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