Nitric Oxide

(USAN)

💊 Chemical information

Azote, monoxyde d’; Azoto oksidas; Azotu(II) tlenek; Kväveoxid; Mononitrogen Monoxide; Nitrogen Monoxide; Nitrogenii oxidum; Nitrogén-monoxid; OHM11771; Oxid dusnatý; Óxido nítrico; Typpioksidi.
NO = 30.01.
CAS — 10102-43-9.
ATC — R07AX01.
ATC Vet — QR07AX01.

Pharmacopoeias.

In Eur..

Ph. Eur. 6.2

(Nitric Oxide). A colourless gas that turns brown when exposed to air. At 20° and at a pressure of 101 kPa, 1 volume dissolves in about 21 volumes of water. Store compressed at a pressure not exceeding 2.5 MPa measured at 15° in suitable containers.

💊 Adverse Effects

Inhaled nitric oxide may lead to the development of methaemoglobinaemia, particularly at higher doses. Although it is a selective pulmonary vasodilator, systemic hypotension may occur. Abrupt withdrawal of therapy may lead to a deterioration in oxygenation and the development of rebound pulmonary hypertension. Nitrogen dioxide produced when nitric oxide combines with oxygen can cause acute lung injury; high concentrations of inhaled nitric oxide are directly irritant to the lungs.
Another possible adverse event is an increased risk of bleeding due to inhibition of platelet aggregation.2-5 Rebound pulmonary hypertension6 and deterioration in oxygenation7,8 have been reported in some children after stopping nitric oxide therapy. Severe systemic hypotension has also been reported9 after starting therapy in a neonate with severe left ventricular dysfunction. Pulmonary oedema has been associated with the use of nitric oxide in 2 patients with CREST syndrome, a form of systemic sclerosis.10 Motor neurone disease in a patient with alcoholism has been partly attributed11 to the use of nitric oxide for pulmonary hypertension.
1. Kinsella JP, Abman SH. Methaemoglobin during nitric oxide therapy with high-frequency ventilation. Lancet 1993; 342: 615.
2. Högman M, et al. Bleeding time prolongation and NO inhalation. Lancet 1993; 341: 1664–5
3. Joannidis M, et al. Inhaled nitric oxide. Lancet 1996; 348: 1448–9
4. Cheung P-Y, et al. Inhaled nitric oxide and inhibition of platelet aggregation in critically ill neonates. Lancet 1998; 351: 1181–2
5. George TN, et al. The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates. J Pediatr 1998; 132: 731–4
6. Miller OI, et al. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet 1995; 346: 51–2
7. Aly H, et al. Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed 1997; 76: F118–F122
8. Davidson D, et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999; 104: 231–6
9. Henrichsen T, et al. Inhaled nitric oxide can cause severe systemic hypotension. J Pediatr 1996; 129: 183
10. Preston IR, et al. Pulmonary edema caused by inhaled nitric oxide therapy in two patients with pulmonary hypertension associated with the CREST syndrome. Chest 2002; 121: 656–9
11. Tsai GE, Gastfriend DR. Nitric oxide-induced motor neuron disease in a patient with alcoholism. N Engl J Med 1995; 332: 1036.

💊 Precautions

Patients given inhaled nitric oxide should be monitored for methaemoglobinaemia and oxygenation. Inhaled nitric oxide and nitrogen dioxide levels should also be monitored. Treatment should not be stopped abruptly since rebound pulmonary hypertension and deterioration in oxygenation may occur. The exposure of workers to nitric oxide and nitrogen dioxide should be limited.
1. CSM/MCA. Inhaled nitric oxide. Current Problems 1996; 22: 8. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2015620& RevisionSelectionMethod=LatestReleased (accessed 02/06/08
2. Cuthbertson BH, et al. Use of inhaled nitric oxide in British intensive therapy units. Br J Anaesth 1997; 78: 696–700
3. Phillips ML, et al. Assessment of medical personnel exposure to nitrogen oxides during inhaled nitric oxide treatment of neonatal and pediatric patients. Pediatrics 1999; 104: 1095–1100.

💊 Pharmacokinetics

Nitric oxide is absorbed systemically after inhalation but is rapidly inactivated by reaction with haemoglobin to form methaemoglobin and nitrate; it has a half-life of only a few seconds. It is excreted mainly in the urine as nitrate.

