targeted oxygen in the resuscitation of preterm infants, a
TRANSCRIPT
ARTICLEPEDIATRICS Volume 139 , number 1 , January 2017 :e 20161452
Targeted Oxygen in the Resuscitation of Preterm Infants, a Randomized Clinical TrialJu Lee Oei, MBBS, FRACP, MD, a, b, c Ola D. Saugstad, MD, PhD, d Kei Lui, MBBS, FRACP, MD, a, b Ian M. Wright, MBBS, MRCP, Paeds, FRACP, e, f, g John P. Smyth, MBBS, FRACP, a, b Paul Craven, MBBS, FRACP, g Yueping Alex Wang, BMed, MPH, PhD, h Rowena McMullan, MBBS, FRACP, i Elisabeth Coates, BSc, c Meredith Ward, MBBS, FRACP, a, b Parag Mishra, MBBS, FRACP, a, b Koert De Waal, MBBS, FRACP, PhD, g Javeed Travadi, MBBS, FRACP, g Kwee Ching See, MBBS, MRCP, j Irene G.S. Cheah, MBBS, MRCP, k Chin Theam Lim, MBBS, MRCP, l Yao Mun Choo, MBBS, MRCPH, l Azanna Ahmad Kamar, MBBS, MRCP, l Fook Choe Cheah, MD, FRACP, PhD, m Ahmed Masoud, MD, n William Tarnow-Mordi, MBBS, MRCPc
abstractBACKGROUND AND OBJECTIVES: Lower concentrations of oxygen (O2) (≤30%) are recommended for
preterm resuscitation to avoid oxidative injury and cerebral ischemia. Effects on long-term
outcomes are uncertain. We aimed to determine the effects of using room air (RA) or 100%
O2 on the combined risk of death and disability at 2 years in infants <32 weeks’ gestation.
METHODS: A randomized, unmasked study designed to determine major disability and death
at 2 years in infants <32 weeks’ gestation after delivery room resuscitation was initiated
with either RA or 100% O2 and which were adjusted to target pulse oximetry of 65% to 95%
at 5 minutes and 85% to 95% until NICU admission.
RESULTS: Of 6291 eligible patients, 292 were recruited and 287 (mean gestation: 28.9 weeks)
were included in the analysis (RA: n = 144; 100% O2: n = 143). Recruitment ceased in June
2014, per the recommendations of the Data and Safety Monitoring Committee owing to loss
of equipoise for the use of 100% O2. In non-prespecified analyses, infants <28 weeks who
received RA resuscitation had higher hospital mortality (RA: 10 of 46 [22%]; than those
given 100% O2: 3 of 54 [6%]; risk ratio: 3.9 [95% confidence interval: 1.1–13.4]; P = .01).
Respiratory failure was the most common cause of death (n = 13).
CONCLUSIONS: Using RA to initiate resuscitation was associated with an increased risk of death
in infants <28 weeks’ gestation. This study was not a prespecified analysis, and it was
underpowered to address this post hoc hypothesis reliably. Additional data are needed.
aSchool of Women’s and Children’s Health, the University of New South Wales, Australia; bDepartment of
Newborn Care, Royal Hospital for Women, Australia; cWestmead International Network for Neonatal Education
and Research, (WINNER Centre), NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; dDepartment of Pediatric Research, Olso University Hospital, University of Oslo, Oslo, Norway; eIllawarra Health
and Medical Research Institute and Graduate Medicine, The University of Wollongong, Australia; fHunter Medical
Research Institute, University of Newcastle, Australia; gDepartment of Neonatology, John Hunter Hospital,
Australia; hFaculty of Health, University of Technology Sydney, Australia; iDepartment of Neonatology, Royal
Prince Alfred Hospital, Australia; jSungai Buloh Hospital, Selangor, Malaysia; kDepartment of Paediatrics,
Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; lDepartment of Paediatrics, University Malaya, Kuala Lumpur,
Malaysia; mDepartment of Paediatrics, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpar, Malaysia;
and nHamad Medical Corporation, Qatar
Dr Oei developed the concept and study design and was responsible for study recruitment and
overall management, analysis, and presentation of data for submission; Drs Lui, Wright, Smyth,
Saugstad, Theam, and Choe developed the concept and study design and were responsible for
reviewing the manuscript; Dr Craven, Dr Clark, and Ms Coates were responsible for recruitment;
Dr Wang was involved in designing the study, overseeing the statistical analysis, and reviewing
the manuscript; Drs Ward, Mishra, De Waal, and Travadi were responsible for recruitment and To cite: Oei JL, Saugstad OD, Lui K, et al. Targeted Oxygen in
the Resuscitation of Preterm Infants, a Randomized Clinical
Trial. Pediatrics. 2017;139(1):e20161452
WHAT’S KNOWN ON THIS SUBJECT: To reduce
oxidative stress, clinicians use lower amounts of
oxygen, including room air, to resuscitate newborn
infants, but the effects of this method on the short
and long-term outcomes of preterm infants are
unknown.
