Neonatal Hypoxic Respiratory Failure
Nitric oxide gas is used in conjunction with ventilatory support and other appropriate therapy to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) in term or near-term (exceeding 34 weeks' gestation) neonates with hypoxic respiratory failure and clinical or ECG evidence of pulmonary hypertension.1, 2, 3, 9, 26
Results from 2 randomized, double-blind, placebo-controlled trials in term or near-term neonates who had hypoxic respiratory failure with or without pulmonary hypertension indicate that inhaled nitric oxide gas (20 ppm mixed with either 100% oxygen or nitrogen) improved the arterial partial pressure of oxygen (PaO2) and decreased the need for ECMO at 303 or 120 days2 compared with ventilatory support and supplemental oxygen or nitrogen (placebo) gas alone.1, 2, 3, 4, 6, 12 In these neonates, hypoxic respiratory failure was caused by idiopathic persistent pulmonary hypertension of the newborn (PPHN) or other underlying conditions (e.g., meconium aspiration syndrome, pneumonia with or without sepsis, respiratory distress syndrome, pulmonary hypoplasia associated with congenital diaphragmatic hernia) and in many cases had not responded adequately to conventional therapy (e.g., vasodilators, IV fluids, bicarbonate therapy, mechanical ventilation).1, 2, 3 The need for ECMO was decreased from 55-57% with placebo or oxygen alone to 31-39% with inhaled nitric oxide.1, 12 In addition, improvement in hypoxemia (as measured by an increase in PaO2, a decrease in oxygenation index [mean airway pressure in cm of water × fraction of inspired oxygen concentration × 100/PaO2 in mm Hg], or in the alveolar-arterial oxygen gradient) was greater in neonates receiving inhaled nitric oxide.1, 2, 6 Nitric oxide therapy reduced the combined incidence of death and/or need for ECMO in these studies but had no effect on mortality alone.1, 2, 3 Long-term follow-up data from one of these clinical trials indicate that neurodevelopmental, behavioral, or medical abnormalities were not increased in patients receiving inhaled nitric oxide at 18-24 months of age.1, 6, 10
Similar beneficial effects (i.e., reduction in combined incidence of death and chronic lung disease) were observed in premature neonates† (less than 34 weeks' gestation) who were undergoing mechanical ventilation for respiratory distress syndrome in a randomized, double-blind, placebo-controlled study.14, 15 However, the manufacturer states that the drug currently is not indicated in this age group.1 Nitric oxide therapy also decreased the incidence of severe intraventricular hemorrhage and periventricular leukomalacia, the principal cause of serious, long-term disability in this patient population.14, 15
Available data suggest that inhaled nitric oxide is most effective in patients with severe persistent pulmonary hypertension who have minimal underlying parenchymal lung disease (idiopathic persistent pulmonary hypertension) and least effective in neonates with pulmonary hypoplasia (e.g., congenital diaphragmatic hernia).1, 3, 4, 5, 6, 7, 9, 12 In a large clinical trial, treatment failure (defined as no response to a dosage of 20 or 80 ppm of nitric oxide and/or an absolute decrease in oxygen saturation exceeding 10%) occurred in 34% of term or near-term neonates with respiratory failure and persistent pulmonary hypertension receiving nitric oxide (20 ppm).2
Prevention of Bronchopulmonary Dysplasia
Inhaled nitric oxide is not recommended for the prevention of bronchopulmonary dysplasia† in preterm neonates (34 weeks' gestational age or younger) requiring respiratory support; results of 4 multicenter, double-blind, placebo-controlled studies in a total of 2600 preterm infants failed to demonstrate evidence of efficacy of inhaled nitric oxide (administered at doses ranging from 5-20 ppm for treatment periods of 7-24 days) for this use.1, 26
Acute Respiratory Distress Syndrome
The manufacturers state that inhaled nitric oxide is not indicated for use in patients with acute respiratory distress syndrome (ARDS)†.1, 26 However, the drug has been used in adults and children with ARDS, generally as a rescue therapy for refractory hypoxemia.1, 17, 18, 20, 21
Treatment of ARDS is largely supportive with mechanical ventilation being the only proven intervention that reduces mortality.18, 25 Nitric oxide is a selective pulmonary vasodilator that may be used adjunctively to improve oxygenation; following inhalation, nitric oxide diffuses to and induces vasodilation in well-ventilated areas of the lung, thus improving the ventilation-perfusion mismatch that occurs in patients with ARDS.17, 18, 20, 22, 23, 24 The role of inhaled nitric oxide in the management of ARDS has been evaluated in multiple randomized controlled studies conducted in both adults and children.17, 19 These studies collectively demonstrated modest and temporary improvement in oxygenation, but no effect on mortality and possible harm (e.g., renal impairment).1, 17, 18, 19, 20, 21, 22 In a systematic review of 14 randomized controlled studies involving 1275 children and adults with ARDS or acute lung injury, treatment with inhaled nitric oxide was associated with transient improvement in oxygenation at 24 hours, but did not reduce mortality or have a beneficial effect on other clinical outcomes (e.g., ICU/hospital length of stay).17 Evidence from 4 of these studies indicated that inhaled nitric oxide increased the risk of renal impairment in adults.17
Based on the currently available evidence, routine use of inhaled nitric oxide is not recommended in patients with ARDS; however, some experts state that the drug may be considered in cases of severe hypoxemia not responsive to conventional ventilation strategies, provided certain precautions are observed.17, 19, 20, 22 Other exceptions for use include patients with documented pulmonary hypertension or severe right ventricular dysfunction.22, 23, 24 Because the risk of renal toxicity appears to be increased with higher concentrations and/or prolonged use of nitric oxide, the minimum effective concentration necessary to improve the ratio of PaO2 to fraction of inspired oxygen (PaO2/FiO2) should be used and the duration of exposure should be minimized.20
Inhaled nitric oxide should be used only under the supervision of a clinician experienced in the use, administration, and hazards of gas mixtures.1 Inhaled nitric oxide should be administered using a calibrated FDA-cleared nitric oxide delivery system.1, 26 The Genosyl® preparation must be used with the Genosyl® delivery system, which is designed to deliver a controlled level of nitric oxide mixed with air (breathing air or oxygen-enriched breathing air).26 The delivery system should include a backup battery power supply to ensure continuous administration during a power failure.1, 4, 26
Inspired nitrogen dioxide and partial pressure of arterial oxygen (PaO2) concentrations should be monitored during inhaled nitric oxide therapy.1, 2, 3, 9, 12, 26 Routine monitoring of methemoglobin also is recommended.1, 9, 12, 26 (See Methemoglobinemia and also see Elevated Nitrogen Dioxide under Warnings/Precautions: General Precautions, in Cautions.)
Abrupt discontinuance of inhaled nitric oxide therapy may result in worsening oxygenation and pulmonary artery pressures, and should be avoided.1, 26 (See Discontinuance of Therapy under Dosage and Administration: Dosage.)
Neonatal Hypoxic Respiratory Failure
The recommended inhalation dosage of nitric oxide gas in term or near-term neonates (those exceeding 34 weeks' gestation) with hypoxic respiratory failure associated with pulmonary hypertension is 20 ppm given continuously for up to for 14 days or until the underlying oxygen desaturation has resolved and the patient is ready to be weaned from therapy.1, 12, 26 Inhaled nitric oxide should be used in conjunction with mechanical ventilation and other supportive therapy to maximize oxygen delivery.1, 2, 3 In clinical trials, the safety and efficacy of inhaled nitric oxide were established in neonates with respiratory failure receiving conventional treatment, such as vasodilators (e.g., tolazoline, sodium nitroprusside),1, 2, 9 IV fluids for volume support,1, 2, 9 bicarbonate therapy for induction of alkalosis,1, 2, 3, 9 and mechanical ventilation.1, 2, 3 In neonates with collapsed alveoli, additional therapies to improve lung expansion have included pulmonary surfactant replacement and high-frequency oscillatory ventilation.1, 4, 5, 7, 9, 12
In several clinical trials, the median duration of treatment with inhaled nitric oxide ranged from 5-60 hours (i.e., generally less than 5 days);2, 3, 5, 9 however, therapy has been continued for up to 2 weeks in some studies.2 Following improvement in oxygenation with the initial dosage of nitric oxide, smaller maintenance dosages (5-6 ppm) have been used.1, 3, 5, 8 Higher than recommended dosages of nitric oxide (e.g., 40-80 ppm) generally have not provided additional benefit but have been associated with an increased incidence of adverse effects,1, 2, 4, 5, 9, 12 and the manufacturer states that dosages exceeding 20 ppm are not recommended.1, 12
Acute Respiratory Distress Syndrome
Various inhaled nitric oxide dosages in the range of 5-10 ppm have been used for the treatment of acute respiratory distress syndrome (ARDS)† in clinical studies in adults and pediatric patients; evidence suggests that concentrations less than 5 ppm are likely to improve oxygenation, while doses greater than 10 ppm may worsen the ratio of PaO2 to fraction of inspired oxygen (PaO2/FiO2).1, 18, 19, 20, 23, 24 In clinical studies, inhaled nitric oxide was given in fixed doses or titrated to response.17 Duration of therapy has ranged from less than 24 hours to 4 weeks (median of 7 days).1, 17
Nitric oxide therapy should not be discontinued abruptly since patients may experience rebound pulmonary hypertension with manifestations such as hypoxemia, oxygen desaturation, bradycardia, decreased cardiac output, and/or systemic hypotension.1, 4, 8, 11 Weaning and discontinuance of nitric oxide therapy generally have been performed in neonates who had adequate oxygenation (as measured by a PaO2 of greater than 50-60 mm Hg, an increase in PaO2 from baseline exceeding 20 mm Hg, oxygen saturation exceeding 92%, lack of appreciable oxygen gradient through the ductus arteriosus or foramen ovale, requirement for an FiO2 less than 0.60) and a mean airway pressure less than 10 cm of water.2, 3, 4, 8, 9, 11
The manufacturers recommend downward titration in several steps when discontinuing nitric oxide therapy, pausing several hours at each step to monitor for hypoxemia.1, 26 Several weaning regimens have been used in clinical studies conducted in neonates with hypoxic respiratory failure, including a stepwise dosage reduction in increments as little as 1 ppm.4, 8, 11 If clinical deterioration occurs during the weaning period, the nitric oxide dosage and/or FiO2 may be increased transiently.4, 5, 8, 9, 11 If deterioration occurs after discontinuance of nitric oxide therapy, such therapy may be reinstituted temporarily at the last dosage used.9
Inhaled nitric oxide is contraindicated in neonates dependent on extrapulmonary right-to-left shunting of blood (e.g., ductal-dependent congenital heart disease).1, 2, 3, 4, 26 (See Uses: Ductus Arteriosus-dependent Congenital Heart Disease, in Alprostadil 24:12.92.)
Abrupt Discontinuance of Therapy
Abrupt discontinuance of nitric oxide therapy can result in oxygen desaturation and a rebound increase in pulmonary artery pressure.1, 4, 12, 26 Hypoxemia and hypotension during acute withdrawal from the drug have been reported during postmarketing experience.1 To minimize this risk, patients should be weaned from therapy by gradually reducing dosage1, 2, 4, 8, 26 and should be monitored for evidence of deterioration during and after weaning.4, 8, 11 If rebound pulmonary hypertension occurs, inhaled nitric oxide therapy should be reinstituted immediately.1, 26 (See Discontinuance of Therapy under Dosage and Administration: Dosage.)
