Cochrane review: Inhaled nitric oxide for respiratory failure in preterm infants

Authors


Abstract

Background

Inhaled nitric oxide (iNO) has been proven to be effective in term infants with hypoxic respiratory failure. The pathophysiology of respiratory failure, and the potential risks, differ substantially in preterm infants. Therefore, analysis of the efficacy and toxicities of iNO in infants born before 35 weeks is necessary.

Objectives

To determine the effect of treatment with iNO on the rates of death, bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), or neurodevelopmental disability in preterm newborn infants (< 35 weeks gestation) with respiratory disease.

Search strategy

Standard methods of the Cochrane Neonatal Review Group were used. MEDLINE, EMBASE, Healthstar and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) were searched, using the following keywords: nitric oxide, clinical trial, and newborn covering the years from 1985 to 2006. In addition, the abstracts of the Pediatric Academic Societies were also searched.

Selection criteria

Randomised and quasi-randomised studies in preterm infants with respiratory disease that compared the effects of administration of iNO gas compared to control, with or without placebo are included in this review.

Data collection and analysis

Data regarding clinical outcomes including death, BPD (defined as oxygen dependence at 36 weeks postmenstrual age), IVH, periventricular leukomalacia (PVL), long term neurodevelopmental outcome and short term effects on oxygenation were excerpted from the trial reports by the investigators. Standard methods of the Cochrane Neonatal Review Group were used. Two investigators extracted, assessed and coded separately all data for each study. Any disagreement was resolved by discussion.

Main results

Eleven randomised controlled trials of inhaled nitric oxide therapy in preterm infants were found. The trials have been grouped post hoc into three categories depending on the entry criteria; entry in the first three days of life based on oxygenation criteria (Kinsella 1999; Hascoet 2004; INNOVO 2005; Van Meurs 2004; Mercier 1999; Dani 2006), routine use in intubated preterm babies (Schreiber 2003; Kinsella 2006) and later enrolment based on an increased risk of BPD (Subhedar 1997; Ballard 2006). The usefulness of the overall analyses was considered limited by the differing characteristics of the studies, and only subgroup analyses were performed.

Trials of early rescue treatment of infants based on oxygenation criteria demonstrated no significant effect of iNO on mortality or BPD. The subgroup of studies with routine use of iNO in intubated preterm infants demonstrated a marginally significant reduction in the combined outcome of death or BPD [typical RR 0.91 (95% CI 0.84, 0.99); typical RD -0.06 (95% CI -0.12, -0.01)]. Later treatment with iNO based on the risk of BPD demonstrated no significant benefit for this outcome in our analysis.

Studies of early rescue treatment with iNO demonstrated a trend toward increased risk of severe IVH, whereas the subgroup of studies with routine use in intubated preterm infants seems to show a reduction in the risk of having either a severe IVH or PVL [typical RR 0.70 (95% CI 0.53, 0.91); typical RD -0.07 (95% CI -0.12, -0.02)].

Later iNO treatment of infants at risk of BPD is given after the major risk period for IVH, and does not appear to lead to progression of old lesions.

Two studies (Schreiber 2003; INNOVO 2005) presented data on long term neurodevelopmental outcome. The early routine treatment study (Schreiber 2003) showed an improved outcome at two years corrected age, while the rescue treatment study (INNOVO 2005) showed no effect of iNO.

Authors' conclusions

iNO as rescue therapy for the very ill ventilated preterm infant does not appear to be effective and may increase the risk of severe IVH. Later use of iNO to prevent BPD also does not appear to be effective. Early routine use of iNO in mildly sick preterm infants may decrease serious brain injury and may improve survival without BPD. Further studies are needed to confirm these findings, to define groups most likely to benefit, and to describe long term outcomes.

Plain Language Summary

Inhaled nitric oxide for respiratory failure in preterm infants

The use of inhaled nitric oxide (iNO) may help reduce breathing failure in preterm babies.Breathing failure in premature newborn babies may be complicated by raised pressure within the vessels that carry blood to the lung (pulmonary hypertension). Medications that cause sedation or muscle relaxation and mechanically assisted breathing (mechanical or assisted ventilation) are used to treat pulmonary hypertension. Nitric oxide is believed to help regulate muscle tone in the arteries of the lungs and, thereby lessen pulmonary hypertension; however, iNO may also cause excessive bleeding (haemorrhage). This review of studies found that nitric oxide therapy may improve the chances of the baby having an improved outcome, but only when used in babies who were mildly ill. These studies indicated that there may be a decrease in serious bleeding in the brain (intracranial hemorrhage). When given to babies who were very ill, iNO did not seem to help, and may have contributed to an increase in intracranial hemorrhage.

Background

Respiratory failure in the preterm newborn may be complicated by pulmonary hypertension (Walther 1992). Conventional therapy for pulmonary hypertension involves respiratory support, which includes assisted ventilation and continuous distending pressure, administration of surfactant and sedation or muscle relaxation if necessary. Support of the systemic circulation with inotropes is often used in the sickest infants. Since the introduction of surfactant, mortality rates from respiratory failure in preterm infants have fallen significantly (Soll 2001). However, some infants do not have adequate improvement in oxygenation following surfactant treatment.

The regulation of vascular muscle tone at the cellular level occurs via nitric oxide (NO). Nitric oxide is generated enzymatically from L-arginine by one of three NO synthases. NO activates guanylyl cyclase by binding to its heme component, leading to the production of cyclic GMP, which causes vasodilatation (Finer 1998).

The pulmonary vascular resistance of fetal animals is regulated by endogenous (Cornfield 1992) or exogenous NO (Kinsella 1992). In several newborn animal models pulmonary hypertension is reversed by inhaled exogenous nitric oxide (Frostell 1991; Roberts 1993). In general, little or no effect of inhaled nitric oxide (iNO) has been demonstrated on the systemic circulation (Finer 1998). Studies in adults and in full term human infants have confirmed that iNO causes selective pulmonary vasodilation, reducing pulmonary artery pressure and improving ventilation/perfusion mismatch. In adult respiratory distress syndrome (ARDS), a reduction in pulmonary arterial pressure and a decrease in intrapulmonary shunting occurs within 40 minutes of iNO treatment (Rossaint 1993). In these patients, the major benefit was likely due to an improvement in ventilation/perfusion matching because iNO will only cause vasodilation in ventilated lung units.

Premature animals with hyaline membrane disease have elevated pulmonary vascular resistance, and pulmonary artery pressure and oxygenation may be improved by iNO (Skimming 1995; Kinsella 1994). These animal models are very similar to premature human neonates with respiratory failure. In the term neonate with hypoxic respiratory failure, iNO decreases the requirement for extracorporeal membrane oxygenation (ECMO), but does not decrease overall mortality (Finer 2000). Although preterm infants with respiratory failure have an increase in pulmonary artery pressure, this elevation of pulmonary artery pressure is rarely sufficient to cause reversal of the ductal shunt. Therefore, the haemodynamic profile differs somewhat from the term neonate. ECMO is not used for preterm infants due to concerns regarding hemorrhagic complications and, therefore, the requirement for ECMO cannot be used as an outcome criterion. The entry criteria used for the studies of iNO in the term neonate have different implications in the preterm since the oxygenation index (OI) does not predict mortality in the preterm infant to the same extent and at the same levels as the OI in term infants.

Because of different pathophysiology, different entry criteria and different outcomes, the results in term infants cannot be extrapolated to the preterm infant.

Preterm infants are at risk of long-term pulmonary disability due to bronchopulmonary dysplasia (BPD). The importance of preventing or ameliorating BPD relates to the association between BPD and the subsequent development of neurodevelopmental impairment (Vohr 2005; Wood 2005), chronic medical illness and re-hospitalisation. If iNO therapy leads to a decrease in the need for ventilator support, it is possible that a reduction in lung injury may lead to preventing or ameliorating BPD. NO participates in both the production of and protection from oxidative injury (McAndrew 1997). Therefore, the effects of iNO therapy on the developing lung deserve careful evaluation before the introduction of iNO into clinical practice.