WHAT THIS STUDY ADDS: This study was
underpowered for the primary outcome. There
are important limitations, but results show that
initiating resuscitation of extremely premature
infants with lower oxygen levels may increase
mortality compared with using 100% oxygen.
by guest on January 8, 2017Downloaded from
OEI et al
One hundred percent oxygen (O2)
has been used for delivery room
resuscitation of newborn infants for
more than a century, 1 but animal 2
and human 3 – 6 data illustrate that
this approach leads to oxidative
stress 5 and organ injury. 6 Saugstad
et al first showed that ventilation
with room air (RA; 21% O2) did not
worsen outcomes compared
with using 100% O2 when used to
resuscitate mature, hypoxic infants. 3, 4
A meta-analysis of randomized
controlled trials of >1300 mostly
term/near-term, hypoxic infants
then showed that RA significantly
reduced the risk of death when used
instead of 100% O2 for resuscitation
(relative risk: 0.71 [95% confidence
interval (CI): 0.54–0.94]; P = .015) 7
and reduced severe encephalopathy. 8
Most infants, however, were recruited
from developing countries, 3, 4
and because RA resuscitation did
not make a difference to 2-year
neurodevelopmental outcomes, 9 the
applicability for using RA in developed
countries with different resuscitation
resources is therefore unclear. 10
Even less clear is the evidence for
using less O2 to stabilize preterm
infants. Preterm infants, in
2
FIGURE 1Patient recruitment.
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PEDIATRICS Volume 139 , number 1 , January 2017
contrast to term infants, may need
supplemental O2 11 because of lung
immaturity, but antioxidant defenses
are also suboptimal until the third
trimester. 12 This scenario leads to a
precarious balance between O2 need
and toxicity. Nevertheless, growing
evidence shows that preterm
infants can be supported in the
short term with <100% O2.
Although this approach has not
been associated with major adverse
consequences, 11, 13 – 21 including
death, 22 cerebral vasoconstriction
(the implications of which are
uncertain) has been noted. 13
Over the last decade,
recommendations for the use of O2
in the delivery suite have changed
substantially. Previously, 100%
O2 was standard of care. 23, 24 After
2006, RA 25 or low levels of fractional
inspired oxygen (FIO2), such as
30%, 26, 27 became the standard of
care for preterm infant resuscitation.
Furthermore, novel preductal
oximetry (SpO2) data from healthy,
spontaneously breathing term 28 and
preterm 29 infants showed that SpO2
increased only gradually after birth.
In 2010, SpO2 targeting was also
recommended as standard of care.
This approach has led to distinct
change in clinical practice. In 2008,
50% of Australian and New Zealand
perinatal centers used 100% O2
to resuscitate preterm infants. 30
However, in 2015, a survey of 630
clinicians from 25 countries found
that only 4 used 100% O2 and >70%
used FIO2 ≤40% O2. 31
Despite these findings, the long-term
implications of using anything other
than 100% O2 to resuscitate preterm
infants are unknown. In 2007, the
To2rpido (Targeted Oxygen in the
Resuscitation of Preterm Infants
and their Developmental Outcomes)
study was designed to examine
2-year outcomes at 2 years of age for
preterm infants <32 weeks’ gestation
after resuscitation with either RA or
100% O2. At that time, only 1 study
had been published 11 to suggest that
preterm resuscitation was possible
with <100% O2. We hypothesized
that using RA would decrease risk
of death and major disability at
2 years of age by 20% compared
with 100% O2, but recruitment
difficulties arose due to loss of
equipoise for using 100% O2. As a
consequence, recruitment had to be
stopped in June 2014 on the advice
of the Data and Safety Monitoring
Committee (DSMC), which
nevertheless recommended that
short-term outcomes be reported
before availability of 2-year primary
outcomes.
