, 880 ppm in nitrogen.

Prescription

  • Charted and signed by registrar/NS-ANP on ventilator chart in ppm.
  • All changes in flow are signed by registrar/NS-ANP.
  • Treatment only initiated on Specialist's orders.

Administration

  • Set up circuit. A person familiar with circuit set up is called in if necessary. Turn on NOx Box or other Nitric Oxide Monitor. Zero the monitor.
  • Connect silicone tubing to box. The water trap and nafion tubing need to hang below the monitor to keep moisture away from the monitor.
  • Attach sampling line to cylinder.
  • Set up scavenging system as shown in nitric clinical guideline.
  • Hand bag baby while circuit is set up via ventilator and until NO levels are steady.
  • Doctor/NS-ANP is present and turns on NO flow (200ml per minute with a ventilator gas flow of 10L/min gives around 17 parts/million).
  • When reading on NOx Box of NO ppm is at prescribed level and stable, reconnect patient to ventilator.

Observation and documentation

  • Concentration of NO is adjusted and documented by Doctor/NS-ANP on ventilator chart in ppm.
  • Nursing staff must have Neonatal IV Drug Certification to nurse a baby receiving nitric oxide.
  • Ensure at the beginning of each shift the concentration of NO prescribed on the ventilator chart is consistent with the level showing on the NO monitor and sign as correct by the nurse.
  • NO and NO2 levels are monitored continuously and checked and documented on the ventilator chart in ppm hourly. Upper safety level of NO determined by medical staff for each individual baby.
  • If NO readout levels rise check that there is not a leak or loose fitting in ventilator circuit. (Ventilator pressures will be reduced and because there is less flow the NO levels rise).
  • If NO2 levels >1ppm notify Doctor/NS-ANP. NO2 levels should not exceed 3ppm in the circuit.
  • Methaemoglobin levels should not exceed 3%. If these exceed this, check the amount of iNO being delivered, and check that the sampling tubing is connected in the correct place.
  • NO monitor must be higher than the water trap and nafion drying tube to prevent water entering it and rendering it unusable.
  • Observe water trap on the monitor line and empty PRN. If this overfills water will run back to baby.
  • Monitor blood pressure continuously and document hourly.
  • Circuits are not changed routinely without discussion with Doctor/NS-ANP as baby will deteriorate rapidly if NO discontinued (due to very short half life of NO).
  • During a circuit change hand bag baby until NO and NO2 monitoring is stable (Doctor/NS-ANP present).
  • When baby is reintubated or hand bag cap ventilator end. DO NOT TURN VENTILATOR OFF AS THE NO AND NO2 LEVELS RISE IN THE TUBING.
  • Observe and monitor baby closely for signs of deterioration during any trial off NO (Consultant orders this to determine need for continuing NO administration).
  • The NO gauge is checked each shift for the amount left in the cylinder. When half empty inform Nurse Manager and a replacement cylinder is ordered.

Storage

  • Store at room temperature. Is guaranteed for 1 year by NZIG Special Gases.
  • Cylinders must always be stored chained onto provided NO trolley.
  • Check for leakage from cylinders using snoop liquid leak detector: - when regulators are attached to a new cylinder. - anytime cylinders are moved
  • A new cylinder should be ordered by NICU Nurse Manager when the cylinder is ½ empty. Full = 2000 psi.

References

  1. 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
  2. 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
  3. 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.
  4. Clinical response to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. Kinsella JP, Neish SR, Ivy DD et al. J Pediatr 1993; 123: 103-8.
  5. Inhaled nitric oxide: a selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn. Geggel RL. J Pediatr 1993; 123: 76-9.
  6. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Roberts JD, Polaner DM, Land P, Zapol WM. Lancet 1992; 340: 818-9.
  7. Low dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340: 819-20.
  8. National Women's Nitric Oxide Information Protocol Newborn Services Unit Review, 15 September 1996.

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Document Control

  • Date last published: 29 March 2018
  • Document type: Drug Dosage Guideline
  • Services responsible: ADHB Pharmacy, Neonatology
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years