Of particular concern in the preterm infant is the effect of iNO on coagulation. Inhaled nitric oxide has been shown to increase bleeding time in adult volunteers (Hogman 1993) as well as in adults ARDS (Samama 1995). This appears to occur via cGMP dependent mechanisms; presumably, intra-platelet cGMP is increased during the passage of platelets through the lung. Preterm infants are at high risk of developing intraventricular haemorrhage (IVH), which has substantial effects on long term developmental outcome. Therefore, is important to evaluate iNO for its effect on IVH rates in the preterm infant.

The few case reports and case series published prior to randomised controlled trials demonstrated that premature infants with severe respiratory failure who have not responded to conventional management, including surfactant and high frequency ventilation, may have improved oxygenation with iNO (Peliowski 1995; Abman 1993; Van Meurs 1997). In these reports, mortality and IVH were frequent.

Skimming et al (Skimming 1997) randomised 23 surfactant treated premature infants requiring conventional mechanical ventilation with at least 50% oxygen to either 5 ppm or 20 ppm of iNO for 15 minutes (non blinded). Twelve infants received 20 ppm and 11 received 5 ppm. The mean gestational age was 28 +/-0.6 wk, and mean postnatal age was 49.8 +/-8.1 hrs. There were significant increases in PaO2, SpO2 and a significant fall in the spontaneous respiratory rate (all P < 0.01). No differences in response between the two doses of iNO were reported. This study suggests that, if iNO is to be used in preterm infants, a dose of 5 ppm would be adequate.

Objectives

To determine the effect of treatment with inhaled nitric oxide (iNO) on oxygenation and the rates of death, bronchopulmonary dysplasia, intraventricular haemorrhage or other serious brain injury, and adverse long term neurodevelopmental outcome in preterm newborn infants who have hypoxic respiratory failure.

Because of substantial variation in the eligibility criteria for the studies which decreases the utility of an overall analysis, the studies were divided post hoc into three groups, with the objective of determining whether iNO reduces those same adverse outcomes in infants treated in the first three days because of defects in oxygenation, infants routinely treated with iNO after intubation, and infants treated at a later age (after three days of age) because of an elevated risk for BPD.

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised clinical trials.

Types of participants

Premature infants (less than 35 weeks gestation) with respiratory failure after adequate treatment with surfactant.

Types of interventions

Inhaled nitric oxide compared to placebo or control in addition to conventional treatment for respiratory failure.

Types of outcome measures

  • Death prior to hospital discharge

  • Bronchopulmonary dysplasia (oxygen dependence at 36 weeks postmenstrual age)

  • Death or bronchopulmonary dysplasia (at 36 weeks postmenstrual age)

  • Intraventricular haemorrhage [any grade and more severe, grades 3 and 4]

  • Periventricular leukomalacia

  • Neurodevelopmental disability (proportion of survivors with neurological abnormality sufficient to affect quality of life, or developmental index more than two standard deviations below the mean, using validated scale at greater than 12 months of age; or mean developmental index among survivors at greater than 12 months of age)

  • Oxygenation within two hours of therapy

  • Retinopathy of prematurity (any stage and stage 3 and greater)

Search methods for identification of studies

Standard methods of the Neonatal Collaborative Review Group were used. The most recent literature search was completed in January 2007, using PubMed to search MEDLINE; the term nitric oxide was used and the search limited to clinical trials, and newborn infants. This search retrieved 130 articles. In January 2007, PubMed was searched using the clinical queries option, searching "nitric oxide and newborn" using the category "therapy" and the broad, sensitive search option which retrieved 1027 articles. EMBASE was searched most recently in November 2006 using the search terms nitric oxide and newborn (preterm, or premature) and, limited to "human", which retrieved 189 titles. The Cochrane Central Register of Controlled Trials was searched using text words "newborn" and "nitric oxide", which retrieved 105 article titles.

The abstracts of the annual Pediatric Academic Societies meetings were also searched from 1995 to 2006.

Data collection and analysis

Each identified trial was assessed for methodological quality with respect to a) masking of allocation b) masking of intervention c) completeness of follow up d) masking of outcome assessment. Trials without a simultaneous control group (e.g. those with historical controls) were rejected.

Inclusion criteria and therapeutic interventions for each trial were reviewed to see how they differed between trials.

Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed. Continuous outcomes were analysed using weighted mean difference, also assuming a fixed effect model. Heterogeneity was evaluated using the I2 statistic.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Eleven published randomised controlled trials of inhaled nitric oxide (iNO) compared to control in preterm infants were identified (Subhedar 1997; Kinsella 1999; Mercier 1999; Srisuparp 2002; Schreiber 2003; Van Meurs 2005; Hascoet 2005; INNOVO 2005; Ballard 2006; Kinsella 2006; Dani 2006).

The entry criteria for the eleven studies were quite dissimilar. In seven trials, enrolment occurred in the first two days of life in most of the infants, all of whom required significantly impaired oxygenation for trial enrolment. Two studies enrolled infants after three days of age; Subhedar 1997 enrolled infants at 96 hours of age and Ballard 2006 enrolled infants after seven days of age. For these two studies, enrolment was based on clinical criteria. In Subhedar 1997, the main eligibility criterion was a score predicting a high risk of BPD. In Ballard 2006, infants were eligible if they were ventilated or, for the smallest infants, receiving CPAP. Thus, infants in the studies of Subhedar and Ballard were entered after the major risk period for the development of IVH, which was not the case for most of the infants in the remaining trials. Schreiber 2003 and Kinsella 2006 differ in that any ventilated preterm infant was considered eligible; therefore, these studies can be considered to be studies of routine iNO rather than "rescue" treatment. The implications for clinical practice are clearly quite different between these three groups of studies, therefore, these studies were analysed separately.

Studies were eligible to be considered in the first group if they included acutely ill ventilated preterm infants, most of whom were enrolled within the first three days of life, if the infants satisfied a severity of illness criterion. There were seven trials of iNO in preterm infants in this group (Dani 2006; Hascoet 2005; INNOVO 2005; Kinsella 1999; Mercier 1999; Srisuparp 2002; Van Meurs 2005). The mean oxygenation indices of infants enrolled in these "rescue" studies ranged from 12 - 32 (32 for INNOVO 2005, 23 for Van Meurs 2005, 18 to 20 in Mercier 1999, and 12 to 15 for Hascoet 2005)

Studies were included in the second group if they enrolled preterm infants who were more than three days old and were at increased risk for BPD. There were two trials of iNO in preterm infants in this group (Ballard 2006; Subhedar 1997). Ballard 2006 reported a respiratory severity score (which cannot be directly converted to the OI as it does not take into account the PaO2, as few eligible infants would have had arterial lines) calculated as FiO2 multiplied by mean airway pressure in cmH2O. The median score was 3.5 in each group, which suggests mild illness.

Studies were eligible for the third group if they enrolled infants early in life (less than three days of age) and required no severity of illness criteria other than being intubated. There were two trials in this category (Kinsella 2006; Schreiber 2003). In the study of Kinsella 2006 the mean OIs were 5.4 (iNO) vs. 5.8 (control); in the study of Schreiber 2003 the median OI was 6.94.

Trials of iNO in preterm infants eligible within the first three days because they met oxygenation criteria

Kinsella 1999

Kinsella and colleagues randomised 80 preterm infants to the blinded administration of 5 ppm iNO or no additional gas (79 had received surfactant). Infants had a baseline cranial ultrasound prior to the administration of the study gas the results of which were noted, but did not constitute an exclusion criterion. Infants were randomised if the arterial to alveolar PO2 ratio was less than 0.1 on two successive blood gases in the first seven days of life. This criterion was chosen in order to enrol infants with an expected mortality of 50%. The study was powered to detect a 30% reduction in mortality with iNO, which led to a planned sample size of 210 infants. A planned interim analysis was performed after 2.5 years and found no detectable difference in the main outcome (survival to discharge). Seven patients were excluded from the analysis of acute oxygenation response because of early protocol violations, but were included in all other outcome data. Forty-eight infants received iNO and 32 infants were controls. Baseline characteristics of the groups were similar, apart from a greater number of infants treated with iNO having no intracranial haemorrhage at the start of the study (73% vs. 59%). PaO2/FiO2 was 42 (SD 18) in the iNO group and 42 (SD 16) in the control group. Treatment was continued for seven days, after which time there were attempts to wean iNO. Study gas was restarted for an increase in oxygenation index of 15% or more. The maximum duration of treatment was 14 days.