METHODS
Study Design
The To2rpido study was an
international multicenter,
nonblinded, randomized controlled
trial involving 2 centers in Australia,
3 in Malaysia, and 1 in Qatar. There
were no changes to the trial design
during recruitment.
Inclusion Criteria
Live-born infants <32 weeks’
gestation or ≤1250 g birth weight
(if gestation was uncertain)
were eligible if their mothers
presented at least 6 hours before
delivery and if informed, written
parental or guardian consent was
obtained. Infants were excluded
at any time if they were diagnosed
with cardiorespiratory or other
3
TABLE 1 Patient Demographic Characteristics
Characteristic RA (n = 144) 100% O2 (n = 143) P or RR (95% CI)
Mothers
Age, y 31 ± 6 31 ± 7 .87
Primigravida 59 (42) 52 (38) 1.1 (0.8–1.5)
Gestational diabetes 14 (10) 15 (10) 0.9 (0.5–1.8)
PIH 28 (19) 18 (12) 1.5 (0.9–2.6)
Chorioamnionitis 20 (14) 26 (18) 0.8 (0.4–1.3)
APH 21 (15) 21 (15) 0.9 (0.6–1.7)
Antenatal steroids 140 (97) 138 (97) 1.0 (0.9–1.1)
Cesarean delivery 95 (66) 108 (75) 0.8 (0.7–1.0)
Infants
Gestation, wk 28 ± 2 28 ± 2 .77
Male sex 80 (55) 73 (50) 1.1 (0.8–1.4)
Birth weight, g 1147 ± 363 1136 ± 321 .79
Apgar score <5 at 5 min 2 (1) 4 (3) 0.5 (0.1–2.7)
Multiple birth 41 (28) 44 (30) 0.9 (0.6–1.3)
Data are presented as mean ± SD or n (%), unless indicated otherwise. APH, antepartum hemorrhage; PIH, pregnancy
induced hypertension; RR, risk ratio.
TABLE 2 Resuscitation and Ventilation Interventions in the Delivery Room
Intervention
in the Delivery Room
Infants
RA (n = 144) 100% O2 (n = 143) RR (95% CI) or P
At birth
No respiratory support 6 (4) 2 (1) 2.9 (0.6–14.5)
CPAP 123 (85) 134 (94) 0.9 (0.8–1.0)
Intubation 43 (30) 41 (29) 1.0 (0.7–1.5)
Adrenaline 1 (1) 0 –
Chest compressions 1 (1) 0 –
At admission to NICU
Age, min 22 ± 12 21 ± 10 .88
pHa 7.2 ± 0.1 7.3 ± 0.1 .39
BE, mmol/La −5.2 ± 4.3 −3.5 ± 3.7 .07
FIO2, % 40 ± 21 41 ± 22 .87
Temperature, °C 36.5 ± 0.6 36.5 ± 0.7 .71
Data are presented as n (%) or mean ± SD, unless indicated otherwise. BE, base excess; CPAP, continuous positive airway
pressure; RR, risk ratio.a RA = 50 infants; 100% O2 = 50 infants.
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OEI et al
abnormalities that had the potential
to affect oxygenation or mortality.
Randomization and Masking
Infants were randomized by
computer-generated sequence once
birth was considered imminent.
They were grouped into blocks of 10
stratified according to gestation (<28
weeks’ gestation and 28–31 weeks’
gestation) to ensure even gestational
distribution. The study was not
masked because ethics committees
considered blinding to be difficult
to achieve, considering that infants
given 100% O2 would theoretically
become pinker more rapidly than
infants started on RA.
Equipment
Each center used a dedicated Rad-7
oximeter (Masimo Corporation, Irvine,
CA) preloaded with the Trendcom
software (Masimo Corporation) to
enable downloading of SpO2 and heart
rates onto an Excel file (Microsoft
Corporation, Bellvue, WA) for later
verification of hard copy data. Rad-7
oximeters were used because they
were equipped with HI-FI trauma
sensors that were able to provide
2-second averaging for maximum
sensitivity to rapid oximetry changes.
Signal Extraction Technology in the
Rad-7 oximeters also used techniques
to optimize SpO2 measurement in
challenging clinical situations (eg,
poor perfusion). 32 Oximeter probes
were placed on the infant’s right wrist
for preductal SpO2 measurement.
