POLICY STATEMENT

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PEDIATRICS Vol. 106 No. 2 August 2000, pp. 344-345

AMERICAN ACADEMY OF PEDIATRICS:
Use of Inhaled Nitric Oxide

Committee on Fetus and Newborn


    ABSTRACT
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Abstract
Recommendation
References

Approval of inhaled nitric oxide by the US Food and Drug Administration for hypoxic respiratory failure of the term and near-term newborn provides an important new therapy for this serious condition. This statement addresses the conditions under which inhaled nitric oxide should be administered to the neonate with hypoxic respiratory failure.

Hypoxic respiratory failure in neonates born at or near term may be caused by such conditions as primary persistent pulmonary hypertension, respiratory distress syndrome, aspiration syndromes, pneumonia or sepsis, and congenital diaphragmatic hernia. Conventional therapies, which have not been validated by randomized controlled trials, include administration of high concentrations of oxygen, hyperventilation, high-frequency ventilation, the induction of alkalosis, neuromuscular blockade, and sedation.1 Despite aggressive conventional therapy, neonatal respiratory failure was associated with a high rate of mortality before the development of extracorporeal membrane oxygenation (ECMO).2,3 Survival and short-term morbidity rates have been superior in term and near-term infants (>= 34 weeks' gestation) treated with ECMO compared with conventional therapy4; however, questions remain about the long-term safety of ECMO.

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator for which the mechanism of action involves guanylyl cyclase activation leading to production of cyclic guanosine monophosphate and subsequent smooth muscle relaxation.5-7 Although several studies have suggested that iNO improves oxygenation,8-14 the US Food and Drug Administration (FDA) evaluated 2 large randomized multicenter controlled trials of term and near-term neonates with hypoxic respiratory failure that demonstrated improved outcome with iNO therapy. The Neonatal Inhaled Nitric Oxide Study Group trial documented that iNO reduced the need for ECMO15 without increasing neurodevelopmental, behavioral, or medical abnormalities at 2 years of age.16 These results were strengthened by the Clinical Inhaled Nitric Oxide Research Group trial, in which iNO reduced the need for ECMO and the incidence of chronic lung disease.17 iNO was not effective for infants with congenital diaphragmatic hernia.18

The limited data to date on hypoxic preterm neonates suggest that low-dose iNO improves oxygenation but does not improve survival.14,19 Additional large randomized trials of iNO in premature neonates are required because they may experience more toxic effects than term and near-term infants.14,19,20

It is critical that infants with hypoxic respiratory failure in whom conventional ventilator therapy fails or is predicted to fail be cared for in institutions that have immediate availability of personnel, including physicians, nurses, and respiratory therapists, who are qualified to use multiple modes of ventilation and rescue therapies. Radiologic and laboratory support required to manage the broad range of needs of these infants is also essential.

iNO should be administered using FDA-approved devices that are capable of administering iNO in constant concentration ranges in parts per million or less throughout the respiratory cycle. Infants who receive iNO therapy should be monitored according to institutionally derived protocols designed to avoid the potential toxic effects associated with iNO administration. These effects include methemoglobinemia (secondary to excess nitric oxide concentrations), direct pulmonary injury (attributable to excess levels of nitrogen dioxide), and ambient air contamination.

In the trials of iNO therapy reported to date, the indication for use has been failure of ventilatory therapy. ECMO, a therapy of proven efficacy, usually is initiated if iNO therapy fails. Therefore, institutions that offer iNO therapy generally should have ECMO capability; if a center lacks ECMO capability, it should work in collaboration with an ECMO center to prospectively establish appropriate iNO failure criteria and mechanisms for the timely transfer of infants to the collaborating ECMO center. The diversity of geography, climate, and transport capabilities necessitates that the "timely transfer" be dictated by the location-specific transport limitations as well as the severity of the infant's illness. Because hypoxic respiratory failure is often rapidly progressive and abrupt discontinuation of iNO may lead to worsening oxygenation,21 the risk of delayed provision of ECMO must be considered carefully when determining the appropriate time of transfer.

Plans for the care and referral of these infants should incorporate the following recommendations.

    RECOMMENDATIONS
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Abstract
Recommendation
References

  1. Infants with progressive hypoxic respiratory failure should be cared for in centers with the expertise and experience to provide multiple modes of ventilatory support and rescue therapies or be transferred in a timely manner to such an institution.
  2. iNO therapy should be given using the indications, dosing, administration, and monitoring guidelines outlined on the product label (http://www.fda.gov). An echocardiogram to rule out congenital heart disease is recommended. Center-specific criteria for treatment failure should be developed to facilitate timely consideration of alternative therapies.
  3. iNO therapy should be directed by physicians qualified by education and experience in its use and offered only at centers that are qualified to provide multisystem support, generally including on-site ECMO capability.
  4. Generally, iNO should be initiated in centers with ECMO capability. If iNO is offered by a center without ECMO capability, for geographic or other compelling reasons, mutually acceptable treatment failure criteria and mechanisms for timely transfer of infants to a collaborating ECMO center should be established prospectively. Transfer must be accomplished without interruption of iNO therapy.
  5. Centers that provide iNO therapy should provide comprehensive long-term medical and neurodevelopmental follow-up.
  6. Centers that provide iNO therapy should establish prospective data collection for treatment time course, toxic effects, treatment failure, use of alternative therapies, and outcomes.
  7. Administration of iNO for indications other than those approved by the FDA or in other neonatal populations, including compassionate use, remains experimental. As such, iNO should be administered according to a formal protocol that has been approved by the FDA and the institutional review board and with informed parental consent.

COMMITTEE ON FETUS AND NEWBORN, 1999-2000
James A. Lemons, MD, Chairperson
Lillian R. Blackmon, MD
William P. Kanto, Jr, MD
Hugh M. MacDonald, MD
Carol A. Miller, MD
Warren Rosenfeld, MD
Craig T. Shoemaker, MD
Jane E. Stewart, MD
Michael E. Speer, MD

LIAISON REPRESENTATIVES
Michael F. Greene, MD
 American College of Obstetricians and Gynecologists
Patricia Johnson, RN, MS, NNP
  American Nurses Association, Association of Women's Health, Obstetric and Neonatal Nurses, National Association of Neonatal Nurses
Arne Ohlsson, MD
 Canadian Paediatric Society
Solomon Iyasu, MBBS, MPH
 Centers for Disease Control and Prevention
Linda L. Wright, MD
 National Institutes of Health

SECTION LIAISONS
Richard Molteni, MD
 Section on Perinatal Pediatrics
Jacob C. Langer, MD
 Section on Surgery

STAFF
James Couto, MA

    FOOTNOTES

The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

    ABBREVIATIONS

ECMO, extracorporeal membrane oxygenation; iNO, inhaled nitric oxide; FDA, US Food and Drug Administration.

    REFERENCES
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Abstract
Recommendation
References
  1. Walsh-Sukys MC, Tyson JE, Wright LL, Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000; 105:14-20 [Abstract/Free Full Text]
  2. Hageman JR, Adams MA, Gardner TH Persistent pulmonary hypertension of the newborn. Trends in incidence, diagnosis and management. Am J Dis Child. 1984; 138:592-595 [Abstract/Free Full Text]
  3. John E, Roberts V, Burnard ED Persistent pulmonary hypertension of the newborn treated with hyperventilation: clinical features and outcome. Aust Paedriatr J. 1988; 24:357-361
  4. UK Collaborative ECMO Trial Group UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75-82 [CrossRef][Medline]
  5. Ignarro IJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987; 84:9265-9269 [Abstract/Free Full Text]
  6. Palmer RM, Ferrige AG, Moncada S Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor. Nature. 1987; 327:524-526 [CrossRef][Medline]
  7. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction [published correction appears in Circulation. 1991;84:2212]. Circulation. 1991; 83:2038-2047 [Abstract/Free Full Text]
  8. Day RW, Lynch JM, White KS, Ward RM Acute response to inhaled nitric oxide in newborns in respiratory failure and pulmonary hypertension. Pediatrics. 1996; 98:698-705 [Abstract/Free Full Text]
  9. Barefield E, Karle VA, Phillips JB III, Carlo WA Inhaled nitric oxide in term infants with hypoxemic respiratory failure . J Pediatr. 1996; 129:279-286 [CrossRef][Medline]
  10. Roberts JD Jr, Fineman JR, Morin FC III, Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med. 1997; 336:605-610 [Abstract/Free Full Text]
  11. Kinsella JP, Truog WE, Walsh WF, 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 [CrossRef][Medline]
  12. Wessel DL, Adatia I, Van Marter LJ, et al. Improved oxygenation in a randomized trials of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics. 1997;100(5). Available at http://www.pediatrics.org/cgi/content/full/100/5/e7. Accessed May 3, 2000
  13. Davidson D, Barefield ES, Kattwinkel J, et al, and the INO/PPHN Study Group 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; 101:325-334 [Abstract/Free Full Text]
  14. The Franco-Belgium Collaborative NO Trial Group Early compared with delayed inhaled nitric oxide in moderately hypoxaemic neonates with respiratory failure: a randomized controlled trial. Lancet. 1999; 354:1066-1071 [CrossRef][Medline]
  15. Neonatal Inhaled Nitric Oxide Study Group (NINOS) Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336:597-604 [Abstract/Free Full Text]
  16. 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; 136:611-617 [CrossRef][Medline]
  17. Clark RH, Kueser TJ, Walker MW, Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000; 342:469-474 [Abstract/Free Full Text]
  18. Neonatal Inhaled Nitric Oxide Study Group (NINOS) Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99:838-845 [Abstract/Free Full Text]
  19. Kinsella JP, Walsh WF, Bose CL, Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomized controlled trial. Lancet. 1999; 354:1061-1065 [CrossRef][Medline]
  20. Van Meurs KP, Rhine WD, Asselin JM, Durand DJ Response of premature infants with severe respiratory failure to inhaled nitric oxide. Pediatr Pulmonol. 1997; 24:319-323 [CrossRef][Medline]
  21. Davidson D, Barefield ES, Kattwinkel J, Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics. 1999; 104:231-236 [Abstract/Free Full Text]
Pediatrics (ISSN 0031 4005). Copyright ©2000 by the American Academy of Pediatrics


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