Mercier 1999

The Franco-Belgium Collaborative NO trial group randomised near term and preterm infants in separate strata and reported most of their results for the two strata separately. The cut off between strata for this study was at 33 weeks gestation. The admission criteria included postnatal age less than seven days and oxygenation index between 12.5 and 30. All except one of the 85 preterm infants received surfactant and the majority (75%) received high frequency ventilation. The majority of the infants were enrolled on the first or second day of life. Infants were randomised to iNO at 10 ppm or control. If the oxygenation index (OI, mean airway pressure x FiO2 x 100)/PaO2) exceeded 30 during the two hour study period, then iNO at 20 ppm was used. The median baseline OI was 18 in the control infants and 20.2 in the iNO group.

Srisuparp 2002

The study of Srisuparp and colleagues was a single institution study that randomised intubated preterm infants of less than 2000 g who had received surfactant, had clinical RDS and were < 72 hours of age. OI entry criteria varied with birthweight; OI was > 4 for infants < 1000 gm, > 6 for infants 1001-1250 g, > 8 for infants 1251 to 1500 g, > 10 for infants 1501 - 11750 g and > 12 for infants 1751 - 2000 g. Infants had central arterial catheters in place and were without major malformations. Treatment was open label iNO at 20 ppm or control. The iNO was weaned by protocol and limited to seven days. This was a pilot study for the Schreiber 2003 study. Although there was no clearly stated hypothesis, the authors stated that they were assessing the effects on oxygenation and potential adverse effects of iNO.

Van Meurs 2005

The study of Van Meurs and colleagues was a multicenter US study. Initial entry criteria were restricted to infants less than 34 weeks gestation with a birth weight between 401 and 1500 g (with three birth weight strata, 401 - 750 g, 751 - 1000 g and 1001 - 1500 g). Eligible infants were receiving assisted ventilation at least four hours after surfactant therapy and were considered at high risk because of an oxygenation index of at least 10 on two consecutive blood gases. This criterion was revised (after the initial interim analysis showed an unexpectedly high mortality rate) to an OI of at least five followed by an OI of at least 7.5 after at least 30 minutes. The primary outcome was the combined outcome of BPD (oxygen dependance at 36 weeks) or death. The actual oxygenation indices of the enrolled patients were 23 (SD 17) in the intervention group and 22 (SD 17) in the control group.

Hascoet 2005

Hascoet and colleagues conducted a multicenter study at ten European centres. Intubated preterm infants were enrolled and randomised, but the randomisation was revealed only if they developed hypoxic respiratory failure, defined as an arterio-alveolar oxygen ratio (a/A02 ratio = Pa02/713 x Fi02 - PaC02) of less than 0.22 between six and 48 hours of age. Unfortunately, much of the reported data refers to the overall group of 860 infants, many of whom were not eligible to receive the assigned intervention. There were 61 iNO infants and 84 control infants actually exposed to the study intervention. If the infants developed refractory hypoxaemia at any time (defined as PO2 < 50 and PCO2 < 50 mmHg for fraction of inspired oxygen FIO2 = 1.0), they were defined as a "failure" in regard to the primary measure of outcome, and iNO was given according to the French Drug Agency recommendations. For all consented infants, initiation of the study intervention occurred when the infant met the hypoxic respiratory failure criteria, defined as the need for mechanical ventilation, FIO2 > 40%, and a/AO2 ratio < 0.22. For the first hour of iNO treatment, a dose of 5 ppm iNO was used. Subsequent dosage was determined according to a/AO2 response. As soon as the response was positive (defined as an a/AO2 increase > 0.22), iNO was decreased to 2 ppm for two hours and then patients were weaned according to results of blood gas evaluations. The primary outcome variable was survival without respiratory support, oxygen supplementation or IVH > grade I to 28 days of age.

INNOVO 2005

This European multicenter study was planned to enrol 200 infants less than 34 weeks gestation and less than 28 days old. Eligibility criteria were "severe respiratory failure requiring assisted ventilation if the responsible physician was uncertain about whether an infant might benefit from iNO". The protocol suggested that iNO be started at 5 ppm and could be doubled up to a maximum of 40 ppm. There were two primary outcome criteria listed in the main publication, but the sample size was calculated based on a reduction in the frequency of the combined outcome of death or severe disability at one year corrected postnatal age. 108 infants were enrolled when the study was terminated

Dani 2006

Dani and colleagues conducted a single centre study that planned to enrol 52 infants less than 30 weeks gestation and less than one week of age. Infants ventilated with severe respiratory distress were eligible if they had an FiO2 > 0.5 and arterial-alveolar oxygen ratio < 0.15 despite surfactant treatment. Forty infants had been enrolled at termination of the study. Mean age at the start of the intervention was 43 hours in the iNO group. Infants were begun on 10 ppm of iNO, decreased to six after four hours, then continued until extubation or until weaning criteria were reached.

Trials of iNO in preterm infants eligible after three days of age because of an elevated risk of BPD

Subhedar 1997

Subhedar and colleagues performed an open randomised trial of iNO in premature infants less than 32 weeks gestation who were enrolled at 96 hours of age if still intubated. The entry criteria included having a "high" risk for developing BPD, based on a previously published risk score (Ryan 1996). The actual score required for eligibility was not given. Infants were randomised in a 2 x 2 factorial design to either iNO only (n = 10), iNO plus dexamethasone (n = 10), dexamethasone only (n = 11) or neither (n = 11). The infants were treated with 20 ppm of iNO with a reduction to 5 ppm according to the response obtained. The dexamethasone dose was 1 mg/kg/day for three days, then 0.5 mg/kg/day for a further three days. Forty-two infants were studied, with a mean birth weight of 882 g (range 416 - 1354 g) and mean gestational age of 27 weeks (range 24 - 30 wk) for the 20 iNO infants compared with a mean birth weight of 762 g (range 520 - 1320 g) and a mean gestational age of 27 weeks (range 22 - 31 wk) for the 22 non-iNO infants. Results were not presented separately for each of the four groups randomised in this study. Almost all data are presented as inhaled nitric oxide vs. no inhaled nitric oxide, regardless of the use of dexamethasone. Therefore, it is not possible to assess possible interactions, or compare the effects of iNO solely in the infants who did not receive steroids.

Ballard 2006

Ballard and colleagues studied infants ≤ 32 weeks of gestation with a birthweight 500 to 1250 g who were receiving mechanical ventilation for lung disease (not apnea) between seven and 21 days of age. Infants with a birth weight of 500 to 799 g who were being treated with nasal continuous positive airway pressure were also eligible. Infants initially received 20 ppm of study gas (iNO or nitrogen placebo) for 48 to 96 hours, and the doses were subsequently decreased to doses of 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 days. The median respiratory severity score (calculated as FiO2 multiplied by mean airway pressure in cmH2O) was 3.5 in each group, which suggests minor respiratory disease. The authors calculated that a severity score of 3.5 is equivalent to an OI between 5 and 9. Twelve percent had a score > 10 in the iNO group and 13% in the control group.

Trials of the routine use of iNO in intubated preterm infants.

Schreiber 2003

This single centre study enrolled intubated premature infants less than 34 weeks gestation and less than 2 kg birthweight at less than 72 hours of age. No specific oxygenation criteria was required. The study used a 2 x 2 factorial design examining seven days of iNO or oxygen placebo and the use of high frequency oscillatory ventilation using the Sensormedics device or conventional ventilation. iNO was started at 10 ppm for the first day, followed by 5 ppm for six days. The iNO intervention was blinded. The entry criteria did not require a prespecified disease severity. The median OI for the iNO group was 7.3 and 6.8 for the control infants. The primary outcome was survival without chronic lung disease (oxygen requirement at 36 weeks postmenstrual age).