The Neopuff Infant Resuscitator
(Fisher and Paykel Healthcare,
Auckland, New Zealand) was used
in all participating centers to deliver
positive-end expiratory pressure–
controlled intermittent breaths at
delivery. Ventilation strategies were
not proscribed as part of the protocol.
O2 blenders were used in all delivery
suites for FIO2 blending.
Defi nition of the Time of Life
Because delayed cord clamping was
practiced in some centers, time of
birth (or time 0) was defined as time
of cord clamping.
Intervention
Respiratory support was initiated
with RA or 100% O2 depending on
randomization. Other aspects of
resuscitation were provided as per
expert committee guidelines at the
time of trial design. 24, 25 Clinicians
were advised by protocol to increase
FIO2 by 10% every minute (or less)
if preductal saturations were <65%
before 5 minutes or <80% after
5 minutes and to decrease FIO2
by 10% every minute if SpO2 was
>95% at any time. FIO2 could be
increased immediately to 100% at
any time if the infant’s heart rate
remained persistently <100 beats/
min despite adequate ventilation
(duration of bradycardia left to
clinical discretion), if SpO2 was <65%
at 5 minutes, or if external cardiac
massage or resuscitation medications
(eg, adrenaline) were required.
Data Collection
Hard copy records of heart rates,
FIO2, SpO2, and resuscitation events
were viewed visually and recorded
by a team member who was not
involved in the resuscitation process.
Ventilatory parameters from
admission into the NICU and until 12
hours of life were also noted.
Outcomes
The primary outcome was death
and major disability at 2 years
corrected age (gestational age plus
chronological age minus 40 weeks).
Major disability was defined as ≥1 of
the following: (1) composite cognitive
score <85 and/or language score
<85 on the Bayley Scale of Infant
Development III; (2) severe visual
loss (<6/60 vision); (3) cerebral
palsy with Gross Motor Function
Classification System level ≥2; or (4)
deafness requiring hearing aids.
Secondary outcomes were as follows:
(1) neonatal morbidities such as
retinopathy of prematurity (ROP)
grade ≥3 33; (2) bronchopulmonary
dysplasia 34; (3) necrotizing
enterocolitis requiring surgery or
resulting in death; and (4) duration of
ventilatory support and respiratory
status on NICU admission.
4
TABLE 3 Hospital Outcomes
Outcome Infants
RA (n = 129) 100% O2 (n = 137) P
Ventilation and cardiorespiratory supporta
Days of respiratory supportb (mean ± SD) 21.6 ± 2.2 35.3 ± 6.5 .01c
Supplemental O2 (mean ± SD) 24.8 ± 17.5 12.4 ± 5.3 .68
Neonatal morbidities and treatment RA (n = 144) 100% O2 (n = 143) OR (95% CI)
BPD 34 (24) 40 (28) 0.7 (0.5–1.1)
Dexamethasone 8 (6) 8 (6) 0.9 (0.4–2.6)
ROP, grade 3 or higher 4 (3) 8 (6) 0.5 (1.5–1.6)
PDA 36 (25) 41 (29) 0.9 (0.6–1.4)
IVH, grade 3 or higher 2 (1) 6 (4) 0.3 (0.1–1.6)
NEC 5 (3.5) 1 (1) 5.0 (0.5–42.2)
Surfactant 88 (62) 95 (66) 0.9 (0.8–1.1)
Surgery 9 (6) 24 (17) 0.4 (0.2–0.8)c
Types of surgery
PDA ligation 1 6
NEC surgery 1 1
Retinal laser therapy 1 5
VP shunt 1 0
Other surgery 5 12
Data are presented as mean ± SD or n (%), unless indicated otherwise. BPD, bronchopulmonary dysplasia; IVH,
intraventricular hemorrhage; NEC, necrotizing enterocolitis; OR, odds ratio; VP, ventriculoperitoneal.a Excludes deceased infants.b Includes mandatory ventilation, continuous positive airway pressure, and high- and low-fl ow nasal cannula.c P < .05.
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PEDIATRICS Volume 139 , number 1 , January 2017
Statistical Analysis, Including Additional Assessments
Sample Size Calculation
A total of 1976 infants (988 infants
in each arm) were required to
demonstrate decreased incidence
of death and neurodevelopmental
disability by 20%, from 30% to 24%,
with a 2-sided, type I error rate of 5%
and 80% power. A correction factor
of 1.15 was applied to account for
15% attrition to follow-up to 2 years
of age.