💊 Uses and Administration

Nitric oxide is an endogenous chemical messenger that acts mainly by stimulating guanylate cyclase in smooth muscle to cause vasodilatation. It is also involved in platelet aggregation, neurotransmission, and the immune system, and possesses antimicrobial, antitumour, and antiviral activity. Endogenous nitric oxide is now recognised to be the same substance as endothelium-derived relaxing factor (EDRF). It is synthesised from L-arginine by the enzyme, nitric oxide synthase, of which three isoforms have been identified. Constitutive isoforms occur in endothelial cells (such as in vascular endothelium, platelets, and the heart) and neuronal cells (in some central and peripheral neurones). Small amounts of nitric oxide are regularly produced by these systems. In contrast, an inducible isoform producing larger amounts of nitric oxide is expressed only after activation by external stimuli such as infection or inflammation. This inducible nitric oxide synthase may be expressed in many cells, including macrophages and cells in vascular smooth muscle, the heart, gastrointestinal tract, and liver. Inhaled nitric oxide is a highly selective pulmonary vasodilator. It is used in the management of term and near-term neonates with hypoxic respiratory failure associated with pulmonary hypertension. It is also used as a diagnostic tool to test acute vasoreactivity in patients with pulmonary hypertension of various aetiologies, and is being studied in other bronchopulmonary disorders and in different age groups. In the management of hypoxic respiratory failure in neonates, nitric oxide is given by inhalation in a usual concentration of 20 ppm. Doses have been titrated above and below this concentration but due to the risk of methaemoglobinaemia, doses above 20 ppm are not generally recommended. The concentration should be reduced gradually before stopping treatment.
1. Hart CM. Nitric oxide in adult lung disease. Chest 1999; 115: 1407–17
2. Vallance P, Chan N. Endothelial function and nitric oxide: clinical relevance. Heart 2001; 85: 342–50
3. Ichinose F, et al. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation 2004; 109: 3106–11
4. Griffiths MJD, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005; 353: 2683–95.

Respiratory disorders.

