Resuscitation of Asphyxiated Newborn Infants With Room Air or
Oxygen: An International Controlled Trial: The Resair 2 Study
Ola Didrik Saugstad, MD*; Terje Rootwelt, MD*; and Odd Aalen, PhD‡
ABSTRACT. Objective. Birth asphyxia represents a
serious problem worldwide, resulting in ;1 million
deaths and an equal number of serious sequelae annually. It is therefore important to develop new and better
ways to treat asphyxia. Resuscitation after birth asphyxia
traditionally has been carried out with 100% oxygen, and
most guidelines and textbooks recommend this; however, the scientific background for this has never been
established. On the contrary, theoretic considerations indicate that resuscitation with high oxygen concentrations
could have detrimental effects. We have performed a
series of animal studies as well as one pilot study indicating that resuscitation can be performed with room air
just as efficiently as with 100% oxygen. To test this more
thoroughly, we organized a multicenter study and hypothesized that room air is superior to 100% oxygen
when asphyxiated newborn infants are resuscitated.
Methodology. In a prospective, international, controlled multicenter study including 11 centers from six
countries, asphyxiated newborn infants with birth
weight >999 g were allocated to resuscitation with either
room air or 100% oxygen. The study was not blinded, and
the patients were allocated to one of the two treatment
groups according to date of birth. Those born on even
dates were resuscitated with room air and those born on
odd dates with 100% oxygen. Informed consent was not
obtained until after the initial resuscitation, an arrangeFrom the *Department of Pediatric Research, National Hospital, Oslo, Norway, and the ‡Section of Medical Statistics, University of Oslo, Oslo, Norway.
Resuscitation of Asphyxiated Newborn Infants With Room Air or Oxygen:
The Second Multicenter Study (Resair 2) study group participants: S. Ramji,
MD, Department of Pediatrics, Maulana Azad Medical College, New Delhi,
India; S. F. Irani, MD, Department of Pediatrics, King Edward Memorial
Hospital, Bombay, India; S. Jayam, MD, Kasturba Hospital for Women and
Children, Madras, India; S. El-Meneza, MD, Faculty of Medicine for Girls,
Al-Azhar University, Cairo, Egypt; A. Narang, MD, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India; M. Khasaba, MD, Department of Pediatrics, Mansoura, Egypt;
S. Sallab, MD, Department of Pediatrics, Mansoura, Egypt; E. A. Hernandez,
MD, Department of Pediatrics, Santo Thomas University Hospital, Manila,
Philippines; T. Talvik, MD, Children’s Hospital, Tartu University, Tartu,
Estonia; P. Ilves, MD, Children’s Hospital, Tartu University, Tartu, Estonia;
G. Samy Aly, PhD, Institute of Childhood Studies, Ain Shams University,
Cairo, Egypt; M. Vento, MD, Department of Pediatrics, Hospital Catolico,
“Casa de Salud” De Santa Ana, Valencia, Spain; F. Garcia-Sala, Department
of Pediatrics, Hospital Catolico, “Casa de Salud” De Santa Ana, Valencia,
Spain; R. Solberg, MD, Department of Pediatrics, Vestfold County Central
Hospital, Tønsberg, Norway.
Resair 2 steering committee members: O. D. Saugstad, MD (Principal Investigator), T. Rootwelt, MD, O. Aalen, PhD, Department of Pediatric
Research, The National Hospital and Institute for Medical Statistics, University of Oslo, Oslo, Norway.
Received for publication Jan 20, 1998; accepted Apr 3, 1998.
Reprint requests to (O.D.S.) Department of Pediatric Research, Rikshospitalet, 0027 Oslo, Norway.
PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Academy of Pediatrics.
ment in agreement with the new proposal of the US Food
and Drug Administration’s rules governing investigational drugs and medical devices to permit clinical research on emergency care without the consent of subjects. The protocol was approved by the ethical
committees at each participating center. Entry criterion
was apnea or gasping with heart rate <80 beats per
minute at birth necessitating resuscitation. Exclusion criteria were birth weight <1000 g, lethal anomalies, hydrops, cyanotic congenital heart defects, and stillbirths.
Primary outcome measures were death within 1 week
and/or presence of hypoxic–ischemic encephalopathy,
grade II or III, according to a modification of Sarnat and
Sarnat. Secondary outcome measures were Apgar score at
5 minutes, heart rate at 90 seconds, time to first breath,
time to first cry, duration of resuscitation, arterial blood
gases and acid base status at 10 and 30 minutes of age,
and abnormal neurologic examination at 4 weeks.
