Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide

Received 13 July 2009; received in revised form 2 September 2009; accepted 14 October 2009. published online 08 February 2010.
Corrected Proof

Objective

In a randomized multi-center trial, we demonstrated that inhaled nitric oxide begun between 7 and 21 days and given for 24 days significantly increased survival without bronchopulmonary dysplasia (BPD) in ventilated premature infants weighing <1250 g. Because some preventative BPD treatments are associated with neurodevelopmental impairment, we designed a follow-up study to assess the safety of nitric oxide.

Study design

Our hypothesis was that inhaled nitric oxide would not increase neurodevelopmental impairment compared with placebo. We prospectively evaluated neurodevelopmental and growth outcomes at 24 months postmenstrual age in 477 of 535 surviving infants (89%) enrolled in the trial.

Results

In the treated group, 109 of 243 children (45%) had neurodevelopmental impairment (moderate or severe cerebral palsy, bilateral blindness, bilateral hearing loss, or score <70 on the Bayley Scales II), compared with 114 of 234 (49%) in the placebo group (relative risk, 0.92; 95% CI, 0.75-1.12; P = .39). No differences on any subcomponent of neurodevelopmental impairment or growth variables were found between inhaled nitric oxide or placebo.

Conclusions

Inhaled nitric oxide improved survival free of BPD, with no adverse neurodevelopmental effects at 2 years of age.

BPD, Bronchopulmonary dysplasia, NO CLD, Nitric Oxide for Chronic Lung Disease, NDI, Neurodevelopmental impairment

a Case Western Reserve University, Cleveland, OH

b Harvard Medical School, Boston, MA

c University of California at San Francisco, San Francisco, CA

d The Children's Hospital of Philadelphia, Philadelphia, PA

e National Children's Medical Center, Washington, DC

f University of Missouri-Kansas City, Kansas City, MO

Reprint requests: Michele C. Walsh, MD, MSE, Rainbow Babies & Children's Hospital, Case Medical Center, MS 6010, 11100 Euclid Ave, Cleveland, OH 44106-6010.

Supported by grants (U01-HL62514, P50-HL56401, P30- HD26979, MRDDRC-P30, and HD26979) from the National Institutes of Health and grants (M01-RR00240, M01-RR00084, M01-RR00425, M01-RR001271, M01-RR00064, and M01-RR00080) from the General Clinical Research Centers Program. Inhaled nitric oxide and the delivery system for the initial trial and support for completion and analysis of follow-up data were provided by INO Therapeutics (now IKARIA). The company was not involved in study design, safety monitoring, data analysis, data interpretation, or manuscript preparation. A.H. was supported by a Career Development award (NICHD K23 HD056299). R.B. received unrestricted grant support for additional biostatistical analyses of the trial from iNO Therapeutics (now IKARIA). M.W. received support from iNO Therapeutics to fund the research nurse coordinator for follow-up of this trial. The authors declare no other conflicts of interest. Registered at ClinicalTrials.gov (NCT00000548).

∗ Additional members of the NO CLD Study Group are available at www.jpeds.com (Appendix).

PII: S0022-3476(09)01025-7

doi:10.1016/j.jpeds.2009.10.011