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* Department of Health Science, Leicester Royal Infirmary, Leicester, United Kingdom
Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
Health Services Research Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
|| Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom
¶ Liverpool Women's Hospital, Liverpool, United Kingdom
# Rosie Hospital, Cambridge, United Kingdom
** Royal Maternity Hospital, Belfast, Republic of Ireland
Institute of Child Health, London, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT AIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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Methods. Infants of <34 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomized to receive or not receive iNO. The study was not blinded.
Findings. Recruited were 108 infants (55 allocated to receive iNO and 53 not allocated to receive iNO) from 15 neonatal units in the United Kingdom and Republic of Ireland. Fifty-nine percent (64 of 108) died, and 84% of the survivors (37 of 44) had signs of some impairment or disability, 9 (20%) of them classified as severely disabled. There was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age (relative risk [RR]: 0.99; 95% confidence interval [CI]: 0.76 to 1.29); death or supplemental oxygen on expected date of delivery (RR: 0.84; 95% CI: 0.68 to 1.02); or death or supplemental oxygen at 36 weeks' postmenstrual age (RR: 0.98; 95% CI: 0.87 to 1.12). There was a trend for infants allocated to the iNO group to spend more time on the ventilator (log rank: 3.6), on supplemental oxygen (log rank: 1.4), and in hospital (log rank: 3.5) than those allocated to receive no iNO. This pattern predominantly reflected the infants who died. Mean total costs at 1 year corrected age were significantly higher in the iNO group, partly because of the costs of the gas but mainly because of the difference in initial hospitalization costs.
Interpretation. Evidence of prolongation of intensive care and increased costs of such care, without clear beneficial effects, implies that iNO cannot be recommended for preterm infants with severe hypoxic respiratory failure.
Key Words: neonatal intensive care • nitric oxide • ventilation • preterm infants
Abbreviations: NO, nitric oxide • iNO, inhaled nitric oxide • INNOVO, Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure • OI, oxygenation index • PaO2, partial pressure of oxygen, arterial • NHS, National Health Service • RR, relative risk • CI, confidence interval • DMC, data-monitoring committee
When it became clear in the late 1980s that the previously unidentified endothelium-derived relaxing factor was in fact nitric oxide (NO), it offered doctors the opportunity to use, for the first time, a selective pulmonary vasodilator in a variety of patient groups. In relation to the newborn (those with respiratory disease frequently have relatively high pulmonary artery pressure), this agent seemed to offer particular therapeutic opportunities.
In preterm infants, increased use of surfactant and antenatal steroids during the early 1990s altered the pattern of preterm lung disease, with fewer infants developing severe acute respiratory failure. As a result, trials of inhaled NO (iNO) were focused on those preterm infants who continued to have major respiratory problems despite antenatal steroids and surfactant, ie, the sickest and smallest infants. A Cochrane review of iNO studies1 includes 3 trials,2–4 the total recruitment of which is 207 preterm infants. Since then, another trial has been reported.5 The earlier studies were each relatively small and are heterogeneous in terms of their characteristics. These individual trials each reported that iNO produced statistically significant short-term improvements in oxygenation, but none showed a statistically significant impact on any medium- or longer-term outcome measure. However, few longer-term follow-up data exist for infants after treatment with iNO.
The other important change in relation to iNO in the last 10 years has been the increase in cost after its designation as a "drug" by the US Food and Drug Administration and the recent granting of a product license by the Medicines and Healthcare Products Regulatory Agency (United Kingdom). The high cost of the intervention means that it is particularly important to assess the relative cost-effectiveness of the agent before recommending its widespread use.
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AIM |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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34 weeks' gestation will be reported elsewhere. |
METHODS |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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Infants of <34 weeks' gestation, aged <28 days, and with severe respiratory failure requiring ventilatory support (and having had surfactant when appropriate) were eligible for trial entry if the responsible clinician was uncertain about whether an infant might benefit from iNO. Infants were excluded if there was at trial entry (1) evidence of an uncorrectable bleeding disorder (defined as a platelet count of <50000 cells per mm3 and a Kaolin partial thromboplastin time of >72 seconds or international normalized ratio of >2), (2) cerebral ultrasound evidence of intraparenchymal lesions (Papile grade IV [for full definition, see Appendix 1]), or (3) a contraindication to continuation of all intensive care (such as severe congenital abnormalities or lethal chromosomal anomaly).
