One trial followed up a selected subgroup of survivors to 18-24 months. There were no significant differences in rates of adverse neurodevelopmental outcomes including cerebral palsy and failure to achieve various milestones; however, the proportion of eligible patients seen was less than 70%.
Analyses that were planned for this review, but not able to be carried out because of lack of published data, included a sub-analysis stratified by gestational age and assessments of the effect on bronchopulmonary dysplasia and retinopathy of prematurity.
Physiologic changes occurring at the birth of a newborn infant are rapid and complex. Normally, this transition is smooth and no intervention on the part of health professionals is needed. However, about 5 - 10% of newborns require some degree of resuscitation, ranging from simple stimulation to assisted ventilation (Saugstad 1998a). It is estimated that about 19% of the over 5 million neonatal deaths worldwide annually are caused by birth asphyxia (WHO 1997). The aim of resuscitation is to prevent not only neonatal death but also the adverse long term neurodevelopmental sequelae associated with birth asphyxia.
The optimal concentration of oxygen for neonatal resuscitation is uncertain. Many textbooks and the advisory statement from the International Liaison Committee on Resuscitation (ILCOR) (Kattwinkel 1999) recommend that resuscitation of the newborn infant should be performed with 100% oxygen. This practice has been challenged by other experts in the field on the basis that little scientific evidence exists to support it. Soll 1999, while recognising the importance of consensus guidelines like the ILCOR statement, suggested that these were based on "precedent rather than clinical evidence". Milner 1998 proposed that while there is some evidence that room air is sufficient to resuscitate asphyxiated babies, there is none to suggest that air is better than 100% oxygen. He suggested a compromise, whereby 30 - 40% oxygen using a blender device should be initially used and modified according to the baby's oxygen saturation.
Evidence from animal studies suggests that room air is as effective as 100% oxygen in resuscitation. Rootwelt 1993 used a newborn pig model, resuscitating asphyxiated animals with either air or 100% oxygen. There were no significant differences between the groups with respect to blood pressure, base deficit, plasma hypoxanthine (a prognostic marker after hypoxic events, Saugstad 1988) and brain morphology.
Concerns have been raised regarding potential adverse effects of the use of excessive oxygen. Mortola 1992 showed that giving 100% oxygen for five min to newborn infants increases their work of breathing by about 45% compared to normoxic infants. This was also associated with an increase of both oxygen consumption by 25% and carbon dioxide production by 17%. The exact mechanism of these effects remains unclear (Mortola 1992). More importantly, high concentrations of oxygen may lead to the generation of excess free radicals. These may overwhelm the natural defence system and increase the risk for development of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD), especially in the preterm population (Frank 1985; Saugstad 1998b). It is also known from animal and human studies that cerebral blood flow is decreased with hyperoxia, potentially increasing the extent of ischaemic injury (Nijima 1988, Lundstrom 1995).
Birth asphyxia and the need for neonatal resuscitation are more common in the developing world. The difficulty of providing 100% oxygen is a limiting factor and if air were as effective it would be the preferred gas for neonatal resuscitation.
It is vital that resuscitation of the newborn infant is performed efficiently. Determining the concentration of oxygen that maximises efficacy and safety is an important component of efforts to further improve techniques of neonatal resuscitation.
Primary objective: To determine if the use of room air reduced the incidence of death or neurological disability when compared with the use of 100% oxygen in newborn infants requiring resuscitation.
Secondary objectives were to determine whether resuscitation using room air, as compared with oxygen, resulted in decreased rates of hypoxic-ischaemic encephalopathy, BPD or ROP; and to compare effects of room air vs oxygen on immediate clinical and biochemical responses to resuscitation. Subgroup analyses were planned on the basis of gestational age (37 or more completed weeks, less than 37 weeks).
Randomised or quasi-randomised trials
Term or preterm neonates requiring intermittent positive pressure ventilation (IPPV) at birth.
Room air versus 100% oxygen. We planned to also include trials comparing intermediate levels of oxygen supplementation with either oxygen or room air.
