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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.)

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Inhaled Nitric Oxide in Preterm Infants.

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The most prevalent finding of this report is the lack of effectiveness of iNO in improving survival or decreasing pulmonary morbidity or neurodevelopmental impairment for preterm infants who receive respiratory support. A systematic review of the evidence and meta-analyses revealed no significant difference between preterm infants ≤ 34 weeks gestational age treated with iNO and control infants in the risk for mortality, BPD at 36 weeks PMA, short term risks (PDA, sepsis, NEC, treated ROP, pulmonary hemorrhage, or air leak), brain injury, motor or cognitive impairment, sensory impairments, growth or many other health outcomes.

The most important positive finding of this review is a meta-analysis of pooled data from 11 RCTs that reported the composite outcome of death or BPD at 36 weeks PMA which found a small (7 percent) but statistically significant reduction in the risk with iNO therapy. Power calculations for sample size determination were performed a priori for death or BPD or its complement, survival without BPD, in eight of the 11 (73%) trials in the meta-analysis. It has been suggested that the study by Ballard, 200634 should not be included in meta-analyses as it had a very different study design as well as the lowest mortality rates when compared to the other RCTs. In a sensitivity analysis, removing Ballard, 2006 from this meta-analysis did not change the effect estimate (RR 0.93) but did result in wider confidence interval that included 1. We feel that the meta-analysis with all 11 trials provides a more complete picture of the available evidence, considering the effect of iNO as a continuum of exposure

By analyzing reported outcomes from the 14 RCTs and, where appropriate, other cohort studies, we tried to glean as much evidence as possible of how exposure to iNO influences preterm outcomes. Some statistically significant differences were reported for a few individual RCTs included in this review. Two large trials37, 58 reported a statistically significant reduction of brain injury in favor of iNO, and raised hopes that iNO may be neuroprotective. One followup study of a RCT found a statistically significant reduction in cognitive and neurodevelopmental impairment.56 One large multicenter trial was stopped early for concern that the iNO group had a higher rate of brain injury,40 and on followup at two years, found a statistically significant increase in the rate of CP with iNO compared to the control group. In contrast, a smaller trial in preterm infants with pulmonary hypertension found a reduction in CP rate with iNO38 None of our meta-analyses of these variables found statistically significant effects of iNO exposure, but variability in definitions of outcome variables hindered our ability to aggregate all of the available data and perform meaningful meta-analyses.

Once iNO was found to be an effective treatment for full term and late preterm infants with hypoxemic respiratory failure,4 attention turned to using it in more immature preterm infants. Some of the earlier and smaller studies of iNO in preterm infants focused on immediate physiological response to iNO (i.e., improvement in oxygenation index, arterial-alveolar oxygenation ratio, changes in echocardiographic estimates of pulmonary artery pressure) and toxicities, including methemoglobinemia, and pulmonary and intracranial hemorrhages.59-61, 64-67 72 Some early studies started with the iNO dose recommended for full term infants, 20 ppm,64, 66, 72 whereas other early studies started at 5 to 10 ppm, and some increased to 20-40 ppm if there was no response.60, 63, 65 The majority of the earlier RCTs began weaning iNO within two to six hours.60, 61, 64-67 An alternative approach views iNO as a potential growth promoter of the lung and its underlying vascular bed, requiring a longer duration of treatment. Since 2003, four well conducted multicenter RCTs and one single center RCT have published their outcomes for 200 or more infants randomized to receive iNO or placebo gas for one or more weeks.34, 37, 40, 58, 62