The existing routines for resuscitation in each participating unit were followed, and the ventilation techniques described by the American Heart Association
were used as guidelines aiming at a frequency of manual
ventilation of 40 to 60 breaths per minute.
Results. Forms for 703 enrolled infants from 11 centers were received by the steering committee. All 94 patients from one of the centers were excluded because of
violation of the inclusion criteria in 86 of these. Therefore, the final number of infants enrolled in the study
was 609 (from 10 centers), with 288 in the room air group
and 321 in the oxygen group.
Median (5 to 95 percentile) gestational ages were 38
(32.0 to 42.0) and 38 (31.1 to 41.5) weeks (NS), and birth
weights were 2600 (1320 to 4078) g and 2560 (1303 to 3900)
g (NS) in the room air and oxygen groups, respectively.
There were 46% girls in the room air and 41% in the
oxygen group (NS). Mortality in the first 7 days of life
was 12.2% and 15.0% in the room air and oxygen groups,
respectively; adjusted odds ratio (OR) 5 0.82 with 95%
confidence intervals (CI) 5 0.50 –1.35. Neonatal mortality
was 13.9% and 19.0%; adjusted OR 5 0.72 with 95% CI 5
0.45–1.15. Death within 7 days of life and/or moderate or
severe hypoxic–ischemic encephalopathy (primary outcome measure) was seen in 21.2% in the room air group
and in 23.7% in the oxygen group; OR 5 0.94 with 95%
CI 5 0.63–1.40.
Heart rates did not differ between the two groups at
any time point and were (mean 6 SD) 90 6 31 versus
93 6 33 beats per minute at 1 minute and 110 6 27 versus
113 6 30 beats per minute at 90 seconds in the room air
and oxygen groups, respectively.
Apgar scores at 1 minute (median and 5 to 95 percentiles) were significantly higher in the room air group (5 [1
to 6.7]) than in the oxygen group (4 [1 to 7]); however, at
5 minutes there were no significant differences, with 8 (4
to 9) versus 7 (3 to 9). There were significantly more
infants with very low 1-minute Apgar scores (<4) in the
oxygen group (44.4%) than in the room air group (32.3%).
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PEDIATRICS Vol. 102 No. 1 July 1998
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There also were significantly more infants with 5-minute
Apgar score <7 in the oxygen group (31.8%) than in the
room air group (24.8%). There were no differences in acid
base status or SaO2 during the observation period between the two groups. Mean (SD) PaO2 was 31 (17) versus
30 (22) mm Hg in cord blood in the room air and oxygen
groups, respectively (NS). At 10 minutes PaO2 was 76 (32)
versus 87 (49) mm Hg (NS), and at 30 minutes, the values
were 74 (29) versus 89 (42) mm Hg in the room air and
oxygen groups, respectively.
Median (95% CI) time to first breath was 1.1 (1.0 –1.2)
minutes in the room air group versus 1.5 (1.4 to 1.6)
minutes in the oxygen group. Time to the first cry also
was in mean 0.4 minute shorter in the room air group
compared with the oxygen group. In the room air group,
there were 25.7% so-called resuscitation failures (bradycardia and/or central cyanosis after 90 seconds) that were
switched to 100% oxygen after 90 seconds. The percentage of resuscitation failures in the oxygen group was
29.8%.
Conclusions. This study with patients enrolled primarily from developing countries indicates that asphyxiated newborn infants can be resuscitated with room air
as efficiently as with pure oxygen. In fact, time to first
breath and first cry was significantly shorter in room airversus oxygen-resuscitated infants. Resuscitation with
100% oxygen may depress ventilation and therefore delay the first breath. More studies are needed confirming
these results before resuscitation guidelines are changed.
Pediatrics 1998;102(1). URL: http://www.pediatrics.org/
cgi/content/full/102/1/e1; asphyxia, newborn infant, room
air, resuscitation, oxygen.
ABBREVIATIONS. HIE, hypoxic–ischemic encephalopathy; CI,
confidence interval; ANOVA, analysis of variance; OR, odds ratio.
B
irth asphyxia continues to represent a major
clinical problem, and worldwide ;4 million
newborn infants are affected annually. It has
been estimated that of these, 1 million die, and an
approximately equal number develop sequelae such
as cerebral palsy, mental retardation, and epilepsy.1
Although birth asphyxia is a more serious problem
in developing countries, still ;6/1000 newborn
infants in developed countries develop hypoxic–
ischemic encephalopathy (HIE) after birth asphyxia,2
and ;25% of the moderate and 75% to 100% of the
severe cases later have major neurodevelopmental
sequelae.3 Therefore it is important to develop new
and more effective ways to prevent and treat
asphyxia.