Primary outcomes:
1. Death (before discharge from initial hospitalisation and before age 5 years)
2. Long term neurodevelopmental outcome at age 5 years (rates of cerebral
palsy on physician assessment, developmental delay, i.e. IQ < 2 standard
deviation on validated assessment tools, e.g. the Stanford-Binet Intelligence
Scale or others)
Secondary outcomes:
3. Signs consistent with hypoxic ischaemic encephalopathy (HIE) Grade
I - III (Grade I: a clinical state of hyperalertness, hyperreflexia and hyperexcitability;
Grade II: a state of lethargy with weak Moro and sucking reflexes, seizures
and hypotonia; Grade III: a state of stupor, flaccidity and absent primitive
reflexes) (Sarnat 1976)
4. Incidence of bronchopulmonary dysplasia (BPD)
5. Incidence of retinopathy of prematurity (ROP)
6. Time to establish regular respirations
7. Time to establish heart rate > 100/min
8. Apgar scores at age five and ten minutes
9. Results of the first arterial blood gas following resuscitation within the first 2 hours of life
In addition to the above criteria which were defined a priori in the
protocol, the following outcomes were added after the eligible studies were
examined.
10. Time to first breath of more than 3 minutes
11. Heart rate at 5 minutes
12. Developmental milestones at 18 to 24 months of age including walking and talking
13. "Abnormal assessment" by a paediatrician at 18 to 24 months
14. Failure of resuscitation according to preset criteria in unblinded
studies or clinician decision to switch treatment in blinded studies
The standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004): infant and resuscitation, MEDLINE; PubMed - 1966 to December 2003: Infant, Newborn (explode) [MeSH heading] and Resuscitation (explode) [MeSH heading] and Oxygen (explode) [MeSH heading], previous reviews including cross references, expert informants and journal hand searching mainly in the English language. Unpublished studies were sought by handsearching the conference proceedings of the Society for Pediatric Research and the European Society for Pediatric Research from 1993 to 2003.
The standard methods of the Cochrane Collaboration and its Neonatal Review
Group were used. Three authors independently identified the studies to be
included, performed a quality assessment and extracted the data. Differences
were resolved after discussion between the reviewers. Reviewers based quality
assessment on 1) blinding of randomisation, 2) blinding of intervention,
3) completeness of follow up and 4) blinding of outcome measurement. The
statistical analysis used the fixed effect model. For categorical data the
relative risk (RR), risk difference (RD) and number needed to treat (NNT)
with 95% confidence intervals were calculated. Continuous data were analysed
using weighted mean difference (WMD). Additional data were provided by Professor
Vento for Vento 2003, including mortality in those randomised and clarification of number of babies included in the study.
The number of babies randomised was used as the denominator for all analyses
where possible. However, for several outcomes, notably long term followup
and blood gas analysis in Saugstad 1998 c outcome data was available for only a proportion of babies. Similarly, in Vento 2003
post-randomisation exclusions meant that the denominator varies for different
outcomes. For further details see Methodological quality of included studies
section 2.
For the summary of the included studies see also table of included studies.
Our search revealed five studies, recruiting 1302 infants, which met our inclusion criteria. Three were single centre studies (Ramji 1993; Vento 2001 a; Vento 2003) and two were multicentred studies (Saugstad 1998 c; Ramji 2003). Ramji 1993 served as a pilot study for the international collaborative study of Saugstad 1998 c. Each of the five trials reported a unique study population.
Study populations: Two studies (Vento 2001 a; Vento 2003) included only term infants; the other three recruited term and preterm infants with a birth weight over 1 kg. The proportion of included preterm infants was small (24% of all included infants) in Saugstad 1998 c, and was not indicated in Ramji 1993 or Ramji 2003. Definition of eligibility for inclusion was consistent across the studies - infants were either apneic or had gasping respirations and/or were bradycardic with a heart rate less than 80/minute. Vento 2001 a and Vento 2003 added criteria of hypotonia and nonresponsiveness to stimulation to the respiratory and heart rate parameters. Vento 2003 excluded post-randomisation babies with a pH on blood gas from the umbilical cord of greater than 7.05. Publication of a meta-analysis by Saugstad, Ramji and Vento (Saugstad 2004) indicates that 13 subjects reported in Ramji 2003 were also reported in Saugstad 1998 c. Saugstad 2004 also indicates that 18 infants reported in Saugstad 1998 c were registered twice in this study. The data included here are uncorrected i.e. as published in the initial reports of these studies. The authors have been contacted and asked to supply the outcome data on these double-counted subjects so that we may correct the data in the next update of this review.