Kinsella 2006

Kinsella and colleagues conducted the largest of the multicenter trials completed to date. The planned sample size of 792 infants was achieved. This study enrolled infants < 34 wk gestation who were ventilated for respiratory failure in the first 48 hours and were expected to remain intubated for more than 48 hours. There was no further requirement for severity of illness. Infants received 5 ppm of iNO or nitrogen placebo until extubation or for up to 21 days. The primary outcome variable was survival without BPD; the main secondary outcomes were severe intraventricular haemorrhage, periventricular leukomalacia and cerebral ventricular dilatation. The oxygenation index at baseline was 5.4 (SD 5.2) in the treatment group and 5.8 (SD 6.7) in the placebo group.

Excluded studies

Skimming 1997

Skimming and colleagues conducted a randomised comparison of the response to 5 and 20 ppm of iNO. All infants received iNO.

Lindwall 2005

This study was a short term (30 minute) crossover study in preterm infants receiving CPAP for respiratory distress syndrome that examined the effects on gas exchange. All infants received iNO either as the first or second gas administered.

Risk of bias in included studies

Trials of iNO in preterm infants eligible within the first 3 days because they met oxygenation criteria

Kinsella 1999

This was a multi centre study with masked allocation and masked intervention. Randomisation was stratified by centre and gestational age (≤ 28 weeks and > 28 weeks). Analysis was by intention to treat. The study was terminated after 80 of the planned 210 infants were enrolled since an interim analysis suggested that a significant benefit was unlikely to be detected "within a reasonable time frame". The interim analysis was planned at the start of the study, but it was not stated if slow enrolment was a pre-designated stopping criterion.

Mercier 1999

This was a multi-centre international trial in which the intervention was unmasked, but the randomisation was adequately concealed by the use of sealed envelopes at the co-ordinating centre. The study was designed with the primary outcome being assessed after two hours. Later treatment with iNO was allowed if the infant's oxygenation worsened such that the OI exceeded 30. Five of the control infants eventually received iNO. The availability of back-up treatment of control infants with iNO limits the ability of the study to address long term outcomes. The study was designed to enrol a total of 360 infants across both gestational age strata, but was terminated because of slowing enrolment after two years. It was not stated whether the early analysis or the cessation criteria of the study were pre-designated. Analysis was by intention to treat. All the baseline characteristics were similar between groups.

Srisuparp 2002

This is a single centre trial in ventilated preterm infants with a birth weight less than 2000 g. Enrolled infants had received surfactant, were less than 72 hours old and had an arterial line in place. Oxygenation criteria allowed randomisation of the smallest babies (≤ 1000 g) with only mild disease OI ≥ 4, and required increasing OI for enrolment of infants with increasing birth weights (up to ≥ 12 in birthweight 1751-2000 g). The adequacy of masking is uncertain as allocation was by a "card-picking scheme". The intervention was not masked. The primary outcome variable was severe IVH. iNO at 20 ppm was weaned within 6-12 hours followed by a weaning protocol that planned weaning within 72 hours unless there was deterioration. The maximum duration of treatment was seven days.

Van Meurs 2005

This was a multi-centre study with masked randomisation using a telephone system. The intervention was masked by the use of simulated flow of gas as a placebo. Analysis was based on intention to treat, and the outcome assessment was masked. All of the infants were assessed for the primary outcome. Initially planned to recruit 440 infants, the study was terminated after 2/3 of the infants had been assessed for the primary outcome, since there appeared to be an increase in severe IVH, but no benefit in terms of the primary outcome. By the time the analysis was completed, 420 infants had been enrolled and the study was terminated.

Hascoet 2005

This was a multicenter trial in 10 tertiary perinatal centres in France and Belgium with masked randomisation using a call-in telephone system. The intervention was not masked. Refractory hypoxaemia before six hours of age occurred in 20 infants, who were therefore not entered into the study. An additional 20 iNO infants and 28 control infants received open label iNO for refractory hypoxaemia, further complicating the analyses of the results because of significant contamination of the control infants. The initially planned sample size was achieved, with approximately the expected incidence of hypoxic respiratory failure.

INNOVO 2005

This multi-centre trial had masked allocation using a telephone system. Treatment assignment was by minimization ("with a probabilistic element") rather than strict randomisation. The intervention was not masked. The analysis was based on intention to treat and follow-up was complete for all except one infant. Follow-up was not formally blinded. Fifty-five iNO and 53 controls were enrolled. The study was stopped at the end of the calendar year 2001, which was apparently pre-planned, although not mentioned in either the on-line version of the trial protocol or the register of controlled trials.

Dani 2006

This study randomised infants using sealed opaque envelopes and, therefore, was presumably masked. The intervention was not masked. The study was terminated after 40 of the initially planned 52 infants were enrolled, following a previously unplanned interim analysis that confirmed the investigators' impression that there was a reduction in bronchopulmonary dysplasia. This early termination provided insufficient protection from type 1 errors.

Trials of iNO in preterm infants eligible after three days of age because of an elevated risk of BPD

Subhedar 1997

In this study, the intervention was unmasked, but the randomisation was adequately concealed by the use of sealed envelopes. The initially planned sample size was for 88 subjects. The study was terminated at a sample size of 42 because at a pre-designated 12 month review, the incidence of the primary outcome death or BPD was much higher than planned, "which would have enabled the planned outcome to be detected with a much smaller group." It was not stated whether this was a pre-designated stopping criterion. Analysis was by intention to treat. Despite randomisation, oxygenation was not well matched at baseline between the groups. Median oxygenation index in control infants was 3.9 (range 1.2 to 11.5) and in the iNO infants it was 7.9 (range 1.6 to 46.7). There was also a greater proportion of males in the iNO group (12/20 vs 5/22). Other baseline characteristics were similar.

Ballard 2006

This study was a multicentre trial with masked allocation. Study gas (iNO or nitrogen) was masked to all except the study respiratory therapist. Follow-up to assessment of the primary outcome was complete and the investigators remained masked. Analysis was by intention to treat. The study was overseen by a data safety monitoring committee, with interim analyses according to pre-planned rules. The study was allowed to proceed to the initially planned sample size.

Trials of the routine use of iNO in intubated preterm infants.

Schreiber 2003

This study was a single centre study with masked randomisation. The iNO intervention was also masked by the use of an oxygen placebo. Analysis was by intention to treat. Follow-up of enrolled infants was complete. Assessment of the primary outcome was performed in a masked fashion. It is not stated whether the long-term neurodevelopmental follow-up was also masked. The planned sample size was achieved.

Kinsella 2006

This study was a multicentre trial with masked allocation. Study gas was masked (iNO or nitrogen). The follow-up was complete with respect to the assessment of the primary outcome, which was assessed in a masked fashion. Analysis was by intention to treat. The study was overseen by a data safety monitoring committee, with interim analyses according to pre-planned rules. The study was allowed to proceed to the initially planned sample size.

Effects of interventions

The usefulness of an analyses that included all trials of iNO in premature infants was considered to be limited because of the differing entry criteria for the studies. The severity of illness criteria and age at entry varied so greatly that pooling the results was not considered appropriate. Control group mortalities also varied substantially (6% to 64%), further emphasizing the differences in the eligible patients only. Subgroup analyses are reported.

As noted above, the trials have been grouped post hoc into three categories that created groups of studies, each of which were fairly homogeneous in terms of age of entry and severity of illness criteria (and control group mortality):

1) entry in the first three days of life based on oxygenation criteria

2) routine use in intubated preterm babies

3) later enrolment based on BPD risk

The post hoc group of studies that randomised ventilated preterm infants with an oxygenation defect in the first few days of life were fairly similar. All studies randomised the infants to low dose iNO. The INNOVO 2005 study did not have clear criteria for entry, the criterion being "if the responsible physician was uncertain about whether an infant might benefit from iNO". Despite this difference, the mortality and BPD frequencies are not dissimilar to the other studies in this group. The methods used for calculation of the oxygenation defect in the remaining studies were different, and not all directly comparable. Several studies reported the OI. In this group of studies, the majority of patients were entered before three days of age, although some allowed enrolment up to seven days of age. The Srisuparp 2002 study was a pilot study of 34 infants and was primarily designed to evaluate the change in oxygenation. Srisuparp 2002 did not report on BPD. Of note, both Hascoet 2005 and Mercier 1999 allowed back up treatment of controls with iNO if their condition worsened to a prespecified degree. This may have led to an underestimate of both benefit and risk. Most of the studies in this group had comparable mortality in the control groups, with a mortality between 30 and 44%; the one exception being INNOVO, with a mortality of 64% in the controls.