Traditionally, newborn infants have been resuscitated with 100% oxygen. In fact, most textbooks and
guidelines in the field recommend the use of 80% to
100% O2.4,5 Although neonatal resuscitation is frequently performed, we have not been able to find
any scientific basis for this recommendation. The
only related experimental study took place in the
1960s, and this study indicates that the outcome in
newborn rabbits resuscitated with room air is comparable with the outcome with 100% O2.6
To investigate whether newborn infants can be
resuscitated with room air, we performed a series of
animal experiments before we carried out a clinical
pilot study in which we resuscitated 42 asphyxiated
newborn infants with room air and 42 with 100% O2.7
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We were able to demonstrate that room air was as
efficient as 100% O2 for resuscitation with regard to
normalization of heart rate, time to first breath, and
acid base status during the first 30 minutes of life.
Apgar scores at 5 minutes were significantly higher
in the room air group. There were no significant
differences between the groups for neurologic symptoms or survival during the first week of life. The
small number of infants in that study precluded
more extensive statistical analyses. Therefore, to test
our hypothesis further, a larger sample size was
needed. Accordingly, a multicenter study was initiated; the results are reported in this article.
METHODS
The protocol was approved by the ethical committee for human
investigation at each participating center. For practical reasons,
informed consent could not be obtained before enrollment. After
resuscitation, informed consent for continued inclusion in the
planned follow-up study was obtained from the parents. This
arrangement was approved by the ethical committees and is in
agreement with the consensus statement from the coalition conference of acute resuscitation and critical care researchers, and the
new proposal of the US Food and Drug Administration’s rules
governing investigational drugs and medical devices to permit
clinical research on emergency care without the consent of the
subjects.8,9
Hypothesis and Study Organization
The hypothesis of the study was that room air is superior to
100% oxygen when asphyxiated newborn infants are resuscitated.
The study was organized as an international multicenter trial with
11 participating centers from six countries. The steering committee
was located in Oslo, Norway. There were one or two contact
persons responsible for the organization at each participating
center. None of the participants had any conflicts of interest.
Based on the sample size calculation and the approximate
incidences of birth asphyxia at the participating centers, the necessary period for recruiting patients was estimated to be 18
months. However, it was decided before the study started that the
enrollment period should not exceed 2 years. Patients were enrolled from June 1, 1994, to May 31, 1996; some of the centers
joined the study after it had started.
Criteria for Inclusion and Exclusion
The entry criterion for enrollment in the study was apnea or
gasping with heart rate ,80 beats per minute at birth necessitating
resuscitation. Exclusion criteria were birth weight ,1000 g, lethal
anomalies, hydrops, cyanotic congenital heart defects, and stillbirths. A stillbirth was diagnosed when a heart rate was never
established.
Treatment Allocation and Guidelines for Management
For practical reasons, the study was not blinded. In addition,
after thorough considerations it was decided that formal randomization was not feasible in this study. Because resuscitation is a
medical emergency requiring immediate treatment, we were concerned that a formal randomization (with, for instance, sealed
envelopes) could have resulted in a delay in treatment. Such a
delay also may have resulted in a reduced number of enrolled
infants, especially the most depressed infants, possibly giving a
nonrepresentative sample. As in the pilot study,7 the infants were
therefore placed in one of the two treatment groups according to
date of birth. Those born on even dates were resuscitated with
room air (room air group), and those born on odd dates were
resuscitated with 100% oxygen (oxygen group).
The existing routines for resuscitation in each participating unit
were followed. A face mask and bag were used, and the infants
were intubated endotracheally when necessary. The ventilation
techniques described by the American Heart Association were
used as guidelines4 aiming at a frequency of manual ventilation of
40 to 60 breaths per minute. At each center, at least two trained
people involved in the study took part in the resuscitation of all
RESUSCITATION OF ASPHYXIATED NEWBORNS WITH ROOM AIR OR OXYGEN
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infants in the study. Resuscitation started immediately after delivery of the infant when a stop watch was started by one of the
members of the resuscitation team.
To reduce any incremental risk of this study to a minimum as
in the pilot study, if an infant treated with room air did not
respond adequately to resuscitation within 90 seconds after delivery, the infant was switched to 100% oxygen. This was designated
treatment failure. Criteria for treatment failure were heart rate
,80 beats per minute and/or central cyanosis at 90 seconds after
delivery, and they were recorded for both groups. Treatment
failures in the room air group, although switched to 100% oxygen
after 90 seconds, were analyzed in the room air group.
The duration of resuscitation was measured from delivery until
the infant had spontaneous breathing with a heart rate .100 beats
per minute, as suggested by the American Heart Association.4
Resuscitation was withdrawn after 30 to 45 minutes if spontaneous breathing had not been established.