Interventions: All five studies compared the use of room air to 100%
oxygen for the resuscitation of the newborn. All studies imply in their
methodology that the resuscitation of the newborn was performed by an experienced
member of a resuscitation team, each applying the unit's treatment protocol.
All trials allowed back-up therapy according to failure of resuscitation
criteria defined in the following section, Major outcomes. Ramji 1993; Saugstad 1998 c and Ramji 2003
allowed infants allocated to room air to receive back-up therapy with 100%
oxygen if they reached predetermined failure criteria. Infants allocated
to 100% oxygen continued to receive this therapy even if the same failure
criteria were reached. Vento 2001 a and Vento 2003
allowed back-up therapy with the alternate gas at the clinician's discretion.
No failure criteria were specified in these two trials.
Major outcomes: The primary outcomes as stated by the authors were as follows: Ramji 1993 - Apgar score and heart rate at 5 minutes, Ramji 2003 - Apgar score at 5 minutes, Saugstad 1998 c - mortality and/or moderate to severe HIE, Vento 2001 a and Vento 2003 - do not state a specific primary outcome. All studies attempted neurological examination in the neonatal period. Saugstad 1998 c
followed up a proportion of infants at 18 to 24 months, assessing their developmental
milestones and the presence or absence of cerebral palsy. Ramji 1993 and Saugstad 1998 c reported blood gas status in the first half hour of life. Saugstad 1998 c; Vento 2001 a; Vento 2003 and Ramji 2003 reported median Apgar scores following initiation of resuscitation.
All included trials reported the outcome of failure of resuscitation,
although this outcome was reported differently in different studies. The
three unblinded studies allowed infants allocated to room air to receive
back-up therapy with 100% oxygen if they reached predetermined failure of
resuscitation criteria i.e. remained cyanosed or bradycardic after 90 seconds
of resuscitation (Ramji 1993; Saugstad 1998 c; Ramji 2003). Saugstad 1998 c and Ramji 2003
also determined the number of infants in the 100% oxygen group who reached
the same failure criteria. In these 3 trials, all outcomes were reported
based on initial group of allocation. The criteria for failure of resuscitation
were not specified in the blinded studies of Vento 2001 a and Vento 2003.
It appears that the decision to use back-up therapy with the alternative
gas was based on an unsatisfactory early clinical response to resuscitation
and was made at the clinician's discretion. Vento 2001 a
reported that no infant in either group required back-up therapy. Additional
data provided by the author allowed us to determine rates of failure of resuscitation
in Vento 2003 for all randomised infants. However, Vento 2003 excluded infants who reached failure criteria from further analysis and other outcome data are not available for these infants.
The methodological quality of each trial was assessed using the criteria of the Neonatal Review Group. For each trial the following were assessed: concealment of allocation schedule, inclusion in the analysis of all randomised participants and blinding of intervention and outcome measurement.
1. Concealment of allocation schedule and generation of allocation sequence
This was inadequate in three studies (Ramji 1993; Saugstad 1998 c; Ramji 2003),
which allocated babies born on even dates to room air and those born on odd
dates to 100% oxygen. The authors were concerned that randomisation after
birth may have delayed treatment and thus reduced numbers of enrolled infants.
Saugstad 1998b reported that 16 infants mistakenly
received the alternative treatment (10 born on even days were given oxygen
and 6 born on odd days, air). Outcomes for these individuals are reported
according to the treatment they received rather than according to the group
to which they were allocated in both the original article and this review.
We will contact the authors to obtain data based on group of allocation
for future updates of this review. Vento 2001 a
described an adequate generation of allocation sequence by using random number
assignment, and the implementation of the allocated treatment was by a nurse
not involved in the resuscitation. Computer generated random numbers and
sealed envelopes were used by Vento 2003.
2. Inclusion in the analysis of all randomised participants
Short term outcomes: Four studies provided in-hospital outcome data for greater than 90% of randomised patients (Ramji 1993; Ramji 2003; Saugstad 1998 c; Vento 2001 a). Vento 2003
excluded 45 of 151 (30%) of randomised patients for the following reasons:
not fulfilling the biochemical entry requirements, having insufficient blood
taken for analysis, switching to the alternative treatment arm and loss of
blinding. Data for the outcomes "death" and "failure of resuscitation" were
provided by the author for all randomised infants. Other outcomes are reported
with the denominator of the remaining 106 infants. The validity of these
outcome data is reduced by the high rate of post-randomisation exclusions.
