Inhaled Nitric Oxide For Respiratory Failure in Preterm Infants

Cochrane Review Update
Neonatology 2012;102:251253 DOI: 10.1159/000338552

Published online: August 15, 2012
Inhaled Nitric Oxide for Respiratory Failure in Preterm Infants
Cochrane Abstract
Background: Inhaled nitric oxide (iNO) is effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure and the potential risks of iNO differ substantially in preterm infants, necessitating study in this population. Objectives: To determine the effect of treatment with iNO on death, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and neurodevelopmental disability in preterm newborn infants with respiratory disease. Search Methods: Standard methods of the Cochrane Neonatal Review Group were used. MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (The Cochrane Library) were searched covering the years from 1985 to 2010. In addition, the abstracts of the Pediatric Academic Societies were also searched. Selection Criteria: Randomized and quasi-randomized studies in preterm infants with respiratory disease that compared the effects of iNO gas to control, with or without placebo were eligible. Data Collection and Analysis: Standard methods of the Cochrane Neonatal Review Group were used. Main Results: Fourteen randomized controlled trials of iNO therapy in preterm infants were found. The trials have been grouped post hoc into three categories depending on entry criteria: entry in the first 3 days of life based on oxygenation criteria, routine use in preterm babies with pulmonary disease, and later enrolment based on an increased risk of BPD. No overall analyses were performed. Nine trials of early rescue treatment of infants based on oxygenation criteria demonstrated
no significant effect of iNO on mortality or BPD. Three studies with routine use of iNO in infants with pulmonary disease also demonstrated no significant reduction in death or BPD [typical RR 0.93 (95% CI 0.861.01)] although this small effect approached significance. Later treatment with iNO based on the risk of BPD (two trials) demonstrated no significant benefit for this outcome in analyses which are possible using summary data. There is no clear effect of iNO on the frequency of all grades of IVH or of severe IVH. Early rescue treatment was associated with a non-significant 20% increase in severe IVH. No effect on the incidence of neurodevelopmental impairment was found.
Reviewers Conclusions iNO as rescue therapy for the very ill preterm infant does not appear to be effective. Early routine use of iNO in preterm infants with respiratory disease does not affect serious brain injury or improve survival without BPD. Later use of iNO to prevent BPD might be effective, but requires further study.
Barrington KJ, Finer N: Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD000509. DOI: 10.1002/14651858.CD000509. pub4.
2012 S. Karger AG, Basel 16617800/12/10240251$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com Accessible online at: www.karger.com/neo
Commentary
Roger F. Soll, Burlington, Vt. Nitric oxide is believed to help regulate muscle tone in the arteries of the lungs and thereby lessen pulmonary hypertension. The use of inhaled nitric oxide (iNO) has been proven effective in the treatment of term infants with severe respiratory failure [1]. The effect of iNO in premature infants is less clear. Barrington and Finer present a systematic review and meta-analysis of 14 randomized, controlled trials of iNO therapy in preterm infants. Due to the clinical heterogeneity of the patients studied in these trials, Barrington and Finer grouped the trials into three categories depending on entry criteria: infants enrolled in the study in the first 3 days of life based on oxygenation criteria, routine use in preterm babies with pulmonary disease, and later enrollment of infants based on an increased risk of bronchopulmonary dysplasia (BPD). In each of these three subgroups, no important clinical effect of iNO was demonstrated. Marginal effects were seen in reducing death or BPD in studies of iNO in routine use as well as in later treatment based on risk of BPD (fig.1). Critics of the meta-analysis have noted the clinical heterogeneity in patient population and dosing of iNO. However, in an individual patient data meta-analysis, Askie et al. [2] evaluated 3,298 infants from 11 of the 13 published trials. They found no statistically significant effect of iNO on death or chronic lung disease (RR 0.96, 95% CI 0.921.01). In an individual patient data meta-analysis, the authors had the ability to look at patient level characteristics; however, gestational age, oxygenation index, evidence of pulmonary hypertension and mode of ventilation did not impact on the results.
The conclusions of the recent National Institute of Health Consensus Development Conference are strongly supported by these analyses. The workshop stated that the available evidence does not support the use of iNO in early routine, early rescue or later rescue regimens in the care of premature infants !34 weeks gestation [3]. Yet, in our clinical practice, on average 5% of all very low birth weight infants are exposed to iNO at some point in their course (interquartile range 05.7%) [4]. Clearly, ongoing studies of the most promising approaches (particularly those infants with early or evolving BPD) are warranted.
Acknowledgment
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal Funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health, USA, under Contract No. HHSN2752011000016C.
References
1 Finer N, Barrington KJ: Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database of Syst Rev 2006;4:CD000399. 2 Askie L, Cutter G, Dani C, Elbourne D, et al: Inhaled nitric oxide in preterm infants: an individual patient data meta-analysis of randomized controlled trials. Pediatrics 2011; 128:729739. 3 Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, Edwards WH, Georgieff M, Gregory K, Johnston MV, Kramer M, Mitchell C, Neu J, Pursley DM, Robinson WM, Rowitch DH: NIH Consensus Development Conference Statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 2011;127:363369. 4 Vermont Oxford Database 2010. http://www.vtoxford.org/.
(For figure 1 see next page.)