Two studies evaluated infants of more than three days of age based on an elevated risk of BPD. These studies were quite different. Subhedar 1997 investigated both iNO and dexamethasone therapy using a factorial design. Infants were selected at 96 hours of age based on having a high risk of developing BPD. Indeed, the investigators found an almost universal incidence of bronchopulmonary dysplasia at 36 weeks. Ballard 2006 enrolled infants who were still ventilator dependent at seven to 21 days of age (or in the case of the smallest infants, 500 to 799 g birth weight, requiring CPAP) without other criteria for an increased BPD risk. Therefore, this trial was not similar to that of Subhedar 1997 with its unique entry criterion and factorial design. For this reason, a sensitivity analysis with and without Subhedar 1997 was performed. As the Subhedar trial had very small numbers of infants enrolled, the results of the analyses with and without this study are identical. The mortality of the control group in Ballard 2006 was only 6%, reflecting the older age at entry compared to the other two groups of studies, as well as a lower severity of illness than in the early rescue studies.

Two studies enrolled infants without specific criteria for disease severity. Schreiber 2003 randomised preterm infants who were ventilator dependent after receiving surfactant, without requiring a specific disease severity. Similarly, Kinsella 2006 enrolled infants less than 34 weeks who were ventilated and expected to be so for more than 48 hours. There were no other severity of illness criteria. Eighty percent had received surfactant. These infants were substantially less sick as demonstrated by the lower oxygenation indices than the infants in the first group of studies. The control group mortalities were again quite comparable in the two studies, 23% and 25%.

Results for each of the subgroups are given below.

DEATH PRIOR TO HOSPITAL DISCHARGE (OUTCOME 01):

All trials assessed survival to discharge and none of the individual trials showed a significant effect. The two subgroups, early studies with oxygenation criteria and entry after three days based on BPD risk, showed no effect on hospital mortality [Early studies with entry based on oxygenation criteria, typical RR 1.05 (95% CI 0.91 1.22); typical RD 0.02 (95% CI -0.04, 0.09); Entry after three days of age based on BPD risk, typical RR 1.06 (95% CI 0.64, 1.74); typical RD 0.00 (95% CI -0.04, 0.05)]. The typical estimate of the relative risk for death prior to hospital discharge from the studies of early routine use was barely significant [typical RR 0.77 (95% CI 0.60, 0.98); typical RD -0.06 (95% CI -0.11, -0.01)].

DEATH PRIOR TO 36 WEEKS POSTMENSTRUAL AGE (OUTCOME 02):

Six studies report this outcome, five of those with early entry based on oxygenation criteria. For infants entered early based on oxygenation criteria, there was no significant effect of iNO on this outcome [typical RR 0.89 (95% CI 0.72, 1.11); typical RD -0.05 (95% CI -0.13, 0.14)]. The study by Subhedar with entry after three days of age based on BPD risk also reported this result and did not show a significant effect.

BRONCHOPULMONARY DYSPLASIA (OXYGEN DEPENDENCE AMONG SURVIVORS AT 36 WEEKS POSTMENSTRUAL AGE) (OUTCOME 03):

All the published studies except Hascoet 2005 and Srisuparp 2002 reported BPD rates at 36 weeks; data from Hascoet were supplied to the review authors by the principal investigator (for four of the iNO infants and 10 of the controls data on oxygen dependency at 36 weeks were missing, although they were known to have survived.) None of the individual trials found a significant effect. There was substantial heterogeneity for each of the subgroups, and none of the subgroups noted a statistically significant difference in BPD.

Studies with entry before three days of age based on oxygenation criteria; typical RR 0.89 (95% CI 0.76, 1.05) (I2 47.8%); typical RD -0.05 (95% CI -0.12, 0.02).

Studies with entry after three days of age based on BPD risk; typical RR 0.89 (95% CI 0.78, 1.02) (I2 85.5%); typical RD -0.07 (95% CI -0.15, 0.01).

Studies of routine use in intubated preterm infants; typical RR 0.96 (95% CI 0.85, 1.08) (I2 64.4%); typical RD -0.02 (95% CI -0.09, 0.04).

DEATH OR BRONCHOPULMONARY DYSPLASIA (OUTCOME 04):

The combined outcome of death or bronchopulmonary dysplasia (or its converse, survival without bronchopulmonary dysplasia) was available for all the studies.

None of the individual trials with entry based on an oxygenation deficit found a significant effect, and this subgroup of studies showed no effect [typical RR 0.95 (95% CI 0.88, 1.02); typical RD -0.04 (95% CI -0.09, 0.02)]. Similarly, the studies with entry after three days of age based on BPD risk did not individually show a significant effect, and the group results were not significant [typical RR 0.90 (95% CI 0.80, 1.02); typical RD -0.06 (95% CI -0.14, 0.01)]. The studies of routine use of iNO in intubated preterm neonates showed a barely significant reduction [typical RR 0.91 (95% CI 0.84, 0.99), typical RD -0.06 [(95% CI -0.12, -0.01), Number Needed to Treat 17 (95% CI 8, 100)].

ANY INTRAVENTRICULAR HAEMORRHAGE (OUTCOME 05):

Three studies reported this outcome. All were studies with entry in the first three days of age based on oxygenation criteria. There was no evidence of an effect of iNO on overall IVH frequency [typical RR 1.0 (95% CI 0.73, 1.37)].

SEVERE INTRAVENTRICULAR HAEMORRHAGE (OUTCOME 06):

Six of the studies with entry in the first three days of age based on oxygenation criteria report on severe IVH. The meta-analysis of these studies showed a trend to an increased incidence of severe IVH [typical RR 1.27 (95% CI 0.99 1.62); typical RD 0.06, 95% CI 0.00, 0.13)].

Since most intraventricular haemorrhage occurs in the first three days of life, the studies with later entry would not be expected to have an effect on IVH. Evolution of pre-existing abnormalities, development of hydrocephalus, or occurrence of periventricular leukomalacia were reported as a single variable by Ballard 2006 and were not different between groups.

Of the studies of routine use of iNO in intubated preterm infants, only Kinsella reported severe IVH as a separate outcome, which was not affected by treatment [RR 0.77 (95% CI 0.55, 1.09); RD -0.04 (95% CI -0.08, 0.01)].

SEVERE INTRAVENTRICULAR HAEMORRHAGE OR PERIVENTRICULAR LEUKOMALACIA (OUTCOME 07):

The studies with entry in the first three days of age based on oxygenation criteria showed no significant effect, but there was a trend to an increase in this adverse outcome [typical RR 1.16 (95% CI 0.93, 1.44); typical RD 0.04 (95% CI -0.02, 0.10)].

The studies of routine use of iNO in intubated preterm infants showed a reduction in this outcome [typical RR 0.70 (95% CI 0.53, 0.91); typical RD -0.07 (95% CI -0.12, -0.02); NNT 14 (95% CI 8, 50)].

NEURODEVELOPMENTAL OUTCOME (OUTCOMES 08-10):

To date, the only studies to report on neurodevelopmental outcome are Schreiber 2003, INNOVO 2005 and Subhedar 1997.

Subhedar 1997: Twenty-two children were still alive at 30 months of age, and 21 of them were formally examined (seven iNO infants, and 14 controls). There were no significant differences in outcomes. The definition of "severe neurodisability" in the outcome manuscript was very similar to our definition of neurodevelopmental disability. The five infants with severe neurodisability (MDI or PDI < 71, cerebral palsy or sensorineural impairment) were all control infants.