Three studies (Ramji 1993; Saugstad 1998 c; Ramji 2003)
included infants resuscitated in air, who were later switched to 100% oxygen;
these infants were analysed by intention to treat. Vento 2001 a reported that all infants received only the allocated treatment.
Long term outcomes: Saugstad 1998 c
attempted follow-up of infants in 7 of the 10 participating centres. Of the
331 eligible infants, 213 were seen by a paediatrician between 18 and 24
months of age.
3. Blinding of intervention
Two studies (Vento 2001 a and Vento 2003)
achieved blinding of the intervention by having the nurse in charge, who
was not involved with the resuscitation, switch the hidden oxygen blender
to either 21% or 100% oxygen. The other three studies (Ramji 1993; Ramji 2003; Saugstad 1998 c) were unblinded. The decision to use back-up therapy was made blind to allocated treatment in Vento 2001 a and Vento 2003 but was not blinded in Ramji 1993; Ramji 2003 and Saugstad 1998 c.
4. Blinding of outcome measurement
No attempt was made to blind outcome assessment in Ramji 1993; Saugstad 1998 c or Ramji 2003. Adequate blinding was achieved by Vento 2001 a and Vento 2003.
1. Death at latest followup (Table 01)
Four studies reported this outcome (Ramji 1993; Ramji 2003; Saugstad 1998 c and Vento 2003). The results of the pooled analysis were heavily influenced by Saugstad 1998 c and Ramji 2003,
which had by far the largest number of recruited neonates. No individual
study found a significant effect. Pooled analysis showed a significant reduction
in mortality in the group allocated to room air [typical RR 0.71 (0.54, 0.94),
typical RD -0.05 (-0.08, -0.01), NNT 20 (12, 100)].
2. Long term neurodevelopmental outcome at age 5 years
No studies reported this outcome using validated assessment tools as
specified in the protocol. The following outcomes are presented as post hoc
findings after review of included studies (Table 02). Saugstad 1998 c
followed up a proportion of eligible infants to 18 to 24 months. There was
no significant difference in the rates of cerebral palsy between groups [RR
1.34 (0.55, 3.24)]. No formal psychometric testing was undertaken; however,
an assessment of achievement of motor and language milestones was presented
and is included in this review as a post hoc analysis. There were no significant
differences in rates of not walking [RR 1.03 (0.47, 2.25)] or not talking
[RR 2.68 (0.69, 10.44)]. Likewise, there was no significant difference in
rates of "abnormal development" as assigned by the examining pediatrician
[RR 1.56 (0.76, 3.22)].
3. Hypoxic ischaemic encephalopathy Grade II or III (Sarnat 1976) (Table 03)
Three trials reported this outcome (Ramji 1993; Ramji 2003 and Saugstad 1998 c).
No individual study found a significant effect and the pooled analysis showed
no significant difference in the rate of Grade II or III encephalopathy [typical
RR 0.84 (0.65, 1.08), typical RD -0.01 (-0.06, 0.04)].
Three studies presented neurological outcomes in the neonatal period (Ramji 1993; Vento 2001 a and Vento 2003).
These are presented as post hoc findings as we did not include this outcome
in our protocol. A full neurological examination at 28 days was reported
as normal in the 72 of 77 surviving infants assessed by Ramji 1993. Vento 2001 a
reported "no differences" between the groups in clinical, EEG or cranial
ultrasound outcomes at 28 days but did not report the details of data collected.
Vento 2003 reported no abnormalities on cranial
ultrasound or EEG assessment in either group and no difference in the rate
of abnormal neurological findings on structured examination.
4. Incidence of bronchopulmonary dysplasia (BPD)
None of the studies reported this outcome.
5. Incidence of retinopathy of prematurity (ROP)
None of the studies reported this outcome.
6. Time to establish regular respirations
Vento 2001 a reported that the time needed
for the onset of "sustained respiratory pattern" was longer in the oxygen
group compared with the room air group (p<0.05). The comparison was illustrated
in graphical form but numerical data were not provided. Vento 2003
found a significantly shorter time to onset of spontaneous respiration in
infants resuscitated with room air [MD -1.5 minutes (-2.02, -0.98)] (Table
04).
