Open Access Highly Accessed Study protocol

Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis

Lisa M Askie1*, Roberta A Ballard2, Gary Cutter3, Carlo Dani4, Diana Elbourne5, David Field6, Jean-Michel Hascoet7, Anna Maria Hibbs8, John P Kinsella9, Jean-Christophe Mercier10, Wade Rich11, Michael D Schreiber12, Pimol Srisuparp13, Nim V Subhedar14, Krisa P Van Meurs15, Merryn Voysey1, Keith Barrington17, Richard A Ehrenkranz16, Neil Finer11 and the Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration1

Author Affiliations

1 NHMRC Clinical Trials Centre, University of Sydney, Australia

2 University of California, San Francisco School of Medicine, San Francisco, USA

3 University of Alabama at Birmingham, School of Public Health, USA

4 Department of Surgical and Medical Critical Care, Section of Neonatology, Careggi University Hospital of Florence, Florence, Italy

5 London School of Hygiene and Tropical Medicine, London, UK

6 Department of Health Science, University of Leicester, Leicester, UK

7 Neonatology, Maternite Regionale Universitaire, Nancy, France

8 Case Western Reserve University and Rainbow Babies & Children's Hospital, Cleveland, USA

9 University of Colorado School of Medicine, Denver, USA

10 Reanimation Pediatrique Hospital, Paris, France

11 Division of Neonatology, University of California, San Diego, USA

12 University of Chicago, Chicago, USA

13 Division of Neonatology, Mahidol University, Bangkok, Thailand

14 Neonatal Unit, Liverpool Women's Hospital, UK

15 Stanford University School of Medicine, USA

16 Division of Neonatology, Centre Hospitalier Universitaire Ste-Justine, Montreal, Canada

17 Department of Pediatrics, Yale University School of Medicine, USA

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BMC Pediatrics 2010, 10:15  doi:10.1186/1471-2431-10-15

Published: 23 March 2010



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.


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.


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.