Outcome Measures
The primary outcome measures were death within 1 week
and/or presence of HIE, grade II or III, according to a modification
of Sarnat and Sarnat.2,10 According to this classification, HIE grade
I (mild) includes irritability, hyperalertness, mild hypotonia, and
poor sucking; grade II (moderate) includes lethargy, seizures,
marked abnormalities of tone, and requirement of tube feeding;
and grade III (severe) includes coma, prolonged seizures, severe
hypotonia, and failure to maintain spontaneous respiration. We
also registered survival after 28 days of life.
Secondary outcome measures were Apgar scores at 5 minutes,
heart rate at 90 seconds, time to first breath, time to first cry,
duration of resuscitation, arterial blood gases and acid base status
at 10 and 30 minutes of age, and abnormal neurologic examination
after 4 weeks, In addition, arterial oxygen saturation was recorded
in some infants by pulse oximetry at 1, 3, 5, and 10 minutes of life.
Time to reach arterial oxygen saturation of 75% also was recorded
if possible. Umbilical cord blood was sampled in eight centers
(time 0), and four obtained arterial blood (three obtained blood by
needle stick and one by catheterization) and four obtained venous
cord blood.
Sample Size and Statistical Analysis
Based on the findings in the pilot study,7 to demonstrate a
significant reduction in mortality and/or moderate to severe HIE
from 15% to 9%, we needed to enroll 920 infants. A reduction from
15% to 8% would, however, require 648 enrolled infants (significance level 0.05; power 80%).
All calculations were performed with SPSS for Windows 6.1.2
(SPSS Inc, Chicago, IL), and graphs produced by Microsoft Power
Point Version 4.0 (Seattle, WA), GraphPad Prism (San Diego, CA),
or SPSS. Mean and SD units are given, and parametric tests
(two-tailed t test) were used when the variables were approximately normally distributed. Median and 95% confidence intervals (CIs) or 5 and 95 percentiles are given, and nonparametric
tests (two-tailed Mann–Whitney U test) were used when the distribution of the variable was not normal. Repeated-measures analysis of variance (ANOVA) and x2 tests were used when appropriate. Logistic or Cox regression analysis was used when the
comparison between the two groups was adjusted for gender,
gestational age, and birth weight.
Interim analyses were performed after 150 and 300 enrolled
infants. Because there were no significant differences between the
two groups with regard to primary outcome measure or mortality
in the first week or within 28 days of life, the study continued.
dates given room air) because of a mistake concerning the date in 15 infants, in one case, oxygen was not
available and the infant was resuscitated with room
air instead. These 16 infants were included in the
data analysis in the group in which they had been
treated. In addition, four enrolled infants who died
were included, although they had potentially lethal
congenital conditions that were not recognized until
resuscitation had been attempted. Two of these infants had diaphragmatic herniae, one had esophageal atresia with tracheoesophageal fistula, and one
had congenital syphilis; all belonged to the room air
group. Therefore, a total of 609 infants were eligible
for analysis (Fig 1).
Table 1 shows the distribution of these 609 infants
in the 10 remaining centers. A total of 107 infants
eligible for enrollment in the recruitment period at
each participating center were not included in the
study, for varying reasons. In some cases, the study
team arrived after the resuscitation was started, and
in others, the obstetricians did not want to have the
infant enrolled. The outcome of these 107 infants was
not recorded.
Nineteen (6.6%) and 17 (5.3%) parents in the room
air and oxygen groups, respectively, did not give
informed consent. These patients consequently were
not enrolled in the follow-up study, which is underway.
Baseline Characteristics
Of the 609 infants enrolled, 288 (47.3%) were resuscitated with room air and 321 (52.7%) with oxygen. This should be related to the fact that there were
49.0% even dates and 51.0% odd dates in the enrollment period. Table 2 shows some important pre- and
perinatal factors. No significant differences between
the two groups were found.
There were 133 females in both the room air group
(46.2%) and the oxygen group (41.4%) (NS). Gestational ages ranged from 27 to 44 weeks in both
groups. Median gestational age (5 to 95 percentile)
was 38.0 (32.0 to 42.0) weeks in the room air group
and 38.0 (31.1 to 41.5) weeks in the oxygen group
(NS). Birth weights ranged between 1000 and 5550 g
in the room air group and between 1000 and 5270 g
in the oxygen group. Median birth weights (5 to 95
RESULTS
Patients
Forms for 703 enrolled infants from 11 centers
were received by the steering committee. Eighty-six
of 94 infants from one center had been included
without meeting the inclusion criteria for resuscitation, and all 94 infants from that center were excluded by the steering committee. Of the remaining
infants, 16 had been allocated to the wrong group (10
born on even dates given oxygen and 6 born on odd
Fig 1. Trial profile of the 609 infants meeting inclusion criteria.