The included studies reported a number of related outcomes not listed
in the protocol for this review. They are, therefore, presented as post
hoc findings. Saugstad 1998 c reported
the proportion of neonates who had their first breath after three minutes
(Table 05). This was significantly reduced in the room air group compared
to the oxygen group, RR 0.53 (0.35, 0.80)]. Ramji 1993
reported that the median time of first breath and interquartile range was
identical for both groups of infants [1.5 minutes (1.0, 2.0)]. Saugstad 1998 c
reported a significantly shorter median (95% CI) time to first breath in
the room air group [1.1 minutes (1.0, 1.2)] compared with those resuscitated
with 100% oxygen [1.5 minutes (1.4, 1.6)].
7. Time to establish heart rate > 100/min
This outcome was not reported by any of the studies. Saugstad 1998 c reported no significant difference in heart rates over the first 30 minutes using repeated measures ANOVA. Ramji 2003 found no significant difference in mean heart rate at 5 minutes of age [MD 0.40 (-2.65, 3.45)] (Table 06).
8. Apgar scores at age five and ten minutes
All five studies reported median Apgar scores. Pooled analysis of this outcome was therefore not possible. Ramji 1993
reported a small difference in median (interquartile range) 5 minute Apgar
scores that was statistically significant, favouring the room air group [8
(7, 9) vs 7 (6, 8)]. Saugstad 1998 c
reported a nonsignificant trend favouring room air for median (95% CI) 5
minute Apgar scores [8 (4, 9) vs 7 (3, 9)] which disappeared at 10 minutes
[8 (5, 10) vs 8 (3.5, 9)]. Vento 2001 a; Vento 2003 and Ramji 2003 found no significant difference in median 5 and 10 minute Apgar scores.
In a related outcome not listed in the protocol, Saugstad 1998 c
reported the proportion of infants with 5 minute Apgar scores less than 7
(Table 7). The result, of borderline statistical significance, favoured the
room air group [RR 0.78 (0.60, 1.00), RD -0.07 (-0.14, 0.00)].
9. Results of the first arterial blood gas within the first 2 hours of life (Table 08)
One study (Vento 2001 a) performed only
an arterial cord blood gas analysis, but no blood gas analysis following
resuscitation. The data from this study were therefore not included in our
analysis. Three studies (Ramji 1993; Saugstad 1998 c; Vento 2003) reported arterial blood gases at 10 to 15 minutes of life.
No individual study found a significant difference in pH and the pooled
analysis also showed no significant difference [WMD 0.01 (-0.01, 0.04)].
Vento 2003 found a significantly lower level
of pCO2 in babies randomised to room air [MD -2.13 mmHg, (-4.08, -0.18)].
The pooled analysis showed a small but significant reduction in pCO2 in babies
allocated to room air [WMD -2.13 mmHg (-4.08, -0.18)].
Vento 2003 reported a significantly lower
pO2 in babies resuscitated with room air [MD -54.10 mmHg (-60.16, -48.04)]
and the pooled analysis also demonstrated a lower pO2 in this group [WMD
-37.09 mmHg (-41.99, -32.19)]. We detected but could not explain significant
heterogeneity in this pooled analysis (p<0.001).
Ramji 1993 and Saugstad 1998 c
reported base deficit. There were no statistically significant differences
for this outcome in the individual trials or the pooled analysis [WMD -0.11
mEq/L (-1.24, 1.02)].
10. Failure of resuscitation (Table 09)
This outcome was included after the results of the included studies were
examined, i.e. it represents a post hoc analysis. All five studies reported
the rate of failure of resuscitation in babies allocated to room air. Ramji 1993
reported that 6 of 42 infants allocated to room air reached failure criteria
but did not report this outcome for babies allocated to 100% oxygen. None
of the other four trials (Ramji 2003; Saugstad 1998 c; Vento 2001 a; Vento 2003)
individually showed a difference in this outcome, and pooled analysis showed
that there was no significant difference in the rates of failure of resuscitation
between the two groups [typical RR 0.96 (0.81, 1.14), typical RD -0.01 (-0.06,
0.04)].
Whether to use air or 100% oxygen for resuscitation of newborn infants at birth is a very important clinical question. We were disappointed that only five controlled studies enrolling a total of 1302 infants could be identified. There are a number of possible reasons for the lack of studies. Firstly, the use of 100% oxygen has been an established treatment for many decades, recommended by experts and used by generations of clinicians. It is therefore difficult to test its effectiveness and safety. Secondly, it is difficult to implement a randomised controlled study within the setting of an acute and unpredictable event, such as the resuscitation of a compromised newborn.