Analysis
Analysis was conducted on an
intention-to-treat basis, after
excluding infants with life-
threatening congenital anomalies
(see Inclusion Criteria section).
Summary statistics (n, mean, SD,
median, minimum, and maximum)
were used for the analysis of
continuous variables. Counts
and percentages were used for
categorical variables. Student’s t test
and Mann-Whitney tests were used
for continuous variables according
to their distributions. The χ2 test was
used for categorical variables. Factors
known to influence mortality were
entered into a regression analysis
of hospital mortality, including: (1)
RA or 100% O2; (2) male sex; (3)
gestation <28 weeks; (4) heart rate
<100 beats/min at 5 minutes; and
(5) SpO2 <80% at 5 minutes. Analyses
were considered significant at
P < .05; no adjustments were made
for multiple comparisons, and
missing data were not imputed.
Interim Analysis and Stopping Guidelines
A difference of at least 3 SDs
in a major endpoint (or in a
combination of major end points)
suggesting net clinical benefit or
harm was considered by the DSMC
as justification to stop the study
prematurely or to increase the
frequency of trial monitoring or to
instigate modification of trial design.
The DSMC planned to review interim
5
TABL
E 4
Mor
talit
y
Vari
able
All I
nfa
nts
Infa
nts
<28
Wee
ks’ G
esta
tion
Infa
nts
Bet
wee
n 2
8 an
d 3
1 W
eeks
’ Ges
tati
on
RA,
n =
144
100%
O2,
n =
143
RR
(95
% C
I)R
A, n
= 4
610
0% O
2,
n =
54
RR
(95
% C
I)R
A, n
= 9
810
0% O
2,
n =
89
RR
(95
% C
I)
All d
eath
s14
(10
)6
(4)
2.3
(0.9
–5.
7), P
= .1
010
(24
)4
(7)a
2.9
(0.9
–8.
7), P
= .0
4b4
(4)
2 (2
)1.
8 (0
.3–
9.6)
, P =
.7
Neo
nat
al d
eath
(d
eath
<28
d)
12 (
8)5
(3)
3.1
(0.9
–11
.1),
P =
.08
8 (1
7)3
(5)
3.1
(0.9
–11
.1),
P =
.11
4 (4
)2
(2)
1.8
(0.3
–9.
6), P
= .7
Dea
th b
efor
e h
osp
ital
dis
char
ge
14 (
10)
5 (3
)2.
6 (0
.9–
7.1)
, P =
.06
10 (
22)
3 (6
)3.
9 (1
.1–
13.4
), P
= .0
1b4
(4)
2 (2
)1.
8 (0
.3–
9.6)
, P =
.7
Age
of d
eath
, d12
(2–
95)
4 (1
–11
)P
= .2
423
(2–
95)
4 (1
–11
)P
= .3
49
(2–
21)
4 (2
–6)
P =
.53
Cau
ses
of d
eath
cN
EC (
n =
1)
IVH
(n
= 1
)N
EC (
n =
1)
Sep
sis
(n =
1)
Res
pira
tory
failu
re (
n =
8)
Res
pir
ator
y
failu
re (
n =
1)
Res
pir
ator
y
failu
re
(n =
2)
Res
pir
ator
y fa
ilure
(n =
1)
BP
D (
n =
1)
Sep
sis
(n =
1)
Sep
sis
(n =
1)
Sep
sis
(n =
1)
Dat
a ar
e p
rese
nte
d a
s n
(%
) or
med
ian
(ra
nge
), u
nle
ss in
dic
ated
oth
erw
ise.
BP
D, b
ron
chop
ulm
onar
y d
ysp
lasi
a; N
EC, n
ecro
tizi
ng
ente
roco
litis
; RR
, ris
k ra
tio.
a
On
e in
fan
t fr
om t
he
100%
O2
grou
p d
ied
of
sud
den
infa
nt
dea
th s
ynd
rom
e 3
mon
ths
afte
r h
osp
ital
dis
char
ge.
b P
< .0
5.c
Ther
e m
ay b
e >
1 ca
use
of
dea
th a
scri
bed
.
by guest on January 8, 2017Downloaded from
OEI et al
data and emerging evidence from
other studies at 25% (n = 500), 50%
(n = 1000), and 75% (n = 1500) of
enrollment and to advise the steering
committee if premature termination
of the trial was required.