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3 and 4–28 days); principal diagnosis at trial entry (acute preterm lung disease [presenting with lung disease immediately after birth and randomized at 3 days of age], chronic preterm lung disease [presenting with lung disease immediately after birth and randomized for continuing problems after 3 days of age], and "other" [in general, these were infants who developed lung disease after recovering from an initial respiratory problem]); and respiratory disease severity at trial entry based on oxygenation indices (OI) of <30 and 30; the OI was calculated from the formula OI = (mean airway pressure in cm H2O x fraction of inspired oxygen x 100)/postductal partial pressure of oxygen, arterial (PaO2) in mm Hg.
During the recruitment phase, the British Oxygen Company (United Kingdom) paid the cost of the supply of NO. The suggested starting dose was 5 ppm, doubling to 10 ppm if no satisfactory response was achieved; if necessary, the dose was doubled again to 20 ppm and then again if required to 40 ppm. A satisfactory response was defined as an increase in postductal PaO2 of >3 kPa (22.5 mm Hg) after the first 15 minutes of giving iNO. If, at any point after having achieved a satisfactory response, an increase in dose did not produce further improvement in oxygenation, then the dose was decreased to the previous level and maintained there. A nested, randomized study of doses of 5, 10, 20, and 40 ppm did not find evidence of a dose-response relationship (J.A., unpublished data). Subsequently, to ensure the lowest possible effective dose, the concentration was repeatedly reduced by 
10% every 2 to 3 minutes until a decrease (2–3%) in oxygen saturations was noted. iNO then was increased to its previous level (reverse dose-response weaning). Infants not showing a significant acute response were continued on iNO at 5 ppm for 12 hours; if there was still no satisfactory response, then they were weaned off of iNO. Infants randomized to the ventilatory support without iNO group were not to receive iNO at a later stage, ie, there should be no "crossover." From January 1999 to December 2001, online centers were asked to return a quarterly log recording some details of the administration of iNO to infants outside of the trial and giving reasons for treatment or nonrecruitment. All other care was left to the discretion of the responsible clinician. Neonatologists and parents were not blinded to the group assignments, although assessment of outcome was without knowledge of randomized or actual treatment when possible.
Outcome was assessed at 2 points: discharge from neonatal services (or prior death) and 1 year corrected age. The primary outcomes were death or severe disability (see Appendix 1 for definitions) at 1 year corrected age (as a composite outcome and also separately) and death before discharge from hospital or chronic lung disease (being on supplemental oxygen at 36 weeks' postmenstrual age and/or on the expected date of delivery).
Secondary measures of outcome (see Appendix 1 for definitions) also included (at discharge from neonatal services): length of stay in hospital; length of time on supplemental oxygen; length of time on ventilatory support; pneumothorax; other pulmonary air leak; pulmonary hemorrhage; major cerebral abnormality; necrotizing enterocolitis; patent ductus arteriosus needing medical treatment; treatment of retinopathy of prematurity; infection (suspected or confirmed on blood culture); and age at which full oral feeding was established. Secondary outcomes at 1 year corrected age included disability and/or impairment of neuromotor development, vision and hearing, respiratory problems, seizures, growth,6 and hospital admissions. This information was obtained by the local pediatrician who completed a brief questionnaire when seeing the child in the routine follow-up clinic.
Data about health service usage during the first hospital stay were collected on the specially developed trial data sheets. Information about health and community service usage and costs to parents between discharge home and 1 year corrected age were ascertained from a series of cross-sectional questionnaires sent to parents at home and mailed at 6 monthly intervals. Some parents received only 1 questionnaire between hospital discharge and 1 year corrected age, and none of the parents received >2 questionnaires. Unit costs for hospital services were taken from the National Health Service (NHS) reference costs database7 and community care costs from work by Netten and Curtis.8 Total costs were estimated by valuing each resource-use item by the appropriate unit cost and are reported in 2002–2003 prices.
The trial size was calculated based on data obtained during a pilot phase of the trial. It was estimated that to detect whether iNO reduced the primary outcome of death or severe disability at 1 year corrected age from 60% to 40% with an 
value of .05 (2-sided) and 80% power would require a total sample size of 200 preterm infants, which would also allow detection of a reduction in the short-term outcome of death before discharge or chronic lung disease from 75% to 55%.