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Eligible and Included Infants According to City
TABLE 1.
Center
Eligible
Included
RA/O2
Delhi
Bombay
Madras
Cairo
Chandigarh
Mansoura
Manila
Tartu
Valencia
Tønsberg
Total
158
132
100
87
47
34
110
30
13
6
716
158
123
100
87
47
34
26
26
6
2
609
64/94
52/71
54/46
47/40
19/28
21/13
16/10
10/16
4/2
1/1
288/321
Abbreviations: RA, room air; O2, oxygen.
TABLE 2.
Maternal and Fetal Variables
Maternal or Fetal Variable
Room Air
Oxygen
Previous pregnancies mean (SD)
2.2 (1.5)
2.3 (1.6)
Previous deliveries, mean (SD)
1.8 (1.3)
1.8 (1.2)
Maternal anemia, n (%)
58/265 (21.9) 66/300 (22.0)
Preeclampsia, n (%)
52/280 (18.6) 61/312 (19.6)
Vaginal delivery, n (%)
169/286 (59.1)* 202/320 (63.1)**
Sedation, n (%)
41/272 (16.8) 43/312 (13.8)
Pain relief, n (%)
119/270 (44.1) 132/305 (43.3)
Fetal bradycardia, n (%)
104/273 (38.1) 118/301 (39.2)
Premature, n (%)
75/288 (26.0) 72/321 (22.4)
BW ,2500 g, n (%)
115/288 (39.9) 137/321 (42.7)
Meconium, n (%)
119/280 (42.5) 140/316 (44.3)
Intubated, n (%)
73/288 (25.3) 82/321 (25.5)
No significant differences between the groups were found.
Maternal anemia: hemoglobin ,10 g/L.
Preeclampsia: systolic blood pressure .140 –160 mm Hg and proteinuria (.0.3 g/24 h, or positive urinary findings for protein)
after 20 weeks of pregnancy.
Breech position: *5.6%, **8.1%.
Prematurity: ,37 weeks gestational age.
Meconium indicates meconium-stained amniotic fluid.
percentile) were 2600 (1320 to 4078) g and 2560 (1303
to 3900) g (NS) in the room air and oxygen groups,
respectively.
Primary Outcome Measure, Mortality, and HIE
None of the 33 infants recruited from the three
European centers died. Mortality among the other
centers did not vary significantly. Death within 7
days (or before discharge if discharged before 7
days), death within 28 days, and death within 7 days
and/or HIE, grade II or III (primary outcome measure) are shown for all centers combined in Table 3.
Mortality before 28 days was borderline significantly
TABLE 3.
lower in the room air group, with odds ratio (OR) 5
0.69. However, with a logistic regression multivariate analysis correcting for gender, birth weight, and
gestational age, this difference was not significant.
HIE grade II or III was not different between the two
groups.
Heart Rate and Apgar Scores
Heart rates (Fig 2) in the room air and oxygen
groups at 1 minute were (mean 6 SD) 90 6 31 versus
93 6 33 and at 90 seconds were 110 6 27 versus
113 6 30. There were no significant differences between the two groups in heart rate over the first 30
minutes of life (repeated-measures ANOVA). The
number of infants with heart rates ,60, 80, or 100
beats per minute did not differ between the two
groups at any time.
Median (5 to 95 percentile) Apgar scores in the
room air and oxygen groups, respectively, were 5 (1
to 6.7) and 4 (1 to 7) (P 5 .004) at 1 minute, 8 (4 to 9)
and 7 (3 to 9) (P 5 .12) at 5 minutes, and 8 (5 to 10)
and 8 (3.5 to 9) (P 5 .29) at 10 minutes (Fig 3). There
were significantly more infants with very low
1-minute Apgar scores (,4) in the oxygen group
(n 5 142/320; 44.4%) than in the room air group (n 5
92/286; 32.3%) (P 5 .001). However, at 5 and 10
minutes of age, this difference between the groups
did not reach significance. There were significantly
more infants with 5-minute Apgar scores ,7 in the
oxygen group (n 5 102/321; 31.8%) than in the room
air group (n 5 71/286; 24.8%) (P 5 .03); however, at
10 minutes, no such difference between the groups
was found.