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Neonatology 2012;102:251253
Cochrane Review Update
Study or subgroup
Treatment events total
Control events total
Weight %
Risk ratio M-H, fixed (95% CI)
Risk ratio M-H, fixed, 95% CI
1.4.1 Studies with entry before three days based on oxygenation Mercier, 1999 18 40 24 45 6.3 Hascoet, 2005 33 57 41 74 10.0 Van Meurs, 2005 167 210 168 210 47.0 Dani, 2006 10 20 18 20 5.0 INNOVO, 2005 49 55 48 53 13.7 Kinsella, 1999 37 48 29 32 9.7 Van Meurs, 2007 7 14 9 15 2.4 Su, 2007 16 32 21 33 5.8
0.84 (0.54, 1.31) 1.04 (0.77, 1.41) 0.99 (0.90, 1.09) 0.56 (0.35, 0.88) 0.98 (0.87, 1.12) 0.85 (0.70, 1.03) 0.83 (0.43, 1.62) 0.79 (0.51, 1.21)
Subtotal (95% CI)
476
482
100.0
0.94 (0.87, 1.01)
Total events 337 358 Heterogeneity: 2 = 9.43, d.f. = 7 (p = 0.22), I2 = 26% Test for overall effect: Z = 1.73 (p = 0.08) 1.4.2 Studies with entry after three days based on BPD risk Ballard, 2006 165 294 182 288 Subhedar, 1997 20 20 21 22 Subtotal (95% CI) 314 310 Total events 185 203 Heterogeneity: 2 = 5.04, d.f. = 1 (p = 0.02), I2 = 80% Test for overall effect: Z = 1.65 (p = 0.10) 1.4.3 Studies of routine use in intubated preterm infants Kinsella, 2006 282 398 295 395 Schreiber, 2003 51 105 65 102 EUNO, 2009 139 401 141 399
90.0 10.0 100.0
0.89 (0.78, 1.02) 1.04 (0.92, 1.19) 0.90 (0.80, 1.02)
58.8 13.1 28.1
0.95 (0.87, 1.03) 0.76 (0.60, 0.97) 0.98 (0.81, 1.18)
Subtotal (95% CI)
904
896
100.0
0.93 (0.86, 1.01)
Total events 472 501 Heterogeneity: 2 = 3.03, d.f. = 2 (p = 0.22), I2 = 34% Test for overall effect: Z = 1.70 (p = 0.09)
0.5 0.7 1 Favours treatment
1.5 2 Favours control
Fig. 1. Effect of iNO on death or BPD at 36 weeks postmenstrual age. Subgroup analyses are presented on stud-
ies with (1) entry before 3 days of age based on oxygenation criteria, (2) studies with entry after 3 days based on risk of BPD, and (3) studies of the routine use of iNO in intubated infants.
Crochane Review Update
Neonatology 2012;102:251253
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Cochrane Review Update

Neonatology 2012;102:251253 DOI: 10.1159/000338552

Inhaled Nitric Oxide for Respiratory Failure in Preterm Infants

(For figure 1 see next page.)

Cochrane Review Update

Treatment events total

Control events total

Risk ratio M-H, fixed (95% CI)

Risk ratio M-H, fixed, 95% CI

Subtotal (95% CI)

0.94 (0.87, 1.01)

90.0 10.0 100.0

0.89 (0.78, 1.02) 1.04 (0.92, 1.19) 0.90 (0.80, 1.02)

58.8 13.1 28.1

0.95 (0.87, 1.03) 0.76 (0.60, 0.97) 0.98 (0.81, 1.18)

Subtotal (95% CI)

0.93 (0.86, 1.01)

0.5 0.7 1 Favours treatment

1.5 2 Favours control

Crochane Review Update

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