Analyses were based on the treatment groups as randomly allocated ("intention to treat"). Comparisons of primary outcomes between treatment groups are presented as relative risks (RRs) with 95% confidence intervals (CIs) and 
2 statistical tests for binary variables, and t tests and median tests for continuous data, as appropriate. Log-rank tests were performed to test comparisons between treatments for time-to-event measures of outcome. The primary outcome measures were stratified for the major prognostic variables: principal diagnosis leading to respiratory distress, postnatal age, and the severity of respiratory disease at trial entry. Homogeneity of RRs between strata was tested (Mantel-Haenzel 2). Data were analyzed by using SAS 8.2.9
An independent data-monitoring committee (DMC) was established to review confidential interim data and to make recommendations to the trial steering committee. There were no formal stopping rules, but the DMC was guided by the Peto-Haybittle rule.10
The sponsor of the trial, the Medical Research Council, established a trial steering committee of which they were ex officio members and also had independent membership to oversee the conduct of the trial.
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RESULTS |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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A total of 108 infants was recruited (55 allocated to receive iNO and 53 controls, allocated to not receive iNO) from 15 neonatal units in the United Kingdom and Republic of Ireland (Fig 1). The formal 1-year follow-up assessment was available for all but 1 of the surviving children (in the no-iNO group) who was formally assessed as alive and "normal" at 6 months of age and known to be alive and well at 1 year. (He was seen by a health visitor at this time but did not attend for formal review by the local pediatrician. Sufficient data were available to be sure he did not meet the definition of having severe disability).
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Mean total costs per infant at 1 year corrected age were significantly higher in the iNO group, partly because of the costs of the gas but mainly because of the difference in initial hospitalization costs (see Table 6). The costs of subsequent hospitalizations and outpatient and community services were also higher for the iNO arm of the study. The sensitivity analysis showed that these findings were robust to realistic variations in the unit costs.
Other than for the outcome "death or supplemental oxygen on expected date of delivery" and the stratifying factor of postnatal age at entry (for which the P value for the test of homogeneity was .04), the overall effect of iNO on the 3 primary outcomes did not differ when the prespecified stratifying factors of postnatal age, principal diagnosis, and respiratory disease severity at trial entry were taken into account (Table 7).
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DISCUSSION |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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An economic assessment was incorporated into the initial design of this study. By the end of recruitment, concerns arose about the costs of NO to the NHS.13,14 Nevertheless, although the trial data indicate significant extra costs associated with its use, these costs seem to be associated with changes in the pattern of survival and increased morbidity (with associated longer hospital stays) rather than simply the costs of the agent itself. A broad approach to costing was taken with costs to a range of agencies included. The results suggest that subsequent hospital and community costs also increase with the use of iNO. The finding that the overall costs were higher with iNO was not sensitive to the unit costs of the gas or the hospitalization. In conjunction with the clinical evidence (no evidence of improvement in outcome), the cost-consequence analysis suggests that iNO is unlikely to offer good value for the money in this population of preterm infants.
It is clearly disappointing that the recruitment targets were not met in this trial. The poorer-than-anticipated recruitment seems to have been the result of several factors. There was a perception by clinicians involved in the study (ie, those in equipoise) that very few infants needed iNO as part of their treatment. Some clinicians were already convinced of the perceived benefits of iNO (largely for infants at or near term) and hence unwilling to join the study. Indeed, based on logs returned from centers participating in the trial, 75 preterm infants who would have been eligible for trial entry received iNO outside the trial. Some clinicians felt that, with such very ill infants, they had to try everything and did not want to omit the use of iNO. Qualitative studies demonstrate the discomfort of some clinicians in their approach to parents of very sick infants,15 particularly in the present research climate in the United Kingdom, in which a great deal of negative publicity has occurred in recent years in relation to the broad topic of perinatal research. This is particularly problematic in terms of pathology studies,15 as evidenced by the low postmortem-examination rate (26%) in this trial. Each of these factors relating to recruitment is also important in a wider context.
The pattern of preterm lung disease, presumably after the wider use of antenatal steroids and surfactant, now means that relatively few infants meet the criteria for severe lung disease, and infants not responding to surfactant tend to have more complicated respiratory problems and poorer outcomes.16,17 Progress in these infants will require trials involving many more units than previously used if recruitment targets, to show small benefits, are to be met. The lack of equipoise about the role of iNO by many clinicians, despite quite sparse data, is clearly worrying and casts doubt on the extent to which clinical practice has really become evidence based. The results of this study and others might be helpful in making clear that what intuitively might seem the best treatment might not help18 and might actually make things worse.19,20
The clinical data from this study are largely in keeping with those from existing trials, which in general have also shown short-term improvements without any change in the rate of adverse events that might have been predicted to occur from the known biological actions of iNO. A very recently published single-center trial5 indicated a benefit of iNO on death and chronic lung disease, but the benefit was only in infants with an OI of <6.9.21
The data from the INNOVO trial about longer-term outcome is of particular importance. The decision not to use the more formal methods of assessment at 1 year was made initially because there was an expectation that the trial would be much larger, and hence the use of specialized pediatric follow-up would not be feasible and would be prohibitively expensive. By the time it became clear that the trial would be smaller, several infants had already been assessed at 1 year, and it was felt inappropriate to change the methods at that point. The 4-year follow-up (currently underway) does, however, involve specialized pediatricians. Even with these caveats, the lack of any significant beneficial effect on any of the existing longer-term clinical outcomes seems clear. Of the 108 infants recruited in both arms of the study, only 6 were alive and considered normal at 1 year (with a seventh alive and normal at 6 months but lost to the 1-year follow-up). Previous experience22 suggests that the number of infants displaying handicaps will grow, particularly those with abnormal neurodevelopment at 1 year corrected age. The surviving infants from this study are currently being reviewed at the age of 4 to 5 years.