Ethics Approval and Trial Registration
The study was approved by
the following: the South Easy
Sydney Human Research Ethics
Committee (06/065), the Hunter
New England Ethics Committee
(09/08/18/5.07) as the principal
Australian site; the University of
Malaya Ethics Committee (601.17);
the Ministry of Health, Malaysia;
Universiti Kebangsaan Malaysia
Committee (1.5.3.5/244/SPP3); and
the Hamad Medical Corporation,
Qatar.
RESULTS
After review by the DSMC, new
recruitment was ceased in June
2014 due to difficulties in meeting
target recruitment rates. Of 6291
eligible patients, 292 infants were
recruited and randomized to
treatment between first January
2008 and June 14, 2014. The
most common reasons for failed
recruitment were: precipitous
delivery, clinician preference, and
inability of the research team to
attend. Two infants were withdrawn
after consent was given, resulting
in randomization of 290 infants
(RA: n = 145; 100% O2: n = 145). A
female infant (gestational age: 26.3
weeks) randomized to the 100% O2
arm was delivered precipitously.
She was included in the 100% O2
group on an intention-to-treat basis,
but her resuscitation data were
not included. Two infants from the
100% O2 group (1 with hypertrophic
cardiomyopathy, 1 with a congenital
diaphragmatic hernia) and 1 from
the RA group (lung hypoplasia and
dysplasia) were excluded after birth
(see Exclusion Criteria and Methods),
leaving 144 infants in the RA group
and 143 infants in the 100% O2 group
to be included in the final analysis
( Fig 1).
Patient Demographic Characteristics
Maternal and infant characteristics
are shown in Table 1. Most mothers
were multiparous and gave birth
via cesarean delivery. Almost all
mothers received at least 1 dose of
antenatal steroids, and there were
no differences between the groups
for significant antenatal problems or
infant parameters. Forty-six (32%) of
144 RA infants and 54 (38%) of 143
100% O2 infants were <28 weeks’
gestation (OR: 0.8 [95% CI: 0.5–1.3];
P = .32).
Resuscitation Outcomes
One infant in the RA group was
given adrenaline and cardiac
compressions. No infant died during
resuscitation or was asystolic. Most
were given continuous positive
airway pressure, and approximately
one-third were intubated. Age at
admission to the NICU, admission
FIO2, and temperature did not differ
( Table 2).
As shown in Fig 2, heart rates were
significantly lower in the RA group
until the third to fourth minute
of life. SpO2 was also significantly
lower in infants in the RA group for
up to minute 8 of life but were not
significantly different thereafter.
Infants commenced on 100% O2
had SpO2 ranges mostly within
recommended targets, 26 but RA
infants did not meet these targets
until minute 8 of life ( Fig 3). Infants
started on 100% O2 received
significantly more O2 until minute
8 of life. FIO2 was not different after
that until nursery admission
( Fig 4 and Table 2). These
differences were not significantly
different between the groups when
the infants were examined according
to gestational age (ie, below or
above 28 weeks’ gestation)
( Figs 2– 4).
Hospital Outcomes
Data for gestational subgroups
(below or above 28 weeks’ gestation)
are included in the Supplemental
Materials.
Morbidities
Infants given 100% O2 required
a significantly longer duration
of respiratory support (defined
as use of mandatory ventilation,
continuous positive airway pressure,
or high- and low-flow nasal
cannula) compared with the RA
group. There was no difference in
prespecified morbidities, including
bronchopulmonary dysplasia, ROP,
patent ductus arteriosus (PDA),
intraventricular hemorrhage, or
necrotizing enterocolitis (Table 3).
Infants in the 100% O2 group were
more likely to require surgery,
predominantly for conditions
occurring after the first few days of
life (eg, hernia repair and for PDA
ligation).
Death
Death before 28 days of age (neonatal
death) or death before hospital
discharge was not significantly
different for all infants. However,
10 (22%) of the infants <28 weeks’
gestation in the RA group died before
6
TABLE 5 Logistic Regression of Factors Associated With Death Before Hospital Discharge
Factor B (SE) P Adjusted Odds Ratio (95% CI)
Initiation of resuscitation with 100% O2 0.7 (0.6) .25 0.5 (0.1–1.6)
Male sex 0.1 (0.5) .81 1.1 (0.4–3.1)
5 min HR <100 beats/min 1.2 (0.7) .08 3.3 (0.8–13.1)
5 min SpO2 <80% 1.4 (0.5) .01a 4.1 (1.3–12.9)
Gestation <28 wk 1.5 (0.5) .04a 4.8 (1.6–14.5)
HR, heart rate.a P < .05.