Schreiber 2003: Schreiber's study showed a significant reduction at two years corrected age in the frequency of a composite outcome of neurodevelopmental disability (cerebral palsy, bilateral blindness, bilateral hearing loss, or a score on the Bayley scales of infant development > 2 SD below the mean). This improvement was largely the result of a decrease in the incidence of a Bayley score more than two SD below the mean. The occurrence of cerebral palsy was similar between the groups.

INNOVO 2005 reported the incidence of major disability at one year of age, which was not different between the groups. Severe disability was defined as: no/minimal head control or inability to sit unsupported or no/minimal responses to visual stimuli (equivalent to developmental quotient < 50, which can be used if at correct age). There was no difference between the groups (7/55 vs 3/53); however, the lack of formal testing and the earlier age at assessment makes this difficult to compare to Schreiber. Differences in definition did now allow these results to be combined in a meta-analysis.

SEVERE RETINOPATHY OF PREMATURITY (OUTCOME 11):

There was no evidence of an effect on severe ROP (only reported by Schreiber et al) .

RETINOPATHY REQUIRING SURGERY (OUTCOME 12)

Studies with entry before three days of age based on oxygenation criteria; typical RR 0.86 (95% CI 0.58, 1.29); typical RD -0.02 (95% CI -0.07, 0.03).

Studies with entry after three days of age based on BPD risk; typical RR 1.04 (95% CI 0.78, 1.38); typical RD 0.01 (95% CI -0.06, 0.08).

Studies of routine use in intubated preterm infants; typical RR 1.09 (95% CI 0.79, 1.50); typical RD 0.01(95% CI -0.04, 0.06).

OXYGENATION WITHIN TWO HOURS OF THERAPY

Kinsella 1999 reported an improvement in PaO2 after 60 minutes of about 40 mmHg compared to about 10 mmHg in the controls.

Subhedar 1997 reported that treated infants had a sustained fall of OI on iNO; there was a greater likelihood of a 25% reduction in oxygenation index or a 0.10 reduction in FiO2 during the first two hours in the treated infants (13/20) compared to the control infants (4/22). This was also reflected by the greater percentage decrease in oxygenation index in the treated group (16.9%) compared to the controls (no change); however, oxygenation index was higher at baseline in the treated infants.

Mercier 1999 demonstrated the effect of iNO on oxygenation at two hours, with a median 5.4 fall in OI for the nitric oxide infants, and a median 3.6 fall in OI for the controls. The oxygenation results were presented in ways that were too variable to allow meta-analysis. Overall, it appeared that improvements in oxygenation were probably more frequent when infants receive iNO compared to no therapy.

Srisuparp 2002 reported significant increases in PaO2 and SpO2 from baseline for the iNO group.

OTHER REPORTED RESULTS:

Pulmonary artery pressure:

Subhedar 1997 reported a reduction in pulmonary artery pressure as assessed by echocardiography within 30 minutes of treatment compared to no change in the control infants.

Duration of assisted ventilation:

Kinsella 1999 found a significant reduction in ventilator days among iNO survivors (median 26, range 3 to 69 days with iNO; median 37, range eight to 395 days in controls). However, Mercier 1999 reported no significant difference in the duration of assisted ventilation among survivors (iNO, median 12 days; control, median 16 days). As only median results were given, with a different descriptor of variance (inter-quartile range), a typical estimate was not currently possible. Hascoet 2005 supplied data regarding ventilator days among iNO treated survivors compared to controls [iNO 14.5 days SD 11.4 (median 9 d); controls 17.1 days SD 16.4 (median 10 d)].

Discussion

This review suggests that there may be subgroups of preterm infants who have a substantial benefit from inhaled nitric oxide therapy, with a reduction in brain injury visible on ultrasound and a potential reduction in mortality. However, even if these benefits are real, the precision of the estimates of these effects are low, and the number needed to treat may be large. There are also other subgroups in whom some evidence exists of adverse effects, specifically an increase in severe IVH, without evidence of benefit.

Mortality

None of the individual trials showed a reduction in mortality. Only the meta-analysis of the two trials that evaluated routine use of iNO in intubated infants demonstrated a potential difference. In this case, the effect was somewhat marginal. The typical RR was 0.77 (95% CI 0.60 to 0.98). The risk difference was -0.06 with a 95% CI of -0.11 to -0.01. Although this is potentially an important effect, the estimate lacks precision. The number needed to treat to save one infant may be as few as nine infants or as many as 100. The other two sub-groups show no effect on mortality.

Survival without bronchopulmonary dysplasia

The studies investigating iNO as a routine treatment in preterm infants showed a modest and barely significant reduction in the combined outcome of death or bronchopulmonary dysplasia. There was heterogeneity in this outcome (I2 of 64.6%), with the larger study (Kinsella 2006) showing no significant effect when the whole sample was analysed. A preplanned subgroup analysis within the Kinsella study reported that it was only the lower risk infants (BW > 1000 g) who had a benefit regarding this outcome. Although the overall analysis was significant in the study of Schreiber 2003, their subgroup analysis showed that it was only the less sick infants (OI less than the median) who benefited. There was no apparent benefit from iNO in studies with entry before three days of age based on oxygenation criteria.

Brain Injury

Both studies of early routine use of iNO in intubated preterm infants showed a reduction in serious ultrasound diagnosed brain injury, either severe intraventricular haemorrhage or the combined outcome of severe haemorrhage or periventricular leukomalacia. The early rescue studies showed no effect on this outcome.

The later studies with entry based on BPD risk would not be expected to affect intraventricular haemorrhage incidence.

Neurological and developmental outcome.

Limited data was available regarding longterm neurodevelopmental outcome. Neurodevelopmental outcome was not improved in the only early rescue study to report the outcome, and has not been reported by most of the studies performed to date.

As for early routine use, Schreiber 2003 demonstrated a reduction in abnormal neurodevelopmental outcome at two years of age, largely due to an improvement in the Bayley scores of mental development. The other study to show an improvement in ultrasound appearances of the brain (Kinsella 2006) has not yet reported longer term outcomes.

Although the published report of Ballard 2006 showed a significant benefit of iNO in improving survival without BPD, our analysis using the RevMan software did not show a significant effect. The source of this discrepancy is unclear. A subgroup analysis from that study suggested that it was only the younger (7 - 14 days) and less sick (severity score < 3.5) infants who benefited.

The early routine use of iNO in intubated preterm infants appeared to decrease the incidence of severe ultrasound demonstrated brain injury [typical RD -0.07 (95% CI 0.12, 0.02); NNT 14 (95% CI 8, 50)]. Although the criteria for study entry for Kinsella 2006 only required the infants to be less than or equal to 34 weeks gestation, in fact, the mean gestational age was 25.6 weeks in each group and the mean birthweight less than 800 g, demonstrating that a higher risk group was enrolled. Similarly, for Schreiber 2003, the actual birth weight was approximately 1 kg for the two groups, and the gestational age less than 28 weeks. In addition, this hospital served a somewhat deprived inner city neighbourhood, with a low rate of antenatal steroid use (less than 60%).

If a population at very low risk for serious brain injury were to be treated, the absolute benefit of iNO would be substantially less. For example, it would be very difficult to show a reduction in severe brain injury in mildly ill infants born at 30 to 32 weeks gestation. Further analysis of the patient characteristics predicting a beneficial response would be helpful. When the results of Schreiber 2003 were published, a suggestion that there might be an effect of maternal ethnicity was made in an accompanying editorial; however the somewhat similar study of Kinsella 2006 did not show an effect of ethnic group.

Based on the currently available data, infants who are less severely sick and of higher birth weight appeared to have the greatest benefit from iNO.

Authors' conclusions

Implications for practice

In very sick preterm infants who meet the criteria for poor oxygenation, rescue therapy with iNO does not improve their survival, survival without BPD, or brain injury, even though oxygenation may be improved in the short term. In fact, there is some evidence of an increase in severe intracranial haemorrhage and of the combined outcome of severe intraventricular haemorrhage or periventricular leukomalacia. In view of these findings, iNO should not be routinely used for preterm infants as a rescue therapy in cases of hypoxic respiratory failure.