Inhaled nitric oxide is a potent and highly selective pulmonary vasodilator used in the management of persistent pulmonary hypertension of the newborn (below) and other conditions leading to hypoxic respiratory failure in neonates. Nitric oxide has also been tried in acute respiratory distress syndrome (below), severe acute respiratory syndrome,1 respiratory failure,2 acute severe asthma,3 primary pulmonary hypertension4,5 including that in pregnancy,6,7 and in pulmonary hypertension associated with a wide range of conditions including chronic obstructive pulmonary disease,8 heart failure,9 postcardiac surgery,10-12 heart or lung transplantation,13 and highaltitude disorders.14
1. Chen L, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis 2004; 39: 1531–5
2. Dobyns EL, 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; 134: 406–12
3. Nakagawa TA, et al. Life-threatening status asthmaticus treated with inhaled nitric oxide. J Pediatr 2000; 137: 119–22
4. Kinsella JP, et al. Selective and sustained pulmonary vasodilation with inhalational nitric oxide therapy in a child with idiopathic pulmonary hypertension. J Pediatr 1993; 122: 803–6
5. Goldman AP, et al. Is it time to consider domiciliary nitric oxide? Lancet 1995; 345: 199–200
6. Lam GK, et al. Inhaled nitric oxide for primary pulmonary hypertension in pregnancy. Obstet Gynecol 2001; 98: 895–8
7. Decoene C, et al. Use of inhaled nitric oxide for emergency Cesarean section in a woman with unexpected primary pulmonary hypertension. Can J Anaesth 2001; 48: 584–7
8. Vonbank K, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax 2003; 58: 289–93
9. Matsumoto A, et al. Inhaled nitric oxide and exercise capacity in congestive heart failure. Lancet 1997; 349: 999–1000. Correction. ibid.; 350: 818
10. Haydar A, et al. Inhaled nitric oxide for postoperative pulmonary hypertension in patients with congenital heart defects. Lancet 1992; 340: 1545
11. Miller OI, et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet 2000; 356: 1464–9
12. Journois D, et al. Effects of inhaled nitric oxide administration on early postoperative mortality in patients operated for correction of atrioventricular canal defects. Chest 2005; 128: 3537–44
13. Rea RS, et al. Role of inhaled nitric oxide in adult heart or lung transplant recipients. Ann Pharmacother 2005; 39: 913–17
14. Scherrer U, et al. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 1996; 334: 624–9.
ACUTE RESPIRATORY DISTRESS SYNDROME. Although inhalation of nitric oxide has been reported to improve oxygenation in patients with acute respiratory distress syndrome, meta-analyses1,2 have failed to confirm any significant mortality benefit, and there is some evidence2 that nitric oxide increases the risk of renal dysfunction.
1. Sokol J, et al. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2003 (accessed 26/09/05)
2. Adhikari NKJ, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. Abridged version: BMJ 2007; 334: 779–82. Full version: http://www.bmj.com/cgi/reprint/334/7597/779 (accessed 31/07/08)
RESPIRATORY DISORDERS IN NEONATES. Inhaled nitric oxide is used in the management of hypoxic respiratory failure in term and near-term neonates.1-3 It has also been studied in premature neonates. Most studies have been in neonates with persistent pulmonary hypertension of the newborn, although varying definitions have been used. A systematic review4 of controlled studies in term and near-term neonates with hypoxic respiratory failure found that oxygenation was improved with inhaled nitric oxide, with a reduction in the need for extracorporeal membrane oxygenation, but no effect on mortality has been shown. A randomised trial5 also found no mortality benefit when nitric oxide was started early in the disease process, although progression was slowed. Neonates with congenital diaphragmatic hernia (CDH), however, have not been shown to benefit,6,7 and nitric oxide is not recommended in such patients,4 although the optimal treatment of this condition is controversial; one study8 suggested that inhaled nitric oxide may have a role in patients with CDH who develop late pulmonary hypertension. Another study9 suggested that the improvement in oxygenation may not be sustained, and that neonates with pulmonary hypoplasia and dysplasia are less sensitive to nitric oxide. The dose of nitric oxide found to be effective in most studies has been from 20 to 80 ppm. However, since nitric oxide is associated with dose-related toxicity, lower doses (1 to 2 ppm) have also been studied. One study10 found no significant difference between high and low doses, but another study11 found that low doses did not improve oxygenation and diminished the response to subsequent higher doses. Inhaled nitric oxide has also been reported to improve oxygenation in premature neonates with hypoxic respiratory failure, but its use is not yet established.12,13 A study14 in premature infants with respiratory distress syndrome suggested that the incidence of chronic lung disease and death was reduced by nitric oxide, and an open study15 in very premature infants who had already developed chronic lung disease also found an improvement in oxygenation with nitric oxide therapy. However, a systematic review16 found that use of rescue nitric oxide therapy in severely ill infants was ineffective, and that late use to prevent chronic lung disease also had no effect. There was some evidence that early routine use in mildly sick infants might improve outcomes, but further studies were needed to identify those infants who were most likely to benefit. There have been concerns that use of inhaled nitric oxide might adversely affect neurodevelopmental outcome more than conventional therapy particularly in premature infants, but followup studies have reported mixed results. Studies in term and nearterm infants,17-19 and in premature infants,20 have found that use of nitric oxide has no effect on neurodevelopment, but there have also been reports of poor neurodevelopmental outcome21 and of improved outcome.22,23 Differences in study design make comparisons between studies difficult, and the effect on neurodevelopment remains to be confirmed.
1. American Academy of Pediatrics Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000; 106: 344–5
2. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr 2000; 136: 717–26
3. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs 2001; 61: 27–39
4. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2006 (accessed 04/06/08)
5. Konduri GG, 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: 559–64
6. Clark RH, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000; 342: 469–74
7. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99: 838–45
8. Kinsella JP, et al. Noninvasive delivery of inhaled nitric oxide therapy for late pulmonary hypertension in newborn infants with congenital diaphragmatic hernia. J Pediatr 2003; 142: 397–401
9. Goldman AP, et al. Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 1996; 98: 706–13
10. Finer NN, et al. Randomized, prospective study of low-dose versus high-dose inhaled nitric oxide in the neonate with hypoxic respiratory failure. Pediatrics 2001; 108: 949–55
11. Cornfield DN, et al. Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension. Pediatrics 1999; 104: 1089–94
12. Subhedar N, Dewhurst C. Is nitric oxide effective in preterm infants? Arch Dis Child Fetal Neonatal Ed 2007; 92: F337–F341
13. Kinsella JP, Abman SH. Inhaled nitric oxide in the premature newborn. J Pediatr 2007; 151: 10–15
14. Schreiber MD, et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003; 349: 2099–2107
15. Clark PL, et al. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002; 86: F41–F45
16. Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2007 (accessed 04/06/08)
17. Rosenberg AA, et al. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr 1997; 131: 70–5
18. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the Neonatal Inhaled Nitric Oxide Study Group (NINOS). J Pediatr 2000; 136: 611–17
19. Konduri GG, et al. Neonatal Inhaled Nitric Oxide Study Group. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr 2007; 150: 235–40
20. Hintz SR, et al. NICHD Neonatal Research Network. Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide. J Pediatr 2007; 151: 16–22.
21. Cheung P-Y, et al. The outcome of very low birth weight neonates (≤1500g) rescued by inhaled nitric oxide: neurodevelopment in early childhood. J Pediatr 1998; 133: 735–9
22. Mestan KKL, et al. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005; 353: 23–32
23. Tanaka Y, et al. Inhaled nitric oxide therapy decreases the risk of cerebral palsy in preterm infants with persistent pulmonary hypertension of the newborn. Pediatrics 2007; 119: 1159–64.

Sickle-cell disease.

Sickle-cell crisis due to vaso-occlusion is an acute complication of sickle-cell disease, requiring hospitalisation, with the use of large volumes of intravenous fluids for dehydration, and analgesia including opioids for pain. Concentrations of nitric oxide metabolites and L-arginine have been found to be low in vaso-occlusive crisis and a study1 in paediatric patients showed that inhaled nitric oxide may be of benefit.
1. Weiner DL, et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 2003; 289: 1136–42.

💊 Preparations

Proprietary Preparations

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Published May 08, 2019.