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PEDIATRICS Volume 139 , number 1 , January 2017
hospital discharge, compared with
3 (6%) infants given 100% O2 (risk
ratio: 3.9 [95% CI: 1.1–13.4]; P = .01).
The most common cause of death was
respiratory failure (n = 13). Infants
in the RA group died slightly later
(median: 12 days; range: 2–95 days)
than infants on 100% O2 (median: 5
days; range: 1–83 days). One infant
<28 weeks’ gestation from the 100%
O2 group died of sudden infant death
syndrome 3 months after hospital
discharge. No other child has died
since hospital discharge (Table 4).
Regression Analysis
Regression analysis showed that
both failure to meet target SpO2 by
5 minutes and gestation <28 weeks
were significantly associated with the
risk of death (adjusted odds ratios:
4.1 and 4.8, respectively) (Table 5);
100% O2, male sex, or low (<100
beats/min) 5-minute heart rate were
not significant associations for death
(model: B, 2.53; SE, 0.23; df = 1; Exp
[B] = 0.08).
DISCUSSION
This study was the largest single
randomized trial to examine
outcomes of very preterm infants
after delivery room resuscitation
was initiated with either lower RA
or higher (100%) O2. We emphasize
that this study was underpowered
due to recruitment difficulties
associated with the lack of equipoise
for using 100% O2. 24 – 26 On the
advice of the DSMC, we stopped
recruitment in June 2014 but
published short-term outcomes
because the results would represent
the single biggest contribution
to any meta-analysis, the highest
level of current evidence. The
contribution of To2rpido data to a
meta-analysis of 504 infants <28
weeks’ gestation shows that lower
(≤30%) or higher (≥60%) O2 (risk
ratio: 0.99 [95% CI: 0.52–1.91])
resuscitation makes no difference
to hospital mortality 35 despite
current clinical preference to use
lower FIO2.31
We emphasize that recruitment for
this study was not stopped because
of the unexpected finding of a 3-fold
increase in deaths in infants <28
weeks’ gestation who were initially
given RA. These infants were
already at a high risk of death
compared with more mature infants,
and the precise etiology of death
cannot be ascertained from this
small group. The results were not
prespecified and due to the small
sample size, a change in just 1 death
7
FIGURE 2Mean (95% CI) heart rates during the fi rst 10 minutes of life. A, All infants. B, Infants <28 weeks’ gestation. C, Infants between 28 and 31 weeks’ gestation.
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OEI et al
in either group would have resulted
in very different outcomes. The
results should be considered only as
hypothesis-generating.
Our secondary results suggest
possible differences in outcomes
for survivors. RA infants needed
less time on supplemental O2 and
respiratory support. This scenario
was noted previously by Vento
et al 15 and may be due to decreased
oxidative injury. 5, 6, 16 Infants on
100% O2 needed more surgery, but
the cause for this requirement is
speculative due to the heterogeneous
nature of the surgeries. Some
surgeries (eg, hernia repairs) can
only be performed if the infant
survives, although others (eg, ROP
and PDA ligation) have been linked
to high O2 exposure. High O2 levels,
for example, increase free radical
production and prostaglandin E2
expression, a ductal relaxant.36
The associations between lower
O2 resuscitation and a decreased
rate of PDA were also noted in a
retrospective population study by
Rabi et al. 37
The present study was designed
before publication of SpO2
target recommendations in
expert guidelines. 26, 27 Despite
widespread acceptance of
these recommendations, 31
the implications of these
trajectories for preterm infants
are unclear. The International
Consensus on Cardiopulmonary
Resuscitation of 2015 makes no
SpO2 target recommendations in
its resuscitation algorithm. 27 Low
SpO2 may not result in immediate
apparent harm, but hypoxia might
lead to delayed cellular damage.
In animal studies, hypoxia is
associated with delayed death,
apoptosis, and irreversible cellular
degeneration.38 In our study, death
occurred slightly later in infants
given RA (12 vs 4 days) but again,
this outcome needs to be verified in
larger studies.