In contrast, the early routine use of iNO in ventilated preterm infants who are not severely ill, but nevertheless are at risk for serious brain injury or BPD, holds promise. With only a single study reporting longer term neurodevelopmental outcomes, caution is suggested before more widespread implementation of this use. Clear criteria for treatment in this population does not currently exist.

In view of the lack of statistically significant benefit and of long term follow-up from the later use of iNO in infants who are at risk of BPD, its use in this clinical situation cannot be recommended at present.

Implications for research

Further studies of the use of inhaled nitric oxide in preterm infants are warranted to confirm and clarify the results of Schreiber 2003 and Kinsella 2006. These studies included infants who were less ill and received iNO as part of routine therapy while intubated. The apparent increase in survival without BPD and the decrease in ultrasound brain injury suggests that infants who are at significant risk for these two outcomes, but nevertheless not seriously ill, would be the most appropriate target subjects. Long term follow-up studies are needed.

Confirmation of the efficacy of such an approach is needed. This would raise questions regarding why such infants would be benefited, while more seriously ill infants would not. It is certainly possible that infants who were sick enough to fulfil the entry criteria of the rescue studies may have already suffered brain and pulmonary injury that was too severe to be improved by nitric oxide/ On the other hand, routine "prophylactic" use may be able to reduce the incidence of such injuries. This possibility warrants further research.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ballard 2006
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: Yes. Completeness of follow up: Yes. Masking of outcome assessment: Yes.
Participants582 infants < 1250 gm on assisted ventilation at 7-21 days (or, if <800 g on CPAP)
InterventionsInhaled NO at 20 ppm initial dose for 48 to 96 hours, the dose was subsequently decreased to 10, 5, and 2 ppm at weekly intervals, with a minimum treatment duration of 24 days
OutcomesSurvival without BPD at 36 wk. Secondary outcomes included the duration of oxygen therapy and the duration of hospitalisation. In addition, they prospectively evaluated the need for hospitalisation and respiratory support, including mechanical ventilation, continuous positive airway pressure, and oxygen supplementation at 40, 44, 52, and 60 weeks of postmenstrual age.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Dani 2006
MethodsSingle centre trial. Masking of allocation: Yes. Masking of intervention: No. Completeness of follow up: Yes. Masking of outcome assessment: No.
Participants40 preterm infants ventilated with severe RDS with FiO2 > 0.5 and arterial-alveolar oxygen ratio < 0.15, despite surfactant treatment.
InterventionsEither iNO at 10 ppm for 4 hours followed by 6 ppm compared to no treatment. Weaning started at 72 hours or when the infant was extubated or when the FiO2 <0.3 with a mean airway pressure <8 cmH2O.
OutcomesThe primary endpoint was death or BPD. Bronchopulmonary dysplasia was defined as oxygen requirement at 36 weeks of postmenstrual age. Secondary endpoints were the evaluation of ventilation changes during INO therapy, the duration of oxygen treatment, NCPAP, and mechanical ventilation, the incidence of PDA, pulmonary hypertension, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), sepsis, and the length of stay in the intensive care unit and in hospital
NotesStudy terminated after 40 infants enrolled. Initially planned to be 26 per group. Unplanned interim analysis was performed because of an impression that the results were significant. No evidence that the analysis was adjusted to account for potential multiple looks at the data.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Hascoet 2005
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: No. Completeness of follow up: Yes. Masking of outcome assessment: No.
Participants860 infants <32 wk enrolled, eligible for study gas if hypoxic respiratory failure i.e. need for mechanical ventilation, FIO2 >40%, and arterio-alveolar O2 ratio <0.22 at 6 to 48 hours of age, n=145.
InterventionsInhaled NO was administered starting at 5 ppm, with adjustments allowed depending on response up to a maximum of 10 ppm. There were 61 eventually treated with iNO, and 84 Controls. Subjects were allowed to receive iNO in either group if they developed refractory hypoxemia.
OutcomesPrimary Outcome was survival to 28 days without Death, need for oxygen, IVH >Grade 1 or refractory hypoxaemia defined as need for 100 oxygen, with PaO2 < 50 Secondary outcomes included incidence and severity of IVH and periventricular leukomalacia (PVL), BPD or steroid treatment, as well as pulmonary hemorrhage, patent ductus arteriosus (PDA), necrotizing enterocolitis, and nosocomial infection.
NotesProvided open label iNO to all infants whenever they met refractory hypoxaemia criteria - 20 infants received treatment before 6 hrs and were not included, and 28 control infants received open label iNO after the randomised intervention.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
INNOVO 2005
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: No. Completeness of follow up: Yes. Masking of outcome assessment: No.
Participants108 preterm infants (<34 weeks) less than 28 days of age, with "severe respiratory failure"
InterventionsInhaled NO usually at 5 ppm up to 40 ppm (n=55) or no supplemental gas (n=53)
OutcomesPrimary outcomes were 1) Death or severe disability at one year corrected postnatal age; 2) Death or continued oxygen need at expected date of birth. Secondary outcomes included 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 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, and hospital admissions
NotesInitially planned 200 subjects.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Kinsella 1999
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: Yes. Completeness of follow up: Yes. Masking of outcome measurement: Yes.
Participants80 preterm infants (< or = 34 weeks) less than 7 days of age, with a/A less than 0.1 on two blood gases after surfactant treatment.
InterventionsInhaled NO at 5 ppm (n=48) or no supplemental gas (n=32) for 7 days after which "trials off" were allowed. Maximum treatment duration was 14 days.
OutcomesPrimary outcome was survival. Bronchopulmonary dysplasia, intraventricular hemorrhage, duration of ventilation were secondary outcomes.
NotesInitially planned 210 subjects.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Kinsella 2006
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: Yes. Completeness of follow up: Yes; Masking of primary outcome: Yes.
Participants793 preterm infants < 34 wks, respiratory failure needing assisted ventilation in first 48 hours
InterventionsInhaled NO at 5 ppm (n=398) or no INO (n=395) for 21 days or until extubation
OutcomesPrimary outcome was death or Bronchopulmonary dysplasia. Secondary outcomes included severe intraventricular haemorrhage, periventricular leukomalacia, and ventriculomegaly
NotesBaseline and follow-up cranial ultrasounds were required.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Mercier 1999
MethodsMulticenter trial. Masking of allocation: Yes. Masking of intervention: No. Completeness of follow up: Yes. Masking of outcome measurement: No
Participants85 preterm infants (<33 weeks) with an OI of 12.5 to 30 at less than 7 days
Interventions10 ppm inhaled NO (n=40) or control (n=45). Open label treatment with NO allowed in controls, if OI exceeded 30.
OutcomesPrimary outcome was a decrease in OI after 2 hours of therapy
NotesInitially planned 360 infants across both gestational age strata.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Schreiber 2003
MethodsSingle centre trial. Masking of allocation: Yes. Masking of treatment : Yes. Completeness of follow up,: Yes. Masking of outcome assessment: Yes.
Participants207 infants < 34 weeks, < 72 hours of age intubated and ventilated for RDS, BW < 2000 gm
InterventionsRandomised to iNO N=105 (starting at 10 ppm for 1 day, then 5 ppm for 6 days thereafter weaned by 1 ppm, stopped if extubated) versus Control N=102; and HFOV N= 102 versus CMV N=105
OutcomesPrimary Outcome was a decrease in death or BPD at 36 weeks
NotesFactorial 2 x 2 design comparing High frequency ventilation to conventional and iNO to placebo gas.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Srisuparp 2002
MethodsSingle centre trial. Masking of allocation: Unclear. Masking of intervention: No. Completeness of follow up: Yes. Masking of outcome assessment: No.
Participants34 infants less than 2000 gm, ventilated after surfactant with an arterial catheter and less than 72 hours of age. Also required to satisfy a severity of illness criterion. OI >4 if birthweight <1000 gm. >6 for birthweight 1001-1250 gm, >8 for 1251-1500 gm, >10 for 1501-1750 gm, and >12 for 1751-2000 gm.
InterventionsiNO at 20 ppm or standard care, trial of weaning after 72 hours, maximum duration 7 days.
OutcomesPrimary outcome was severe intraventricular hemorrhage (grade 3 or 4).
NotesPerformed as a preliminary pilot study, prior to Schreiber 2003
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Subhedar 1997
MethodsSingle center randomized comparison of inhaled nitric oxide, dexamethasone, combined therapy and control, using a 2 x 2 factorial design. Masking of allocation: Yes. Masking of intervention: No. Completeness of follow-up: Yes. Masking of outcome measurement: No.
Participants42 preterm infants less than 32 weeks gestation with a "high risk" of developing BPD.
InterventionsInhaled nitric oxide initially administered at 20 ppm and weaned if effective (n=20), or control (n=22). Dexamethasone at 1 mg/kg/d for 3 days followed by 0.5 mg/kg/d for 3 days, n=21 (3 infants received a lower dose) or no steroids, n=21.
OutcomesPrimary outcome was survival without bronchopulmonary dysplasia. Secondary outcomes included duration of ventilation, intraventricular hemorrhage and other neonatal complications.
NotesInitially planned 88 subjects.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Van Meurs 2005
MethodsMulticenter trial. Multicenter trial. Masking of allocation: Yes. Masking of intervention: Yes. Completeness of follow up: Yes. Masking of outcome assessment: Yes.
Participants420 preterm infants, < 34 weeks, OI >=10 on 2 blood gases 30 min to 12 hours apart. at least 4 hours after surfactant
InterventionsInhaled Nitric Oxide initially at 5 ppm to 10 ppm ( 210) or placebo ( 210) (if no response at 10 ppm study gas was stopped). Weaning at least 10 hours after initiation, maximum duration was 336 hours.
OutcomesPrimary Outcome was reduced death or BPD at 36 weeks. Secondary outcomes were grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia, the number of days of assisted ventilation and oxygen use, the length of hospitalization, and threshold retinopathy of prematurity.
NotesInitially planned 220 infants per arm stopped by the Data monitoring committee because of apparent increase in severe IVH with no evidence of benefit.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Characteristics of excluded studies [ordered by study ID]