Though two studies included preterm neonates with birth weight of over 1 kg, the total number remained small and no separate analysis was reported. We were therefore not able to perform a sub-group analysis of effects on outcomes in the preterm population as we intended in our protocol.
Caution should be exercised in the application of the results of this meta-analysis for two reasons. Firstly, the majority of infants from the three biggest studies (Ramji 1993; Saugstad 1998 c; Ramji 2003) were recruited in developing countries, where ante- and perinatal care, resuscitation equipment and perinatal mortality rates differ from those in developed countries. Therefore it is uncertain whether the results of these studies can be applied to hospitals in countries with more resources. Secondly, there are methodological problems which may affect the validity of the results. Randomisation and blinding were inadequate in three studies (Ramji 1993; Saugstad 1998 c; Ramji 2003). Furthermore, the short follow up time of 28 days in most studies and the limitations of the one study (Saugstad 1998 c) that did attempt long term follow-up (high drop out rate, lack of blinding of assessors, no standardised psychometric testing) leave unanswered the important question of which treatment is more effective in minimising neurodevelopmental impairment.
The reported death rates in included studies showed a significant difference favouring the room air group. This was heavily influenced by the multicenter trials of Saugstad 1998 c and Ramji 2003, which enrolled a total of 1040 infants. There were no deaths in either arm of the trial in the three European centres participating in Saugstad 1998 c. Long term followup (Saugstad 1998 c), with the limitations outlined above, showed no significant difference in rates of adverse neurodevelopmental outcomes.
The use of back-up oxygen in babies allocated to room air has important implications for the applicability of the results of this systematic review. Although the number of babies reaching failure of resuscitation criteria did not differ between the groups, 168 of 635 (26.5%) allocated to room air in the five trials received back-up use of 100% oxygen.
Results favouring the room air group for some short term outcomes (proportions not crying by three minutes and proportions having five minute Apgar scores less than seven) are notable and should stimulate further evaluation of this policy. The clinical importance of a higher arterial pO2 in the 100% oxygen group is uncertain. The other outcomes, such as symptoms suggestive of HIE or the other arterial blood gas parameters, were not significantly different.
A systematic review and meta-analysis has been undertaken by Saugstad, Ramji and Vento (Saugstad 2004). Their overall findings, with respect to neonatal mortality, were similar to ours. However, differences in numbers of included subjects are noted. Saugstad 2004 was able to take into account the double counting issues apparent in Saugstad 1998 c and Ramji 2003. Saugstad 2004 was also able to include the subset of randomised subjects reported in Vento 2001 b, which resulted in a larger total number of patients included (1737 vs 1302 in our review). Saugstad 2004 did not report separately one of the studies we included (Vento 2001 a). Interestingly, Vento 2001 b reported a much greater treatment effect favouring air than other included studies. Odds ratios were used by Saugstad 2004; for mortality Vento 2001 b reported an OR of 0.11 (0.01, 0.90) compared to an pooled OR of 0.57 (0.42, 0.78) in this review. Although no formal measure of heterogeneity was reported in Saugstad 2004, it is likely that inclusion of this study would lead to substantial heterogeneity for the pooled outcome of mortality. This is in contrast to the consistency observed in the studies included in our review.