Barrington and Finer conducted a systematic review of the evidence for efficacy and toxicities of iNO in preterm infants born before 35 weeks gestation, updated in 2007.31 They grouped 11 RCTs into categories based on inclusion criteria: 1) the early routine use of iNO (i.e., RCTs that treated preterm infants on mechanical ventilation in the first three days after birth) found a marginally significant reduction in death or BPD, RR 0.91 (95 percent CI 0.84, 0.99), and, in severe IVH, IPH or PVL, RR 0.70 (CI 0.53, 0.91); 2) early rescue treatment based on oxygenation inclusion criteria found no significant differences in death or BPD but a trend toward increased risk of severe IVH; and 3) enrollment based on increased risk of BPD at four or more days after birth, and there were no statistically significant effects of iNO on mortality or BPD or increase progression of IVH. They were able to report on neurodevelopmental outcomes from only two RCTs.56, 76

The strength of the evidence was graded for all outcomes included in each key question and the results are presented below (Tables 11 to 15). A summary of the meta-analyses completed, by key question and outcome, is provided in Table 16.

Table 11. Strength of evidence for articles addressing Key Question 1.

Table 11

Strength of evidence for articles addressing Key Question 1.

Table 12. Strength of evidence for articles addressing Key Question 2.

Table 12

Strength of evidence for articles addressing Key Question 2.

Table 13. Strength of evidence for articles addressing Key Question 3.

Table 13

Strength of evidence for articles addressing Key Question 3.

Table 14. Strength of Evidence for articles being addressed by Key Question 4.

Table 14

Strength of Evidence for articles being addressed by Key Question 4.

Table 15. Strength of Evidence for articles being addressed by Key Question 5.

Table 15

Strength of Evidence for articles being addressed by Key Question 5.

Table 16. Summary of meta-analyses.

Table 16

Summary of meta-analyses.

Our review differs from the Barrington and Finer Cochrane review31 in that there have been three more RCTs published: 1) a small Asian RCT of 65 infants with severe respiratory distress syndrome (Su, 200865), 2) a report of the 29 infants born below 34 weeks gestation but with birth weight above 1500 g from the NICHD Neonatal Research Network (Van Meurs, 2007),39 and 3) a large multicenter trial of 800 infants with gestational ages of 24 to 28 weeks.62 In addition, we were charged with a broader mission: to review the data regarding a number of short term risks, long term pulmonary and neurodevelopmental outcomes, outcomes among subpopulations, and the effects of iNO dose, timing, duration, and concurrent therapies on outcomes. By using a broader definition to include outcome at one year corrected for degree of prematurity, and finding more recent outcome studies, including one with outcomes at four to five years, we were able to review long term outcomes for eight RCTs.30, 35, 36, 39, 44, 56, 57, 76 The Barrington and Finer Cochrane systematic review31 makes a valid point that the studies of iNO in preterm infants vary substantially in their eligibility criteria. The RCTs also vary widely in dose, method, and duration of administration of iNO. But the focus of studying effects of iNO on preterm infants has evolved from immediate pulmonary or cardiovascular effects, to how it may influence the growth and maturation of the developing lung and its cardiovascular support. To provide another perspective, we chose to view the variation in respiratory disease severity, iNO dose, method, and duration of iNO administration as varying degrees of iNO exposure on a continuum of degree of organ maturation, as measured by postmenstrual age. Postmenstrual age is the sum of gestational age at birth and chronological age, and is currently the best measure of preterm maturation that we have. We view brain injury and neurodevelopmental outcomes also in terms of degree of maturation (i.e., PMA) when exposed to iNO. The heterogeneity of our meta-analyses for the composite brain injury variable and for cognitive impairment could be explained by the effect of iNO in the two trials that included preterm infants with birth weights over 1500 g (Schreiber, 2003 and Van Meurs, 2007).39, 58 The bigger infants are more likely to be the more mature infants, and may benefit more from iNO effects on pulmonary blood flow because they are better able to autoregulate their cerebral blood flow.

A recent individual patient data meta-analysis has been presented,95 but has not yet been published. A synthesis of data on short term outcomes on 3298 preterm infants (< 37 weeks) from 11 trials found no statistically significant differences in death or CLD, RR 0.96 (0.92, 1.01) or in severe neurological abnormalities on neuroimaging, RR 1.12 (0.98, 1.28).95 They concluded that there was a lack of evidence to support the “indiscriminate” use of iNO in treating preterm infants with respiratory failure.