Blood Gases, Oxygen Saturation, and Acid Base Status
Blood gases and acid base status are given in Table
4. In umbilical cord blood and at 10 minutes of life,
no differences in Pao2 between the groups were
found; however, at 30 minutes, Pao2 was significantly higher in the oxygen group than in the room
group [89 (42) mm Hg; n 5 156 vs 74 (29) mm Hg;
n 5 115; P 5 .002]. Paco2 was not significantly different between the groups in umbilical cord blood, at
10 minutes, or at 30 minutes of life. Base deficit and
pH did not differ between the groups either in umbilical venous or arterial cord blood or in arterial or
capillary blood at 10 or 30 minutes of life. There was
no difference in base deficit at any time point between survivors and nonsurvivors.
Total Number of Registered Infants With Adverse Outcome
Event
a
Death within 7 d
Death within 28 da
Death within 28 db
Death within 7 d or HIE grade II or IIIa
HIE grade II or IIIa
RA
35/288 (12.2%)
40/288 (13.9%)
40/267 (15.0%)
61/288 (21.2%)
47/288 (16.3%)
O2
48/321 (15.0%)
61/321 (19.0%)
61/294 (20.7%)
76/321 (23.7%)
55/321 (17.1%)
Univariate
Multivariate
OR
95% CI
OR
95% CI
0.79
0.69
0.67
0.87
0.94
0.49–1.26
0.44–1.06
0.43–1.04
0.59–1.27
0.62–1.45
0.82
0.72
0.71
0.94
1.04
0.50–1.35
0.45–1.15
0.44–1.14
0.63–1.40
0.67–1.63
a
N 5 609 (univariate) and N 5 589 (multivariate). Death number (percent) in room air (RA) and oxygen (O2) groups and OR for various
adverse events when comparing the room air group versus the oxygen group. The multivariate analysis is adjusted for gender, gestational
age, and birth weight. The 73 infants in the room air group that had been switched to oxygen after 90 seconds because of so-called
resuscitation failure (see text) were analyzed in the room air group.
b
Compared with children followed for 28 days. N 5 561 (univariate) and N 5 543 (multivariate). At 28 days, 21 infants were lost to
follow-up in the room air group and 27 infants in the oxygen group.
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Fig 2. Heart rates between 1 and 30 minutes after birth in infants
resuscitated with room air or 100% oxygen. Mean and SD are
given. Open bars indicate room air group; hatched bars, oxygen
group. No significant differences between the two groups were
found.
air and oxygen groups, respectively (P 5 .004), and
time to first cry was 1.6 (1.5 to 1.7) minutes in the
room air group and 2.0 (1.8 to 2.2) minutes in the
oxygen group (P 5 .006). Median (95% CI) duration
of resuscitation was 2.0 minutes in both groups (P 5
.09); at 30 minutes, 38 infants were on artificial ventilation. Median (95% CI) time to reach Sao2 of 75%
was 1.5 (1.4 to 1.6) minutes in the room air group
(n 5 103) versus 2.5 (1.9 to 3.1) minutes in the oxygen
group (n 5 109) (P 5 .27). At each time point, more
room air infants had taken their first breath than O2
infants (Fig 4). All P values are adjusted for gender,
gestational age, and birth weight by Cox regression
analysis.
In the room air group, there were 73/284 (25.7%)
so-called treatment failures who were switched to
oxygen 90 seconds after delivery. However, if the
same criteria (bradycardia and/or central cyanosis
after 90 seconds) were applied to the oxygen group,
the number was 88/295 (29.8%), not significantly
different from that for the room air group. These
infants had a high mortality both at 7 days (33% vs
28%; NS) and at 28 days of life (41% vs 35%; NS) in
the room air and oxygen groups, respectively.
DISCUSSION
Fig 3. Apgar scores at 1, 5, and 10 minutes after birth in infants
resuscitated with room air or 100% oxygen. Median values and 5
to 95 percentiles are given. Open bars indicate room air group;
hatched bars indicate oxygen group. *P 5 .004.
Arterial oxygen saturation was measured with
pulseoximetry in all centers at 1, 3, 5, and 10 minutes
of age, however, in only a limited number of patients, and it did not differ significantly between the
two groups (repeated-measures ANOVA). Mean
(SD) Sao2 was in the room air and oxygen group,
respectively, at 1 minute [65 (11)% n 5 75 versus 61
(14)% n 5 67]; 3 minutes [82 (13)% n 5 87 versus 81
(11)% n 5 91]; 5 minutes [86 (10)% n 5 102 versus 88
(10)% n 5 103]; and 10 minutes [90 (6)% n 5 112
versus 91 (7)% n 5 120].
Median (5 to 95 percentile) Fio2 at 10 minutes was
0.21 (0.21 to 1.00) in the room air group and 0.23 (0.21
to 1.00) in the oxygen group (P , .0001). However, at
30 minutes, the values were not significantly different at 0.21 (0.21 to 1.00) in both groups.