Lindwall 2005No untreated control group. Short term randomized crossover trial of response to iNO in infants on CPAP.
Skimming 1997No untreated control group, This was a randomized comparison of 5 and 20 ppm for 15 minutes in preterm infants.

Characteristics of ongoing studies [ordered by study ID]

EUNO
Trial name or titleThe effects of nitric oxide for inhalation on the development of chronic lung disease in pre-term infants
Methods 
ParticipantsPreterm infants
InterventionsInhaled NO compared to control
Outcomes 
Starting date 
Contact informationJ-C Mercier
NotesProjected sample size: 800 Projected end date: November 2007

Data and analyses

Download statistical data

Table Comparison 1.. Inhaled NO compared to control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death before discharge11 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Studies with entry before three days based on oxygenation7912Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.91, 1.22]
1.2 Studies with entry after three days based on BPD risk2624Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.64, 1.74]
1.3 Studies of routine use in intubated preterm infants21000Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.60, 0.98]
2 Death before 36 weeks postmenstrual age6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Studies with entry before three days based on oxygenation5458Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.72, 1.11]
2.2 Studies with entry after three days based on BPD risk142Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.74, 3.34]
3 Bronchopulmonary dysplasia among survivors at 36 weeks10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Studies with entry before three days based on oxygenation6595Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.76, 1.05]
3.2 Studies with entry after three days based on BPD risk2573Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.78, 1.02]
3.3 Studies of routine use in intubated preterm infants2961Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.85, 1.08]
4 Death or bronchopulmonary dysplasia at 36 weeks10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Studies with entry before three days based on oxygenation6864Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.02]
4.2 Studies with entry after three days based on BPD risk2624Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.80, 1.02]
4.3 Studies of routine use in intubated preterm infants21000Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.84, 0.99]
5 Intraventricular hemorrhage (all grades)3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Studies with entry before three days based on oxygenation3254Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.73, 1.37]
6 Intraventricular hemorrhage (grade 3 or 4)6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Studies with entry before three days based on oxygenation5708Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.99, 1.62]
6.2 Studies with entry after three days based on BPD risk00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
6.3 Studies of routine use in intubated preterm infants1793Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.55, 1.09]
7 Intraventricular hemorrhage (grade 3 or 4) or periventricular leukomalacia8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Studies with entry before three days based on oxygenation6807Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.93, 1.44]
7.2 Studies with entry after three days based on BPD risk00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
7.3 Studies of routine use in intubated preterm infants2947Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.53, 0.91]
8 Neurodevelopmental disability2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Studies with entry after three days based on BPD risk121Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.01, 2.71]
8.2 Studies of routine use in intubated preterm infants1138Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.33, 0.87]
9 Cerebral Palsy2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 Studies with entry after three days based on BPD risk121Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 6.90]
9.2 Studies of routine use in intubated preterm infants1138Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.40, 3.20]
10 Bayley MDI or PDI <-2SD1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Studies of routine use in intubated preterm infants1138Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.33, 0.93]
11 Severe retinopathy of prematurity (Stage 3 or more)1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 Studies of routine use in intubated preterm infants1207Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.22, 1.54]
12 Retinopathy of prematurity requiring surgery5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Studies with entry before three days based on oxygenation3608Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.58, 1.29]
12.2 Studies with entry after three days based on BPD risk1582Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.78, 1.38]
12.3 Studies of routine use in intubated preterm infants1793Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.79, 1.50]
Figure Analysis 1.1.

Comparison 1 Inhaled NO compared to control, Outcome 1 Death before discharge.

Figure Analysis 1.2.

Comparison 1 Inhaled NO compared to control, Outcome 2 Death before 36 weeks postmenstrual age.

Figure Analysis 1.3.

Comparison 1 Inhaled NO compared to control, Outcome 3 Bronchopulmonary dysplasia among survivors at 36 weeks.

Figure Analysis 1.4.

Comparison 1 Inhaled NO compared to control, Outcome 4 Death or bronchopulmonary dysplasia at 36 weeks.

Figure Analysis 1.5.

Comparison 1 Inhaled NO compared to control, Outcome 5 Intraventricular hemorrhage (all grades).

Figure Analysis 1.6.

Comparison 1 Inhaled NO compared to control, Outcome 6 Intraventricular hemorrhage (grade 3 or 4).

Figure Analysis 1.7.

Comparison 1 Inhaled NO compared to control, Outcome 7 Intraventricular hemorrhage (grade 3 or 4) or periventricular leukomalacia.

Figure Analysis 1.8.

Comparison 1 Inhaled NO compared to control, Outcome 8 Neurodevelopmental disability.

Figure Analysis 1.9.

Comparison 1 Inhaled NO compared to control, Outcome 9 Cerebral Palsy.

Figure Analysis 1.10.

Comparison 1 Inhaled NO compared to control, Outcome 10 Bayley MDI or PDI <-2SD.

Figure Analysis 1.11.

Comparison 1 Inhaled NO compared to control, Outcome 11 Severe retinopathy of prematurity (Stage 3 or more).

Figure Analysis 1.12.

Comparison 1 Inhaled NO compared to control, Outcome 12 Retinopathy of prematurity requiring surgery.

What's new

27 October 2008AmendedConverted to new review format.

History

Protocol first published: Issue 1, 1999

Review first published: Issue 1, 1999

1 March 2007New search has been performedThis review is an update of the existing review "Inhaled nitric oxide for respiratory failure in preterm infants" (Barrington 2006).
  This update includes additional information regarding completed trials by Ballard, Kinsella and Srisuparp.
  Overall analyses have been deleted as study characteristics differed too much for this to be useful. Subgroup analyses are presented instead.
1 March 2007New citation required but conclusions have not changedSubstantive amendment

Contributions of authors

Both reviewers were involved in development and writing of the review protocol, as well as performing the literature search, appraisal, and data extraction and completion of the final review.

Declarations of interest

Dr Barrington was Chair of the Canadian Medical Advisory Committee for iNO therapeutics for one meeting in 2004.

Ancillary