The trials of Saugstad 1998 c and Ramji 2003 demonstrate that relatively large trials are possible, and Vento (Vento 2001 a; Vento 2003) has shown that randomisation of participants and blinding of caregivers can be achieved. The methodological limitations of the studies included in this review preclude a definitive answer to the question of whether room air or 100% oxygen is the superior gas in the resuscitation of the newborn at birth. However, note must be taken of the reduced mortality in room air group in the pooled analysis.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Ramji 1993 | Concealment of allocation: No - quasi-randomised by date of birth (even dates=room air, odd dates=100% oxygen) Blinding of intervention: No Completeness of followup: Yes for short-term outcomes - 100% followup for in-hospital outcomes but No for outcomes at 28 days (86%) Blinding of outcome measurement: No | Single centre study. 84 neonates with apnoea and/or heart rate < 80 bpm and a birth weight > 999 g. | Room air (n=42) or 100% oxygen (n=42) via intermittent positive pressure ventilation (IPPV) with ambu bag and mask at 60 bpm. Backup use of 100% O2 allowed for room air group, if baby remained cyanotic or bradycardic at 90 sec (all infants analysed on an intention to treat basis). | Death. Arterial blood gas status at 10 and 30 minutes of life. Neurological examination at 0-3, 4-7 and 28 days of life. | This study was designed in Oslo, Norway and performed in New Delhi, India. It served as a pilot study for a bigger study (Saugstad 1998). | C |
| Ramji 2003 | Concealment of allocation: No - quasi-randomised by date of birth (even dates=room air, odd dates=100% oxygen) Blinding of intervention: No Completeness of followup: Yes. Blinding of outcome measurement: No | Multicentred (4 Indian units) study. 431* neonates weighing more than 1000g having a heart rate <100/minute and/or apneic and unresponsive to stimulation. Excluded lethal anomalies, hydrops fetalis, congenital pulmonary or cardiac defects. | Room air (n=210) or 100% oxygen (n=221) via intermittent positive pressure ventilation (IPPV) with infant resuscitation bag and mask at 60 bpm. Backup use of 100% O2 allowed for room air group, if baby remained cyanotic or bradycardic at 90 sec (all infants analysed on an intention to treat basis). | Death in first 7 days. Apgar scores at 1, 5 and 10 minutes, time to first breath and to first cry, duration of resuscitation, hypoxic ischemic encephalopathy (Sarnat classification) in first week. | C | |
| Saugstad 1998 c | Concealment of allocation: No - quasi-randomised by date of birth (even=room air, odd=100% oxygen), Blinding of intervention: No, Complete follow-up: Yes (91%) for short term outcomes, No for long term (<70% of eligible infants from the 7 of 10 participating centres had 18 month follow-up). Blinding of outcome assessment: No | Multicentred (11 units) study. 609** neonates with apnoea or gasping and/or heart rate < 80 bpm and a birth weight > 999 g. | Room air (n=288) or 100% oxygen (n=321) via IPPV with ambu bag and mask at 40 - 60 bpm. Endotracheal intubation, if necessary. Backup use of 100% O2 allowed for room air group, if baby remained cyanotic or bradycardic at 90 sec (all infants analysed on an intention to treat basis). | Primary: Death within 1 week and by 28 days and/or presence of HIE grade 2 - 3. Secondary: Apgar score at 5 min, heart rate at 90 s, time to first cry, arterial blood gases and neurological examination at 28 days of life. Long term follow-up performed by experienced paediatricians at 18 to 24 months. Motor and language milestones and the presence/absence of cerebral palsy were assessed. An overall judgement of whether "abnormal development" was present was made but the criteria for this diagnosis were not specified. | This study was conducted in 11 centers from six countries. | C |
| Vento 2001 a | Concealment
of allocation: Yes - nurse not involved in the resuscitation switched between
21% and 100% oxygen on the basis of random number. Blinding of intervention:
Yes Complete followup: Yes for in-hospital outcomes but uncertain for 28
day outcomes. Blinding of outcome assessment: Yes. | Single centre study. 40 term neonates with clinical and blood gas changes consistent with asphyxia: apneic, hypotonic, unresponsive to stimuli and bradycardic (heart rate < 80/min). | Room air (n=19) or 100% oxygen (n=21) via IPPV with bag and mask at 30 bpm. The other set parameters were a maximal gas flow of 6 L/min and a maximum inspiratory pressure of 40 mbar. Backup use of 100% O2 allowed for room air group and vice versa, at the clinician's discretion. | Apgar scores at 1, 5, and 10 minutes. Time of first cry and time of onset of regular respirations. Neurological examination, cranial ultrasound and electroencephalogram at 28 days of life. | No babies in either group received backup therapy. | A |
| Vento 2003 | Concealment of allocation: Yes - sealed opaque envelope. Blinding of intervention: Yes - nurse not involved in the resuscitation switched between 21% and 100% oxygen for resuscitation. Complete follow-up: No - 45 of 151 randomised excluded after randomisation. Outcome assessment blind: Yes. | Single centre study. 151 term infants were randomised. Published outcome data were available for 106 neonates with clinical and blood gas signs of asphyxia which included - hypotonic, apneic, unresponsive to external stimuli, pale, bradycardic (heart rate < 80/min) and pH less than or equal to 7.05. | Room air (n=51) or 100% oxygen (n=55) via IPPV with bag and mask. Otherwise "standard" warming suctioning and endotracheal intubation at clinical team's discretion. Backup use of 100% O2 allowed for room air group and vice versa at the clinician's discretion. | Apgar scores at 1, 5, and 10 minutes. Time of first cry and time of onset of regular respirations. Arterial blood gases at time of first spontaneous breath and when "clinically stable". Structured neurological exam, EEG and cranial ultrasound at 1 week and 1 month of age. | Data on death and failure of resuscitation provided by Prof Vento for all babies randomised. | A |
| Study | Reason for exclusion |
| Vento 2001 b | This study presented a single centre's experience over 6 years using air for newborn resuscitation. Included in the 830 infants reported in this article were an unspecified number randomised to either air or 100% oxygen. Outcomes of randomised infants are not reported separately in this paper. and it was therefore excluded from this review. |
Ramji S, Ahuja S, Thirupuram S, Rootwelt T, Rooth G, Saugstad OD. Resuscitation of asphyxiated newborn infants with room air or 100% oxygen. Pediatric Research 1993;34:809-11.