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CONCLUSIONS |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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MEMBERS OF THE INNOVO TRIAL COLLABORATING GROUP |
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TOPABSTRACTAIMMETHODSRESULTSDISCUSSIONCONCLUSIONSMEMBERS OF THE INNOVO...REFERENCES |
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Data Co-ordinating Centre London: K. Diallo, D. Elbourne, P. Hardy, S. Robertson, K. Tomlin, and A. Truesdale.
Clinical Co-ordinating Centre Leicester: D. Field, P. Cornick, and R. Smith.
Recruiting centers (numbers in parentheses denote numbers of infants recruited): J. Staines and A. Hoyle, Ayrshire and Arran Hospital, Irvine, UK (1); A. Ryan and L. Bradfield, Erinville Hospital, Cork, Republic of Ireland (4); A. Khakoo and P. Nambia, Hillingdon Hospital, Middlesex, UK (5); S. Sinha, J. Robins, S. Jollye, and J. Gavey, James Cook University Hospital, Middlesborough, UK (4); S. Bohin, A. Campbell, and K. Ray, Leicester Royal Infirmary, Leicester, UK (19); N. Subhedar, J. McLennan, and B. Shaw, Liverpool Women's Hospital, Liverpool, UK (23); J. Murphy, G. Duffy, and P. Doughty, National Maternity Hospital, Dublin, Republic of Ireland; R. Nicholl and S. Lindsay, Northwick Park Hospital, Harrow, UK (5); J. Ahluwalia, N. Whitehead, L. Scott, and M. Starace, Rosie Hospital, Cambridge, UK (11); J. Moorcraft and G. Collins, Royal Glamorgan Hospital, Llantrisant, UK (3); A. Curley, D. Grier, D. Sweet, and N. Sittlington, Royal Maternity Hospital, Belfast, UK (60); A.C. Fenton, M. Ward Platt, and D. Summers, Royal Victoria Infirmary, Newcastle Upon Tyne, UK (5); P. Midgley and V. Pover, Simpson Maternity Memorial Pavilion, Edinburgh, UK (2); A. Emmerson, A. Chaudhuri, S. Dalton, M. Chiswick, P. Mir, Y. Oluwole, and J. May, St Mary's Hospital, Manchester, UK (17); and J. Hawdon, M. Nugent, and S. Beatson, University College Hospital, London, UK (1).
Data Monitoring Committee: A. Grant, S. Evans, and E. Hey.
Advisory Groups: D. Elbourne, R. Grieve, and C. Normand (economic); D. Elbourne, D. Field, A. Johnson, N. Marlow, and L. Mutch (neurodevelopmental follow-up); C. Beardsmore and J. Stocks (respiratory); C. Wright, S. Gould, A. Howatson, and W. Squier (pathology); A. Goldman, K. Cleaver, D. Macrae, and R. Mupanemunda (technical); and S. Kotecha and D. Shuker (toxicology).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Reprint requests to (D.F.) Department of Health Science, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom. E-mail: david.field{at}uhl-tr.nhs.uk
D.F. and D.E. were the co–principal investigators for the trial; D.F., D.E., A.T., A.C.F., N.S., J.A., H.L.H., J.S., and C.N. were on the steering committee, developed the trial protocol, and oversaw the conduct of the trial; D.F., A.C.F., N.S., J.A., and H.L.H. entered infants into the trial; D.E., P.H., and K.T. conducted the main analyses; R.G. and C.N. conducted the economic analyses; and all authors contributed to the drafting of the article and approved the final report.
Conflicts of interest: D.F. has been a paid speaker and has received support from British Oxygen and Ino Therapeutics, and N.S. has received educational support from Ino Therapeutics.
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REFERENCES |
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