The driving force behind the studies of iNO in preterm infants who receive respiratory support is the search for an effective treatment that improves survival and pulmonary health without increasing the risk of adverse short and long term outcomes. As many as one third to one half of the preterm infants enrolled in the studies discussed in this report died in the NICU. Most of the survivors had residual chronic lung disease (BPD) that significantly prolonged their hospitalization and influenced their quality of life after discharge home from the NICU. In the two studies that reported it, only 20 to 40 percent of survivors in both the iNO and control groups had normal neurodevelopmental outcomes at one to two years.30, 35, 36 As cohort studies and RCTs of iNO in preterm infants born at or before 34 weeks gestation were being conducted, off label use of iNO in this population dramatically increased. One publication reported a six fold increase in its use between 2000 and 2008 in a large multisite pediatric group.47

Whether the small statistically significant reduction of death or BPD we found on meta-analysis is clinically meaningful depends on one’s point of view. When compared to the evidence amassed for the efficacy iNO in treating full term infants and preterm infants born after 34 weeks gestation with respiratory failure, a reduction of death or BPD by less than 10% is very weak. But many parents would grasp at even that small a difference in their sick preterm infant’s chances in surviving without BPD or NDI. We agree with Barrington and Finer in their 2007 Cochrane review31 and Askie, 2010 (abstract)96 that current evidence does not support the routine use of iNO to treat preterm infants. We do not conclude, however, that we should abandon the possibility that iNO may someday become a component of a treatment strategy for some preterm infants receiving respiratory support. Several factors contribute to our recommendation to continue the study of iNO: 1) our finding a small but statistically significant difference in death or BPD at 36 weeks PMA, the common primary outcome variable of 73 percent of RCT conducted to date; 2) the statistically significant finding of a diminished need for chronic pulmonary medication at one year corrected age, suggesting less severe lung disease in those treated with iNO, and 3) no studies have been powered to detect meaningful differences in infant functional outcome or quality of life with iNO treatment compared to standard therapy.

Treatment of preterm infants born at or below 34 weeks gestation with iNO should occur only in the context of rigorously conducted RCTs that have the power to detect meaningful long term outcomes. Strategies for treatment need to consider how different preterm infants are from full term infants. Their immature organs are not prepared to support extrauterine life, persistent pulmonary hypertension is not as much of a problem early in the disease process, they lack important natural defenses (e.g., surfactant, cortisol, immune responses), and their response to organ injury seems to vary depending on degree of maturation. Studies of iNO therapy to date have enrolled and treated infants based on gestational age and chronological age, both imperfect measures of maturity. Degree of lung and brain maturation seems to be a very important variable, and treatment should be viewed in terms of postmenstrual age, a construct that better reflects organ maturation. Consideration of postmenstrual age at the time of initiation and duration of iNO therapy may help select subgroups of infants most like to benefit from the therapy. Funded, ongoing basic research into the mechanisms by which iNO may influence the developing lung can provide insight into how to design future clinical trials. Evaluating the effect of iNO on brain injury requires neuroimaging before treatment, as well as on serial studies. BPD at 36 weeks PMA and evidence of brain injury are important mediators. Prolonged hospitalizations, use of supplemental oxygen and pulmonary medications after NICU discharge, prevalence of reactive airway disease and recurrent hospitalizations (as reported by Ballard, 200634 and Hibbs, 200744) are more important indicators of pulmonary function and health.44 Neurodevelopmental outcomes and functional abilities in childhood are far more important outcomes than evidence of brain injury on neuroimaging studies. Careful assessment of the few statistically significant but inconsistent differences with iNO exposure, combined with ongoing basic science and clinical research on the developing lung and brain, their response to and recovery from injury can provide insights that lead to testable hypotheses for future randomized controlled trials.


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