Inhaled nitric oxide rapidly combines with hemoglobin to form methemoglobin (a form that does not transport oxygen); this effect appears to be dose related and has been reported to occur at doses of 40 ppm or greater.1, 12, 17, 26 Careful monitoring for methemoglobinemia is therefore necessary.24 It can take 8 or more hours for steady-state methemoglobin concentrations to be attained.1, 26 Methemoglobinemia generally resolves within several hours following dosage reduction or discontinuance of the drug.1
Methemoglobin blood concentrations should be monitored within 4-8 hours of initiating inhaled nitric oxide and periodically1, 2, 3, 4, 5, 26 during treatment; dosage should be adjusted to optimize oxygenation.1, 4, 26 If methemoglobinemia does not resolve after adjustment of nitric oxide dosage or discontinuance of therapy, the patient may be treated with IV ascorbic acid, IV methylene blue, or blood transfusion as clinically appropriate.1, 16, 26
Nitrogen dioxide, which forms from the combination of oxygen and nitric oxide, can cause acute lung injury.1, 7, 13, 26 In a study evaluating exposure of intensive-care unit staff to nitrogen oxides during administration of nitric oxide therapy (20 ppm) to pediatric patients, exposures to nitrogen dioxide were below the ceiling limit of 5 ppm for the entire work shift, and below the 15-minute exposure of 1 ppm established by the Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH), respectively.13 OSHA has set an exposure limit of 5 ppm for nitrogen dioxide.1, 26
Inspired nitrogen dioxide concentrations should be monitored during inhaled nitric oxide therapy.1, 26 If there is an unexpected change in nitrogen dioxide concentration or if the concentration reaches 3 ppm (or 0.5 ppm if using the Genosyl® delivery system) when measured in the breathing circuit, the delivery system should be assessed and recalibrated according to the manufacturer's directions; dosage of inhaled nitric oxide and/or FiO2 should be adjusted as appropriate.1, 26
Inhaled nitric oxide can increase the risk of pulmonary edema, increased pulmonary capillary wedge pressure, worsening left ventricular dysfunction, systemic hypotension, bradycardia, and cardiac arrest in patients with preexisting left ventricular dysfunction.1, 26 If such effects occur, nitric oxide should be discontinued and symptomatic treatment provided.1, 26
The manufacturers state that efficacy and safety of inhaled nitric oxide have been established in term or near-term neonates with hypoxic respiratory failure and evidence of pulmonary hypertension; there is no information regarding use in other age groups.1, 12, 26 However, there is evidence from a randomized, double-blind, placebo-controlled study of beneficial effects in premature neonates (younger than 34 weeks' gestation) with respiratory distress syndrome who received inhaled nitric oxide therapy while undergoing mechanical ventilation.14, 15 There is also evidence from several randomized studies demonstrating potential use in children with acute respiratory distress syndrome (ARDS)†.17, 19, 22, 23, 24
Efficacy has not been established for the prevention of bronchopulmonary dysplasia in preterm neonates 34 weeks' gestational age or younger.1, 26
Adverse effects occurring in 5% or more of patients receiving nitric oxide include hypotension, withdrawal manifestations (e.g., increased pulmonary artery pressure, decreased partial pressure of arterial oxygen [PaO2]), increase in or return to right-to-left shunting of blood, atelectasis, hematuria, hyperglycemia, sepsis, infection, stridor, and cellulitis.1, 12, 26
The risk of methemoglobinemia may be increased when nitric oxide is used concomitantly with nitric oxide donor compounds (e.g., sodium nitroprusside, nitroglycerin, prilocaine).1, 26
Nitric oxide is a vasodilating agent.1, 8, 10 The drug is commercially available as a gas for inhalation in a mixture of nitric oxide (800 ppm) and nitrogen (INOmax®) and also is available as a drug-device combination (Genosyl®).1
Endogenous nitric oxide is produced by many cells of the body and relaxes smooth muscle by increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP), which lowers intracellular calcium concentrations and results in vasodilation.1, 8, 9 When inhaled as a gas, nitric oxide diffuses from the alveoli into vascular smooth muscle and causes selective pulmonary vasodilation.1, 8, 9, 12
Persistent pulmonary hypertension of the newborn (PPHN) is a developmental defect or acquired condition in which pulmonary vascular resistance is high, resulting in right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale and subsequent hypoxemia.1 Exogenously administered nitric oxide gas appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, thereby redistributing pulmonary blood flow away from regions with poor gas exchange (as indicated by ventilation/perfusion ratios) toward regions with better gas exchange.1, 4 When inhaled, nitric oxide is rapidly metabolized; thus, the inhaled drug does not affect systemic vascular resistance.1, 6, 8, 9, 10 The metabolic products of nitric oxide that reach systemic circulation are predominantly methemoglobin and nitrate.1 (See General Precautions: Methemoglobinemia, under Warnings/Precautions in Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | Gas | 800 ppm | Genosyl® | Vero Biotech |
1. INO Therapeutics. INOmax® (nitric oxide) gas for inhalation prescribing information. Bedminster, NJ; 2019 Feb.
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; 336:597-604. [PubMed 9036320]
3. Clark RH, Kueser TJ, Walker MW et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med . 2000; 342:469-74. [PubMed 10675427]
4. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr . 2000; 136:717-26. [PubMed 10839866]
5. Kinsella JP, Truog WE, Walsh WF et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr . 1997; 131:55-62. [PubMed 9255192]
6. Finer NN, Barrington KJ. Nitric oxide therapy for the newborn infant. Semin Perinatol . 2000; 24:54-65.
7. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs . 2001; 61:27-39. [PubMed 11217869]
8. Aly H, Sahni R, Wung JT. Weaning strategy with inhaled nitric oxide treatment of persistent pulmonary hypertension of the newborn. Arch Dis Child . 1997; 76:F118-22.
9. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics . 1997; 99:838-45. [PubMed 9190553]
10. 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; 136:611-7. [PubMed 10802492]
11. Davidson D, Barefield ES, Kattwinkel J et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics . 1999; 104:231-6. [PubMed 10429000]
12. INO Therapeutics, Clinton, NJ: Personal communication.
13. Phillips ML, Hall TA, Sekar K et al. Assessment of medical personnel exposure to nitrogen oxides during inhaled nitric oxide treatment of neonatal and pediatric patients. Pediatrics . 1999; 104:1095-100. [PubMed 10545553]
14. Schreiber MD, Gin-Mestan K, Marks JD et al. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med . 2003; 349:2099-107. [PubMed 14645637]
15. Martin RJ. Nitric oxide for preemies—not so fast. N Engl J Med . 2003; 349:2157-9. [PubMed 14645644]
16. Sinisterra S, Miravet E, Alfonso I et al. Methemoglobinemia in an infant receiving nitric oxide after the use of a eutectic mixture of local anesthetic. J Pediatr . 2002; 141:285-6. [PubMed 12183731]
17. Gebistorf F, Karam O, Wetterslev J et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev . 2016; :CD002787. [PubMed 27347773]
18. Alessandri F, Pugliese F, Ranieri VM. The Role of Rescue Therapies in the Treatment of Severe ARDS. Respir Care . 2018; 63:92-101. [PubMed 29066591]
19. Griffiths MJD, McAuley DF, Perkins GD et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res . 2019; 6:e000420. [PubMed 31258917]
20. Papazian L, Aubron C, Brochard L et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care . 2019; 9:69. [PubMed 31197492]
21. Cherian SV, Kumar A, Akasapu K et al. Salvage therapies for refractory hypoxemia in ARDS. Respir Med . 2018; 141:150-158. [PubMed 30053961]
22. Cheifetz IM. Pediatric ARDS. Respir Care . 2017; 62:718-731. [PubMed 28546374]
23. Tamburro RF, Kneyber MC, Pediatric Acute Lung Injury Consensus Conference Group. Pulmonary specific ancillary treatment for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med . 2015; 16(5 Suppl 1):S61-72. [PubMed 26035366]
24. Pipeling MR, Fan E. Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA . 2010; 304:2521-7. [PubMed 21139113]
25. Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA . 2018; 319:698-710. [PubMed 29466596]
26. Vero Biotech. Genosyl® (nitric oxide) for inhalation prescribing information. Atlanta, GA; 2019 Dec.