Time to First Breath, First Cry, and SaO2 of 75%,
Duration of Resuscitation, Treatment Failure
Median (95% CI) time to first breath was 1.1 (1.0 to
1.2) minutes and 1.5 (1.4 to 1.6) minutes in the room
In this prospective, international multicenter
study, we have not been able to verify the hypothesis
that room air is superior to 100% oxygen for resuscitation of newborn infants. However, the study indicates that asphyxiated newborn infants can be resuscitated just as well with ambient air as with 100%
oxygen. In fact, uncorrected neonatal mortality
tended to be lower in the room air group compared
with the oxygen group (OR 5 0.69; 95 CI 5 0.44 –
1.06). However, when correcting for gender, gestational age, and birth weight, this reduction in mortality was not significant.
The Apgar scores at 1 minute were significantly
lower, and the time to first cry and first breath were
significantly longer in the oxygen group, compared
with the room air-resuscitated group. There also
were more infants with low Apgar scores at 1 and 5
minutes of age in the oxygen group, indicating some
possible unknown adverse effects by using 100%
oxygen for resuscitation.
The theoretic background for this study was based
on our findings from the mid-1970s when we demonstrated that the purine metabolite hypoxanthine
accumulates in body fluids and tissues during hypoxia.11,12 Because hypoxanthine is a potential oxygen
radical generator, we suggested that the injury often
noted in the posthypoxic reoxygenation period could
be caused by an explosive generation of oxygen radicals by the hypoxanthine–xanthine oxidase system.11
This hypothesis could explain the well known oxygen paradox, a phenomenon describing that injury
related to hypoxia occurs, to a large extent, in the
reoxygenation period.12–14 Because it had been shown
in vitro that the amount of oxygen radicals produced
by the hypoxanthine–xanthine oxidase system increases with the oxygen concentration as well as with
the hypoxanthine concentration,15 we, therefore, suggested that resuscitation should be performed with
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TABLE 4.
Blood Gases and Acid Base Status
0 Min
Room Air
pO2 mm Hg
pCO2 mm Hg
pH
BD mmol/L
a
31 (17)
50 (15)
7.11 (0.14)i
14.7 (6.1)o
10 Min
Oxygen
b
30 (22)
50 (19)b
7.12 (0.18)j
14.2 (6.7)p
Room Air
a
76 (32)
39 (14)c
7.17 (0.11)k
14.0 (5.0)q
30 Min
Oxygen
d
87 (49)
38 (13)d
7.15 (0.13)l
14.5 (5.4)r
Room Air
e
74 (29)
32 (13)g
7.25 (0.10)m
11.2 (5.2)s
Oxygen
89 (42)f *
30 (11)h
7.26 (0.12)n
12.1 (5.8)t
n 5 107, b n 5 127, c n 5 69, d n 5 80, e n 5 115, f n 5 156, g n 5 116, h n 5 157, i n 5 166, j n 5 197, k n 5 134, l n 5 135, m n 5 192, n n 5
219, o n 5 154, p n 5 177, q n 5 132, r n 5 134, s n 5 188, t n 5 207.
Mean (SD) values are given. Po2 and Pco2 are from arterial blood. pH and base deficit (BD) at 0 min are from either umbilical vein or artery
and at 10 and 30 minutes after birth from either capillary or artery. *P 5 .002 compared with room air value.
a
Fig 4. Kaplan–Meier plot showing the proportion that had not
taken the first breath in room air- and oxygen-resuscitated newborn infants. Time to first breath was significantly longer in the
oxygen-resuscitated group compared with the room air-resuscitated group. In the oxygen group, 60/313 (19.2%) required .3
minutes to take the first breath compared with 28/284 (9.9%) in
the room air group (OR 5 0.47; 95% CI 5 0.29 – 0.76).
as low a concentration of supplemental oxygen as
possible.12
In a series of experiments in young and newborn
pigs that we have performed in recent years to test
whether resuscitation can be carried out with room
air, we were able to demonstrate that room air resuscitation normalizes blood pressure, acid-base variables, hypoxanthine in plasma and brain microdialysate, cerebral blood flow, and somatosensory
evoked potentials as efficiently as resuscitation with
100% O2.16 –20 In addition, brain morphologic changes
4 days after the hypoxic insult were similar in both
groups of piglets.17
The present study showed a delay in the onset of
respiration in infants resuscitated with 100% oxygen
compared with room air. This could be one explanation for the lower 1-minute Apgar scores found in the
oxygen group. Resuscitation with 100% oxygen perhaps may induce lung atelectasis or depress ventilation or other vital functions of the infants. In newborn hypopneic lambs ventilated with 100% oxygen,
the minute ventilation already was reduced after 45
seconds compared with room air-ventilated animals;21 thus, it is possible that resuscitation with
oxygen depresses ventilation quickly.
