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Allen MC, Donohue P, Gilmore M, et al. Inhaled Nitric Oxide in Preterm Infants. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Oct. (Evidence Reports/Technology Assessments, No. 195.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Inhaled Nitric Oxide in Preterm Infants.

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5Future Research

Future studies on the efficacy of iNO therapy for preterm infants that require respiratory support should have strong conceptual frameworks that test hypotheses on the mechanism by which iNO therapy improves pulmonary or neurodevelopmental outcomes. Such research should measure biomarkers of this mechanism of action, beyond improvement in oxygenation and neuroimaging. Inhaled NO has been given to infants as prophylaxis to prevent the development of BPD, as rescue therapy for respiratory failure, and as treatment in those with evolving BPD. Future studies should postulate and test hypotheses concerning the role of iNO in improving outcomes for any of these conditions or groups of preterm infants.

Bronchopulmonary dysplasia at 36 weeks PMA and intraventricular hemorrhage, intraparenchymal hemorrhage, and periventricular leaukomalacia are useful intermediate variables and should be thought of in that context. Although neuroimaging of brain injury can monitor for safety, the more important outcomes for future RCTs are neurodevelopmental outcomes and function in childhood. Standardized tools that measure childhood quality of life and functional outcomes would assess the long term impact of iNO on health and development. Considerations of the frequency of pulmonary rehospitalization, chronic and episodic pulmonary medication, and missed school days would provide a broader context in which to view the efficacy of iNO. Studies should be powered to assess pulmonary, neurodevelopmental, and health outcomes at two to five years or more. Measuring such outcomes will require substantial investment by funders. What follows are considerations for future research.

Other Future Research Needs


  • RCTs must be adequately powered to assess the effect of iNO on subgroups of preterm infants, such as those of varying birth weight.
  • Special care must be taken if infants born at the limit of viability are included in randomized controlled trials. These infants do not yet have alveoli (gas exchange occurs through their terminal bronchioles) and their brains do not yet have gyri or sulci. They are most vulnerable to organ injury, which may be most evident on long term followup. Every effort must be taken to obtain pulmonary, neurodevelopmental and health followup for all infants in this category.
  • There may be a value to viewing the use of iNO in terms of postmenstrual age, which is a better measure of degree of maturation and takes into account both gestational age and chronologic age in developing preterm infants.


  • Since the goal is to support pulmonary and brain development in the NICU, courses of iNO given for weeks, not days, should be studied.
  • Mode of ventilation should be considered in randomization schemes for trials restricted to infants < 1500 grams, those at highest risk for death, BPD, and neurodevelopmental impairment, to adequately address the question concerning mode of delivery.
  • As many of the smallest preterm infants are managed with CPAP or high flow nasal cannula alone, without intubation, information concerning iNO delivery with these devices is needed.


  • Future RCTs should require neuroimaging by standardized protocols before trial enrollment, to detect the occurrence and progression of brain injury during iNO treatment.
  • Studies should be powered to assess long term neurodevelopmental, pulmonary, and other health outcomes.
  • Outcomes should focus on functional status and quality of life, as well as neurodevelopmental disabilities.
  • Studies are needed to provide information on resource utilization such as rehospitalizations, medications, physicians’ visits. Future focus should be on the real pulmonary problems of prolonged hospitalizations, use of supplemental oxygen, and pulmonary medications after NICU discharge, prevalence of reactive airway disease, and recurrent hospitalizations.
  • Consideration should be given to assess longer term childhood outcomes (e.g., pulmonary function tests, school performances).
  • Cost benefit analyses should be conducted with multicenter RCTs of iNO.


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