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Published on: May 4, 2021
Inhaled nitric oxide in preterm infants: a systematic review and individual patient data meta-analysis
Lisa M Askie1, Roberta A Ballard, Gary Cutter
1NHMRC Clinical Trials Centre, University of Sydney, Australia. laskie@ctc.usyd.edu.au
Insights
Inhaled nitric oxide (iNO) shows potential to reduce death or chronic lung disease in preterm infants. Further analysis is needed to confirm benefits and identify patient characteristics influencing iNO effectiveness.
Area of Science:
- Neonatal Medicine
- Respiratory Medicine
- Clinical Trials
Background:
- Preterm infants on ventilation face risks of pulmonary and cerebral injury.
- Inhaled Nitric Oxide (iNO) is used for pulmonary hypertension and hypoxic respiratory failure in term infants.
- Previous studies on iNO in preterm infants show conflicting results regarding benefits for death or chronic lung disease (CLD).
Purpose of the Study:
- To confirm or refute conflicting results on iNO efficacy in preterm infants.
- To determine patient or treatment characteristics that predict benefit from iNO.
- To conduct an individual patient data meta-analysis for robust findings.
Main Methods:
- Individual patient data meta-analysis (MAPPiNO Collaboration).
- Inclusion of randomized controlled trials comparing iNO to control in ventilated preterm infants.
- Intention-to-treat analysis with log-binomial and linear fixed effects models.
Main Results:
- 13 trials (3567 infants) are eligible; 11 trials (3298 infants) are participating.
- Data analysis is anticipated to commence in late 2009.
- Results are expected to be publicly available in 2010.
Conclusions:
- The MAPPiNO collaboration aims to provide definitive evidence on iNO's role in preterm infants.
- Understanding factors influencing iNO response can optimize its clinical application.
- This meta-analysis will clarify iNO's benefit in reducing mortality and CLD.
Background:
Preterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants.
Methods/Design:
The Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification.
Discussion:
Thirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010.