A retrospective population study
by Rabi et al 37 of 2326 infants ≤27
weeks’ gestation from Canadian
NICU units supports the need for
more evidence before lower O2
resuscitation can be universally
recommended. After changes
to the Canadian resuscitation
guidelines from 100% O2 to RA or
lower O2, infants after the change
(n = 1244) were more likely to die
or have severe neurologic injury
(adjusted odds ratio: 1.36 [95%
CI: 1.11–1.66]) than those born
before the guideline change (n =
1082). 39 The researchers noted that
they did not have data regarding
individual O2 exposure, and it would
be misleading to attribute major
8
FIGURE 3Mean (95% CI) SpO2 during the fi rst 10 minutes of life. A, All infants. B, Infants <28 weeks’ gestation. C, Infants between 28 and 31 weeks’ gestation.
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PEDIATRICS Volume 139 , number 1 , January 2017 9
ABBREVIATIONS
CI: confidence interval
DSMC: Data and Safety
Monitoring
Committee
FIO2: fractional inspired oxygen
O2: oxygen
PDA: patent ductus arteriosus
SpO2: pulse oximetry
RA: room air
ROP: retinopathy of prematurity
outcomes to the initial levels of
FIO2 used.
There are limitations to our study.
Due to difficulties in recruiting, the
study was stopped prematurely and
is significantly underpowered for
the primary outcome. Furthermore,
ethics committees did not allow
either blinding or consent waiver.
Personnel who are not involved in
clinical care may be able to respond
to SpO2 changes more promptly, and
the difference is demonstrated in a
meta-analysis which showed that
masked studies had lower mortality
rates in the lower O2 arms. 35
Parental consent may also take time
and exclude the sickest infants. 40
Finally, the study was conducted
over a long period when clinical
practice undoubtedly changed, with
clinicians most likely becoming
more adept at SpO2 targeting and
FIO2 blending. 31 Whether this
factor has an effect on outcomes is
uncertain.
CONCLUSIONS
The results of this study must be
interpreted with caution due to
its small sample size. However, it
remains the largest randomized
controlled trial to date. Our non-
prespecified but potentially
concerning finding of increased
hospital death in infants
<28 weeks’ gestation resuscitated
with RA emphasizes the critical
need to urgently examine this
knowledge gap further with
large and well-designed trials.
Failure to do so could lead to
irreversible harm to thousands of
preterm infants around the world
every year.
ACKNOWLEDGMENTS
The authors thank the DSMC for their
support and advice regarding this
study (Prof Nicholas Evans [chair],
Prof Val Gebski, and Dr Wendy
Hague).
FIGURE 4Mean (95% CI) FiO2 administered to infants during the fi rst 10 minutes of life. A, All infants. B, Infants <28 weeks’ gestation. C, Infants between 28 and 31 weeks’ gestation.
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10
revising of the manuscript; Drs Ching, Cheah, Mun, and Kamar were responsible for recruitment in Malaysia and revising of the manuscript; Dr Masoud was
responsible for recruitment in Qatar and revising the manuscript; and Dr Tarnow-Mordi was responsible for overseeing the running of the study, supervision of
the study, and for reviewing the manuscript. All authors approved the manuscript for submission.
This trial has been registered with the Australian and New Zealand Clinical Trials Network Registry (www. anzctr. org. au/ ) (ACTRN 12610001059055) and the
National Malaysian Research Registry (www. nmrr. gov. my) (NMRR-07-685-957).
DOI: 10.1542/peds.2016-1452
Accepted for publication Oct 14, 2016
Address correspondence to Ju Lee Oei, MBBS, FRACP, MD, Department of Newborn Care, Royal Hospital for Women, Barker St, Randwick, NSW, Australia, 2031.
E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2017 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.
FUNDING: Supported by the Thrasher Research Fund for Children, United States, and the Leslie Stevens Fund for Newborn Research, Australia.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.
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Masoud and William Tarnow-MordiTheam Lim, Yao Mun Choo, Azanna Ahmad Kamar, Fook Choe Cheah, Ahmed
Mishra, Koert De Waal, Javeed Travadi, Kwee Ching See, Irene G.S. Cheah, ChinYueping Alex Wang, Rowena McMullan, Elisabeth Coates, Meredith Ward, Parag Ju Lee Oei, Ola D. Saugstad, Kei Lui, Ian M. Wright, John P. Smyth, Paul Craven,
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