Ramji 2003 {published data only}
Ramji S, Rasaily R, Mishra P, Narang A, Jayam S, Kapoor A, Kambo I, Mathur A, Saxena N, Saxena B. Resuscitation of asphyxiated newborns with room air or 100% oxygen at birth: A multicentric clinical trial. Indian Pediatrics 2003;40:510-17.
Saugstad 1998 c {published data only}
Saugstad O, Ramji S, Irani S, El-Meneza S, Hernandez E, Vento M, Talvik T, Solberh R, Rootwelt T, Aalen O. Resuscitation of newborn infants with 21% or 100% oxygen: Follow-up at 18 to 24 months. Pediatrics 2003;112:296-300.
* Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: The Resair 2 study. Pediatrics 1998;102(1):e1.
Vento 2001 a {published data only}
Vento M, Asensi M, Sastre J, Garcia-Sala F, Pallardo FV, Vina J. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 2001;107:642-47.
Vento 2003 {published data only}
Vento M, Asensi M, Sastre J, Lloret A, Garcia-Sala F, Vina J. Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. Journal of Pediatrics 2003;142:240-46.
Vento M, Asensi M, Sastre J, Garcia-Sala F, Vina J. Six years of experience with the use of room air for the resuscitation of asphyxiated newly born term infants. Biology of the Neonate 2001;79:261-7.
* indicates the primary reference for the study
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| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Room air versus 100% oxygen | ||||
| 01 Death at latest follow up | 4 | 1275 | RR (fixed), 95% CI | 0.71 [0.54, 0.94] |
| 02 Long term neurodevelopmental outcome | RR (fixed), 95% CI | Subtotals only | ||
| 03 Hypoxic ischemic encephalopathy Grade 2 or 3 | 3 | 1124 | RR (fixed), 95% CI | 0.84 [0.65, 1.08] |
| 04 Onset of spontaneous respiration (min) | 1 | 106 | WMD (fixed), 95% CI | -1.50 [-2.02, -0.98] |
| 05 Time to first breath more than 3 minutes | 1 | 605 | RR (fixed), 95% CI | 0.53 [0.35, 0.80] |
| 06 Heart rate at 5 minutes | 1 | 431 | WMD (fixed), 95% CI | 0.40 [-2.65, 3.45] |
| 07 5 minute Apgar score < 7 | 1 | 609 | RR (fixed), 95% CI | 0.78 [0.60, 1.00] |
| 08 First arterial blood gas after resuscitation within 2 h of life | WMD (fixed), 95% CI | Subtotals only | ||
| 09 Failure of resuscitation | 3 | 1231 | RR (fixed), 95% CI | 0.96 [0.81, 1.14] |
Prof Andreas A Schulze, MD
Professor
Obstetrics and Gynecology
Ludwig Maximilian University, Klinikum Grosshadern, Munechen
Muenchen
GERMANY
E-mail: Andreas.Schulze@gyn.med.uni-muenchen.de
Dr Anton Tan
Specialist Registrar
Paediatric Department
Alder Hey Children's Hospital
Eaton Road
Liverpool
UK
L12 2AP
E-mail: toni.tan@doctors.org.uk
| The review is published as a Cochrane review in The
Cochrane Library, Issue 2, 2005 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |