Skip to Content
A home for paediatricians. A voice for children and youth.

Practice point

CPS

Inhaled nitric oxide use in newborns

Posted: Feb 10, 2023

The Canadian Paediatric Society gives permission to print single copies of this document from our website. For permission to reprint or reproduce multiple copies, please see our copyright policy.

Principal author(s)

Souvik Mitra MD, Gabriel Altit MD; Canadian Paediatric Society, Fetus and Newborn Committee

Paediatr Child Health 2023 28(2): 119–122.

Abstract

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, is used as a therapeutic modality in infants with hypoxemic respiratory failure (HRF) associated with persistent pulmonary hypertension of the newborn (PPHN). iNO should ideally be initiated following echocardiographic confirmation of PPHN. Use of iNO is recommended in late preterm and term infants who develop HRF despite optimal oxygenation and ventilation strategies. However, routine iNO use in preterm infants on respiratory support is not recommended. iNO may be considered as a rescue modality in preterm infants with early-onset HRF when associated with prolonged rupture of membranes or oligohydramnios, or late-onset HRF in the context of bronchopulmonary dysplasia-associated pulmonary hypertension (PH) with severe right ventricular failure. A trial of iNO may also be considered for infants with congenital diaphragmatic hernia with persistent HRF despite optimal lung recruitment, and with echocardiographic evidence of supra-systemic PH and adequate left ventricular function.

Keywords: Hypoxemic respiratory failure; Inhaled nitric oxide; Newborn; Persistent pulmonary hypertension of the newborn.

Inhaled nitric oxide (iNO) is used as a therapeutic modality in infants with hypoxemic respiratory failure (HRF) associated with persistent high pulmonary vascular resistance and resultant right-to-left shunting of blood through the foramen ovale, ductus arteriosus and/or intrapulmonary channels, referred to as persistent pulmonary hypertension of the newborn (PPHN) [1] [3]. This practice point updates a previous CPS document published in 2012 [4].

Mechanism of action

Nitric oxide (NO) is produced endogenously from L-arginine by NO synthase. NO diffuses into vascular smooth muscle cells leading to vasodilation and improved ventilation/perfusion (V/Q) matching [5][6]. When administered, iNO is a selective pulmonary vasodilator in infants with HRF associated with pulmonary arterial hypertension.

Administration

iNO therapy using approved delivery systems should be initiated and supervised by experienced clinicians at tertiary neonatal intensive care units (NICUs) as well as other units providing critical care to newborns. Continuous iNO therapy can be initiated during neonatal transport by trained neonatal retrieval personnel.

Initiation and dosing

Recommendation: The diagnosis of PPHN should be established with echocardiography before initiating iNO if possible, or if not possible, echocardiography should certainly be obtained after iNO is initiated.

Initiation of iNO may be guided by oxygenation index (OI) (see discussion in “Indications for use” section). However, OI requires a value of partial pressure of oxygen (PaO2) by arterial sampling, which may not always be feasible. Recently, the oxygen saturation index (OSI), using oxygen saturation (SpO>2) by pulse oximetry, has been described as well correlated with OI in neonates with HRF, allowing for continuous monitoring without arterial sampling. Studies are needed to further outline the role of OSI in the initiation and titration of iNO [7], but this marker may be useful in resource-limited settings, such as during neonatal transport [8].

iNO should be initiated at 20 ppm in near-term and term infants [2][9]. The expected clinical response (improved oxygenation, cardio-respiratory stability), is rapid, occurring in <30 minutes [2][9]. If there is no clinical response, the iNO dose may be increased up to 40 ppm [2]. ­­If after 30 minutes there is no clinical response, iNO should be discontinued.

In very or extreme preterm infants, iNO may be initiated at 5 to 10 ppm and increased up to 20 ppm [10][11]. The concentration of NO2 (nitrogen dioxide) in the inspired mixture should be maintained below 0.5 ppm.

Weaning

Weaning protocols should be implemented as part of care bundles to reduce practice variation, costs, and unnecessary exposure [12],[13]. After clinical response iNO may be weaned by 50%, provided the OI remains at ≤10, pre-ductal SpO2 does not decrease by ≥5%, and/or FiO2 does not increase by ≥10% [4][14]. When a dose of  5 ppm has been reached, iNO may be decreased by steps of 1 ppm (every 30 minutes to 2 h) until discontinuation, provided the infant remains well oxygenated at <60% FiO2 [2][15]. Abrupt cessation of iNO should be avoided because  it may be followed by rebound severe hypoxemia [16]. If deterioration occurs during weaning or after treatment discontinuation, the dose should be increased to the prior level or iNO therapy should be re-started. When the infant has improved, weaning should be re-attempted based on clinical or echocardiographic evaluations (or both) [4].

Safety considerations

iNO has a short half-life of 2 to 6 seconds. No severe side effects have been reported at the starting dose of 20 ppm and up to 40 ppm. Potential toxicities include: NO2 (causing pulmonary cytotoxicity) and methemoglobin production (levels >2.5% may contribute to toxicity), decreased platelet aggregation, increased risk of bleeding, and surfactant dysfunction [2][17].

One Australian cohort study demonstrated that iNO was associated with a significantly higher risk of childhood cancer (aOR 4.3 (2.3 to 8.2)) [18]. However, confounding by indication cannot be ruled out, because infants receiving iNO were also sicker and substantially exposed to other potential carcinogenic agents, such as imaging radiation and prolonged oxygen therapy [18][19].

Indications for use

Use in late-preterm and term infants

Evidence from randomized controlled trials (RCTs) suggests that iNO use in near-term and term infants with HRF reduces the combined outcome of need for extracorporeal membrane oxygenation (ECMO) or death, but may not impact the rates of neurodevelopmental impairment (NDI) [15] (Table 1). Controversy exists regarding the degree of HRF severity at which to initiate iNO therapy. The incidence of death or ECMO appears to be strongly correlated with the OI at trial enrolment. Infants in the early RCTs, where iNO was initiated at a mean OI of >40, had a mortality or ECMO rate of >40%, while infants who received iNO at an OI of 15 to 20 had a mortality or ECMO rate of 10.2% [20].

Recommendation: Use of iNO is recommended in late preterm or term infants with HRF (OI >15 to 20 or PaO2 <100 mmHg in 100% oxygen) despite implementation of management strategies to optimize oxygenation and ventilation. Echocardiographic confirmation of normal left ventricular function and absence of congenital heart disease characterized by ductal-dependent systemic blood flow before initiating iNO are recommended.

Use in preterm infants born <35 weeks gestational age (GA)

Substantial practice variation has been documented with iNO use in preterm infants in Canada. A retrospective analysis of newborns <34 weeks admitted to NICUs participating in the Canadian Neonatal Network showed that 4% received iNO (831/19,525), with a variation in iNO use by centre ranging from 0% to 15.5% [21]. iNO has been considered in the following scenarios:

Early-onset acute HRF

RCT evidence suggests that iNO does not reduce death or bronchopulmonary dysplasia (BPD) when initiated as a therapeutic modality for early-onset (≤3 days of age) HRF, and may result in a small increase in severe intraventricular hemorrhage (IVH) [9] (Table 1). Routine iNO use in preterm infants does not reduce death or BPD, and has no impact on severe IVH or neurodevelopment [9]. A cohort study (n=7639) demonstrated that iNO in early HRF (maximal FiO2 >60% on day 1 or 3) in infants born <26 weeks GA or in extremely low birth weight (<1000 grams) infants did not reduce death or NDI [22]. Recent observational studies described an association between iNO use and improved survival without brain injury or NDI in extremely preterm infants who developed refractory HRF following exposure to prolonged rupture of membranes (PROM) [23][24]. A recent cohort study showed that early iNO treatment may slightly improve survival among extremely preterm neonates with pulmonary hypoplasia and PPHN (hazard ratio 0.67; 95% CI, 0.45 to 1.01) [25].

Recommendation: Routine iNO use in preterm infants on respiratory support is not recommended. iNO may be considered as a rescue modality in preterm infants with early-onset refractory HRF when associated with PROM or oligohydramnios.

Rescue iNO therapy for acute-onset HRF in infants with BPD

A small observational study (n=10) using cardiac catheterization showed that infants with BPD demonstrated reduction in pulmonary artery pressures and pulmonary-to-systemic vascular resistance ratio (PVR/SVR) when exposed to iNO [26]. Another small observational study (n=10) showed that exposure to iNO for 15 minutes improved echocardiographic markers of right ventricular (RV) function and PVR in extremely preterm infants with BPD-PH [27]. No RCTs have been conducted on iNO use in this specific population. During an acute PH crisis with RV failure, expert consensus from the American Heart Association and American Thoracic Society suggests use of iNO as a part of a multi-modal management strategy [28].

Recommendation: In preterm infants with HRF or severe RV failure in the context of BPD-PH, rescue therapy with iNO may be considered if other respiratory management strategies, such as optimized ventilator support or postnatal corticosteroids (or both), have failed to resolve the hypoxemic crisis or RV failure. When there is no clinical response following initiation of iNO, therapy should be promptly discontinued.

Use in congenital diaphragmatic hernia (CDH)

Despite lack of RCT evidence, infants with CDH are still exposed to iNO, with one study (n=3367) reporting an average of 62% iNO use per centre (range, 0% to 100%) [29]. In this study, 36% of infants without PH were treated with iNO and, adjusting for other clinically relevant variables, iNO use was associated with increased mortality [29]. A cohort of 131 infants with CDH (95 received iNO) demonstrated that iNO improved oxygenation and reduced ECMO need in the subpopulation with PH and normal left ventricular (LV) function [30].

Recommendation: In infants with CDH and HRF despite optimal lung recruitment and with echocardiographic evidence of supra-systemic PH and adequate LV function, a trial of iNO may be considered. In the absence of appreciable echocardiographic or clinical improvement, iNO therapy should be promptly discontinued.

Future research

Benefits and harms of iNO in extremely preterm infants with early acute and severe BPD-associated HRF need to be accurately quantified to develop strong recommendations for or against the increasing use of iNO for such conditions.

Summary of key recommendations

  1. The diagnosis of persistent pulmonary hypertension of the newborn should be established with echocardiography before initiating inhaled nitric oxide (iNO) if possible, or if not possible, echocardiography should certainly be obtained after iNO is initiated.
  2. Use of iNO is recommended in late preterm or term infants with hypoxemic respiratory failure (HRF) despite implementation of management strategies to optimize oxygenation and ventilation.
  3. Routine iNO use in preterm infants on respiratory support is not recommended. iNO may be considered as a rescue modality in preterm infants with early-onset refractory HRF when associated with prolonged rupture of membranes or oligohydramnios.
  4. In preterm infants with HRF or severe right ventricular (RV) failure in the context of bronchopulmonary dysplasia-pulmonary hypertension (BPD-PH), rescue therapy with iNO may be considered if other respiratory management strategies have failed to resolve the hypoxemic crisis or RV failure.
  5. In infants with congenital diaphragmatic hernia (CDH) and HRF despite optimal lung recruitment and with echocardiographic evidence of supra-systemic PH and adequate left ventricular (LV) function, a trial of iNO may be considered.

Table 1. Effect of iNO on clinical outcomes: Evidence from RCTs

Near-term or term infants with hypoxemic respiratory failure (HRF)

 

Outcomes

 

Number of participants (studies)

 

Relative risk (95% CI) and GRADE certainty of evidence

Death or use of ECMO

859 (8 RCTs)

RR 0.66

(0.57 to 0.77) (High)

ECMO before discharge

815 (7 RCTs)

RR 0.60

(0.50 to 0.71) (High)

NDI at 18 to 24 months among survivors

301 (2 RCTs)

RR 0.97

(0.66 to 1.44) (Low)

Near-term or term infants with congenital diaphragmatic hernia and HRF

Death or use of ECMO

84 (2 RCTs)

RR 1.09

(0.95 to 1.26) (Moderate)

ECMO before discharge

84 (2 RCTs)

RR 1.27

(1.00 to 1.62) (Moderate)

Preterm infants with early-onset acute HRF (<3 days)

Death before discharge

1066 (10 RCTs)

RR 1.02

(0.89 to 1.18) (High)

Death or BPD

958 (8 RCTs)

RR 0.94

(0.87 to 1.01) (High)

Severe IVH (grade 3 or 4)

773 (6 RCTs)

RR 1.20

(0.98 to 1.47) (High)

Preterm infants >3 days of age at risk for BPD

Death before discharge

1075 (3 RCTs)

RR 1.18

(0.81 to 1.71) [High]

Death or BPD

RR 0.92

(0.85 to 1.01) [High]

NDI

498 (2 RCTs)

RR 0.90

(0.74 to 1.09) [Moderate]

BPD (bronchopulmonary dysplasia); CI (confidence interval); ECMO (extracorporeal membrane oxygenation); GRADE (Grading of Recommendation, Assessment, Development, and Evaluation); iNO (inhaled nitric oxide); IVH (intraventricular hemorrhage); NDI (neurodevelopmental impairment); RCT (randomized controlled trial); RR (relative risk)

Acknowledgements

This practice point has been reviewed by the Community Paediatrics and Drug Therapy and Hazardous Substances Committees of the Canadian Paediatric Society.

CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE (2021-2022)

Members: Gabriel Altit MD, Nicole Anderson MD (Resident Member), Heidi Budden MD (Board Representative), Souvik Mitra MD, Michael R. Narvey MD (Chair), Eugene Ng MD, Nicole Radziminski MD

Liaisons: Eric Eichenwald MD (Committee on Fetus and Newborn, American Academy of Pediatrics), William Ehman MD (College of Family Physicians of Canada), Danica Hamilton RN (Canadian Association of Neonatal Nurses), Chloë Joynt MD (CPS Neonatal-Perinatal Medicine Section Executive), Chantal Nelson PhD (Public Health Agency of Canada)

Principal authors: Souvik Mitra MD, Gabriel Altit MD

References

  1. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalation nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340(8823):819–20.
  2. 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.
  3. Roberts JD, Fineman JR, Morin FC, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997;336(9):605–10.
  4. Peliowski A; Canadian Paediatric Society, Fetus and Newborn Committee. Inhaled nitric oxide use in newborns. Paediatr Child Health 2012;17(2):95-97.
  5. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;333(6174):664–66.
  6. Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA. 1994;91(16):7583–87.
  7. Muniraman HK, Song AY, Ramanathan R, et al. Evaluation of oxygen saturation index compared with oxygenation index in neonates with hypoxemic respiratory failure. JAMA Netw Open 2019;2(3):e191179.
  8. Garrido F, Gonzalez-Caballero JL, Lomax R, Dady I. The immediate efficacy of inhaled nitric oxide treatment in preterm infants with acute respiratory failure during neonatal transport. Acta Paediatr 2020;109(2):309–13.
  9. Konduri GG, Solimano A, Sokol GM, et al. 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(3 Pt 1):559–64.
  10. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2017;1(1):CD000509.
  11. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353(1):13–22.
  12. Ahearn J, Panda M, Carlisle H, Chaudhari T. Impact of inhaled nitric oxide stewardship programme in a neonatal intensive care unit. J Paediatr Child Health 2020;56(2):265–71.
  13. Elmekkawi A, More K, Shea J, et al. Impact of stewardship on inhaled nitric oxide utilization in a neonatal ICU. Hosp Pediatr 2016;6(10):607–15.
  14. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999;103(3):610–18.
  15. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017;1(1):CD000399.
  16. Davidson D, Barefield ES, Kattwinkel J, et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999;104(2 Pt 1):231–36.
  17. Yoshida K, Kasama K. Biotransformation of nitric oxide. Environ Health Perspect 1987;73:201–05.
  18. Dixon F, Ziegler DS, Bajuk B, et al. Treatment with nitric oxide in the neonatal intensive care unit is associated with increased risk of childhood cancer. Acta Paediatr 2018;107(12):2092–98.
  19. Lakshminrusimha S, Kinsella JP, et al. Just Say No to iNO in Preterms—Really? J Pediatr 2020;218:243–52.
  20. Sokol GM, Konduri GG, Van Meurs KP. Inhaled nitric oxide therapy for pulmonary disorders of the term and preterm infant. Semin Perinatol 2016;40(6):356–69.
  21. Soraisham AS, Harabor A, Shivananda S, et al. Trends and variations in the use of inhaled nitric oxide in preterm infants in Canadian neonatal intensive care units. Am J Perinatol 2016;33(7):715–22.
  22. Chandrasekharan P, Lakshminrusimha S, Chowdhury D, et al. Early hypoxic respiratory failure in extreme prematurity: Mortality and neurodevelopmental outcomes. Pediatrics 2020;146(4):e20193318.
  23. Baczynski M, Ginty S, Weisz D, et al. Outcomes of hypoxic respiratory failure at birth associated with previable rupture of membranes. J Perinatol 2018;38(8):1087–92.
  24. Chandrasekharan P, Kozielski R, Kumar VHS, et al. Early use of inhaled nitric oxide in preterm infants: Is there a rationale for selective approach? Am J Perinatol 2017;34(5):428–40.
  25. Ellsworth KR, Ellsworth MA, Weaver AL, Mara KC, Clark RH, Carey WA. Association of early inhaled nitric oxide with the survival of preterm neonates with pulmonary hypoplasia. JAMA Pediatr 2018;172(7):e180761.
  26. Mourani PM, Ivy DD, Gao D, Abman SH. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. Am J Respir Crit Care Med 2004;170(9):1006–13.
  27. Sehgal A, Blank D, Roberts CT, Menahem S, Hooper SB. Assessing pulmonary circulation in severe bronchopulmonary dysplasia using functional echocardiography. Physiol Rep 2021;9(1):e14690.
  28. Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation 2015;132(21):2037–99.
  29. Putnam LR, Tsao K, Morini F, et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr 2016;170(12):1188–94.
  30. Lawrence KM, Monos S, Adams S, et al. Inhaled nitric oxide is associated with improved oxygenation in a subpopulation of infants with congenital diaphragmatic hernia and pulmonary hypertension. J Pediatr 2020;219:167–72.

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.

Last updated: Feb 9, 2024

In this section

Related information

statements and practice points

Paediatrics & Child Health