Arthur, a 16-month-old boy with a history of Trisomy 21 has been admitted to PICU following a repair of an Atrioventricular Septal Defect via a thoracotomy.
He underwent cardiac bypass for a total duration of 110 minutes and had an uncomplicated procedure with no residual septal defect and only mild regurgitation of the AV valves.
He is intubated, ventilated and sedated with three chest drains and temporary pacing wires in situ.
The receiving PICU consultant suggests arranging for inhaled nitric oxide (iNO) to be available in the bedspace.
What is iNO?
Inhaled Nitric oxide (iNO) is a short-acting selective pulmonary vasodilator used to reduce pulmonary vascular resistance.
It is usually produced by endothelial cells in the body and acts locally to alter pulmonary vascular tone. Its production can be affected by inflammation, exposure to cardiac bypass and by pulmonary vascular abnormalities.
How does it work?
Inhaled nitric oxide diffuses into the smooth muscle cells within the pulmonary vessels and into the bloodstream. It then increases cGMP within the cells causing smooth muscle relaxation.
It has a very short half-life in the range of seconds to minutes and is subsequently metabolised in the bloodstream by haemoglobin to nitrogen oxides. These are renally excreted within 48 hours.
When is it used?
Persistent Pulmonary Hypertension of the Newborn (PPHN)
Pulmonary vascular pressures can remain high after birth either idiopathically or due to conditions such as neonatal sepsis or meconium aspiration syndrome. Right-to-left shunting (usually via a patent foramen ovale or the ductus arteriosus) causes systemic desaturation which does not typically respond to increasing the inspired oxygen concentration.
iNO therapy improves oxygenation by reducing right-to-left shunting and reduces the need for extracorporeal membrane oxygenation (ECMO) support for term neonates with PPHN.
There is no clear benefit for preterm neonates.
Post-operative Pulmonary Hypertension
Cardiac bypass causes pulmonary endothelial dysfunction and a reduction in endogenous nitric oxide production.
Children who have cardiac lesions causing pulmonary over-circulation (i.e. left-to-right shunts) are at high risk of post-bypass pulmonary hypertension. Trisomy 21 appears to be associated with particularly high risk.
Pulmonary hypertensive crises occur with an acute rise in pulmonary vascular resistance that leads to ventricular failure, systemic hypotension and if not rapidly treated, cardiac arrest. In cases where the anatomy permits a right-to-left shunt, pulmonary hypertension may present as hypoxaemia with reduced end-tidal CO2 and more preservation of the cardiac output.
iNO can be used acutely to treat these pulmonary hypertensive crises, and there is also some evidence that routine administration for high-risk infants reduces the incidence of postoperative pulmonary hypertensive crises.
Refractory hypoxaemia in Paediatric Acute Respiratory Distress Syndrome (pARDS)
Secondary pulmonary hypertension can occur in pARDS due to changes within the pulmonary microvasculature.
iNO reduces ventilation-perfusion mismatch by causing vasodilation in areas of well aerated lung. Studies show improved oxygenation, but no overall mortality reduction.
Dosing
Doses of iNO ranging from 5 to 80 ppm have been studied; most patients show a response between 5 and 20 ppm. Doses of >40 ppm have little added benefit with a higher risk of developing toxicity.
Toxicity
When mixed with oxygen, NO is rapidly oxidised to Nitrogen Dioxide (NO2), an irritant which causes diffuse pulmonary inflammation and oedema. Inline NO2 monitoring should be used in all delivery systems, with audible high-level alarms set – see Delivery & Monitoring below.
On diffusing into the bloodstream, iNO reacts with the iron molecule in haemoglobin to form methaemoglobin (MetHb), which has less affinity for oxygen and so reduces oxygen carrying capacity. MetHb levels in the bloodstream are usually <1% and should be monitored on blood gases during iNO therapy to ensure they remain in the safe range of <5%.
Neonates are particularly susceptible to methaemoglobinemia. Elevated MetHb levels are usually reversed by reducing the iNO dose. If levels remain high and there is evidence of tissue hypoxia, Methylene Blue is the next line of management.
Delivery & Monitoring
Nitric Oxide is a colourless odourless gas delivered via the inspiratory limb of ventilator circuits. It can also be used during High Frequency Oscillatory Ventilation (HFOV). Non-invasive delivery is possible, but is not yet common practice.
It must be delivered using a designated system that can provide real-time in-line monitoring of Nitrogen Dioxide (NO2) by-production. High NO2 alarm limits should be set at 1ppm, alongside alarms for FiO2 and iNO intended dose ranges.
Due to the risk of rebound pulmonary hypertension on sudden discontinuation of iNO, the circuit should be prepared to allow the administration of iNO via a secondary breathing circuit, and a reserve supply should be easily accessible.
Nitric Oxide can also inhibit platelet aggregation and function, and so it is recommended that children receiving iNO have regular platelet count checks and monitoring for bleeding, including intracranial bleeding in high-risk infants(18).
Arthur remains ventilated overnight and continues to receive 20ppm iNO. He is maintaining his oxygen saturations with FiO2 0.6 and has not had any hypotensive episodes.
The following day he is felt to be stable enough to begin weaning the iNO.
You are instructed to maintain the FiO2 at 0.6 and reduce the iNO by 5ppm every six hours until the dose is 5ppm, then to reduce by 1ppm every few hours until off.
Weaning iNO therapy
Nitric oxide should be weaned gradually to avoid the phenomenon of rebound pulmonary hypertension. This is thought to occur due to downregulation of endogenous nitric oxide production during iNO therapy and delayed endothelial cell recovery.
Most clinical protocols recommend weaning FiO2 down to 0.6 prior to commencing any iNO weaning, then reducing the dose of iNO in reducing increments over a period of several hours while observing for increasing FiO2 requirements or deterioration in arterial oxygen concentrations. The length of treatment will depend on the underlying aetiology of the pulmonary hypertension. Patients with ongoing concerns about pulmonary hypertension may need to be transitioned to longer term treatments, such as sildenafil.
Key Summary Points
Inhaled nitric oxide is a short-acting selective pulmonary vasodilator that causes minimal systemic hypotension.
The largest evidence base exists for its use in PPHN, but it is also commonly used to manage pulmonary hypertension post cardiac bypass and in pARDS.
Effective dosing is generally between 5-20 ppm.
iNO should be delivered by a circuit with real time monitoring of iNO dose, FiO2 delivery and NO2 production.
Methaemoglobinemia (MetHb >5%) is a rare side effect of iNO therapy and can be treated with reducing the iNO dose, then with Methylene Blue.
iNO should be weaned slowly, while monitoring for rebound pulmonary hypertension which can be significant and severe.
About PICSTAR
PICSTAR is a trainee-led research network open to all doctors, nurses and allied health trainees within Paediatric Intensive Care. We are the trainee arm of the Paediatric Critical Care Society – Study Group (PCCS-SG) and work with them on research, audit and service evaluation.
If you would like to join PICSTAR and get involved in projects, have ideas you would like to propose or get advice/mentorship via PCCS-SG, don’t hesitate to contact us at picstar.network@gmail.com. See their website for more: https://pccsociety.uk/research/picstar/
References
1. Williams DLH. A chemist’s view of the nitric oxide story. Org Biomol Chem. 2003;(1):441–119.
2. Ichinose F, Roberts JD, Zapol WM. Inhaled Nitric Oxide. Circulation. 2004 Jun 29;109(25):3106–11.
3. Roberts Jesse D., Fineman Jeffrey R., Morin Frederick C., Shaul Philip W., Rimar Stephen, Schreiber Michael D., et al. Inhaled Nitric Oxide and Persistent Pulmonary Hypertension of the Newborn. N Engl J Med. 1997;336(9):605–10.
4. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. The Lancet. 1992 Oct 3;340(8823):819–20.
5. 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(9):597–604.
6. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev [Internet]. 2017 [cited 2024 Apr 19];(1). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD000399.pub3/full
7. Schulze-Neick I, Li J, Penny DJ, Redington AN. Pulmonary vascular resistance after cardiopulmonary bypass in infants: Effect on postoperative recovery. J Thorac Cardiovasc Surg. 2001 Jun 1;121(6):1033–9.
8. Roberts JD, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation. 1993 Feb;87(2):447–53.
9. Miller OI, Tang SF, Keech A, Pigott NB, Beller E, Celermajer DS. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. The Lancet. 2000 Oct 28;356(9240):1464–9.
10. Moloney ED, Evans TW. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome. Eur Respir J. 2003 Apr 1;21(4):720–7.
11. Dobyns EL, Cornfield DN, Anas NG, Fortenberry JD, Tasker RC, Lynch A, et al. Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure. J Pediatr. 1999 Apr;134(4):406–12.
12. Kinsella JP, Abman SH. Inhaled nitric oxide therapy in children. Paediatr Respir Rev. 2005 Sep 1;6(3):190–8.
13. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R, et al. Inhaled Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, Dose-Response, Multicenter Study. Pediatrics. 1998 Mar 1;101(3):325–34.
14. Weinberger B, Laskin DL, Heck DE, Laskin JD. The Toxicology of Inhaled Nitric Oxide. Toxicol Sci. 2001 Jan 1;59(1):5–16.
15. RCEM Learning Methaemoglobinaemia Reference [Internet]. RCEMLearning. [cited 2024 Jul 11]. Available from: https://www.rcemlearning.co.uk/reference/methaemoglobinaemia/
16. Bernasconi A, Beghetti M. Inhaled nitric oxide applications in paediatric practice. Images Paediatr Cardiol. 2002;4(1):4–29.
17. INOmax | European Medicines Agency (EMA) [Internet]. 2008 [cited 2024 Aug 1]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/inomax
18. Cheung PY, Salas E, Schulz R, Radomski MW. Nitric oxide and platelet function: implications for neonatology. Semin Perinatol. 1997 Oct;21(5):409–17.
19. Abernethy C. NHS Greater Glasgow and Clyde Guidelines – Nitric oxide therapy in the neonate: guideline for the use of inhaled nitric oxide [Internet]. NHSGGC; 2024 [cited 2024 Jul 11]. Available from: https://www.clinicalguidelines.scot.nhs.uk/nhsggc-guidelines/nhsggc-guidelines/neonatology/nitric-oxide-therapy-in-the-neonate-guideline-for-the-use-of-inhaled-nitric-oxide/
20. Westrope C, Hall L, Iqbal A. Indications and Use of Inhaled Nitric Oxide (iNO) [Internet]. Leicester Children’s Hospital; 2022 [cited 2024 Jul 11]. Available from: https://secure.library.leicestershospitals.nhs.uk/PAGL/Shared%20Documents/Inhaled%20Nitric%20Oxide%20(iNO)%20UHL%20Childrens%20Intensive%20Care%20Guideline.pdf
21. Moore L, Gasparini R, Newborn Services Clinical Practice Committee. Nitric Oxide [Internet]. Starship Children’s Hospital; 2021 [cited 2024 Jul 11]. Available from: https://starship.org.nz/guidelines/nitric-oxide/