It is known from animal and clinical studies in
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adults that 100% O2 in some circumstances reduces
oxygen consumption,22,23 and there are indications
that the energy metabolism of the brain might be
affected.20,24,25 In premature animals and human infants, an opposite effect has been found because
hyperoxia has been shown to increase oxygen consumption.26 In full-term newborn infants at 1 to 2
days of life, it was found that after a few minutes of
hyperoxia (100% O2), the work of breathing and the
metabolic rate were increased. Immediately after the
onset of hyperoxic breathing, there was a decrease in
minute ventilation. This response was, however,
short-lasting and quickly reversed into an increase in
ventilation.26
In one study on adult dogs, a decreased neurologic
survival was found when 100% oxygen versus room
air was given after cerebral ischemia.27 Furthermore,
a reduced cerebral blood flow was detected at 2
hours of age in preterm infants supplemented with
80% oxygen versus room air immediately after
birth.28 The brain of the newborn infant may respond
differently to 100% oxygen than the brain of adult
animals, and whether resuscitation with 100% oxygen might be harmful obviously needs further investigation.
In this study, we found it necessary to use a
quasirandomized method of allocating infants to the
two treatment groups, namely according to odd or
even dates of birth. This was necessary to simplify
enrollment in the different centers because delay in
resuscitation could be detrimental to the infants.
From a statistical point of view, this form of systematic assignment should, however, represent a satisfactory procedure. The use of odd and even dates
and related types of allocation has been used previously in a number of other works, many of them
studies of emergency procedures.29 –33
Nonetheless, because the study was not strictly
randomized, an important question when evaluating
the significance of the present results is whether the
two groups were similar, or if there was evidence of
bias. The resuscitation teams at each participating
center did its utmost to avoid any bias in the recruitment. For instance, the number of infants included in
each group corresponds closely with the number of
even and odd dates in the enrollment period. A
completely balanced randomization would have resulted in 298 room air- and 311 oxygen-resuscitated
infants, which is close to the 288 and 321 who were
actually enrolled into each group. Also, the similarity
in birth weight, gestational age, and severity of as-
RESUSCITATION OF ASPHYXIATED NEWBORNS WITH ROOM AIR OR OXYGEN
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phyxia evaluated by acid-base variables in umbilical
cord blood of the two groups indicates that there has
been no or only minor selection bias. Furthermore,
because the study was not blinded, a bias in treatment is possible. For instance, we did not record the
ventilation pressure used or the postresuscitation
care, thus, differences in handling of the infants in
the two groups cannot be ruled out.
The centers from developed countries participating in this study enrolled few patients because of a
low number of births and a low incidence of birth
asphyxia. Because the mortality in the three European centers was zero in this study, the high mortality in our study therefore reflects the present situation in many developing countries. Therefore, the
results of this investigation cannot be extrapolated
directly to units with a low mortality. However, we
still believe the data also may have important implications for developed countries.
Whether there are differences in long-term neurologic outcome cannot be answered in the present
study, but a follow-up investigation of the enrolled
infants between 18 and 24 months of age is underway.
In conclusion, this study has not demonstrated
significantly improved survival by using room air
instead of 100% O2 for newborn resuscitation. However, it indicates that resuscitation of asphyxiated
newborn infants can be performed with room air just
as efficiently as with 100% O2. Room air-resuscitated
infants also seem to recover more quickly than do
infants resuscitated with 100% oxygen, as assessed
by Apgar scores, time to first breath, and time to first
cry. Although the present study has some limitations, it represents a first step in the evaluation of
newborn resuscitation routines. This study does not
justify changes of the present routines in itself; these
should not be changed until studies in both developed and developing countries confirm the present
results. Nevertheless, this investigation shows that
optimal resuscitation routines should be assessed
more carefully, perhaps also in developed countries.
ACKNOWLEDGMENTS
This study was funded by the Laerdal Foundation for Acute
Medicine and the Norwegian Council for Research.
Professor Henry Halliday and Professor Gosta Rooth kindly
revised this manuscript.
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Resuscitation of Asphyxiated Newborn Infants With Room Air or Oxygen: An
International Controlled Trial: The Resair 2 Study
Ola Didrik Saugstad, Terje Rootwelt and Odd Aalen
Pediatrics 1998;102;1DOI: 10.1542/peds.102.1.e1
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