21o SIMPOSIO INTERNACIONAL DE NEONATOLOGIA

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em especial a Dra. Suerda, Dra. Andrea Sueli e a Dra. Ana Caroline.
Saturacao-Alvo de Oxigenio para Prematuros Extremos apos
o Estudo NeOProM
 Review
Neonatology 2016;109:352358
DOI: 10.1159/000444913
Oxygen Saturation Targets for Extremely
Preterm Infants after the NeOProM Trials
Ben J. Stenson
Neonatal Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
Key Words
Extremely preterm infants Neonatal Oxygen Prospective
Meta-Analysis Pulse oximeter saturation
Abstract
Five randomized controlled trials comparing lower (8589%)
versus higher (9195%) pulse oximeter saturation (SpO2) tar-
gets for extremely preterm infants have now been reported
from the United States of America, Canada, the United King-
dom, Australia and New Zealand. These trials included more
than 4,800 infants, and they provide robust evidence to per-
mit comparison of these target ranges and consider the next
steps for clinicians and researchers. The lower SpO2 range
was associated with a significant increase in the risk of death.
There was no significant difference between the two target
ranges in the rate of disability at 1824 months, including
blindness. A significant difference between groups in the
risk of the composite primary outcome of death or disability
in favour of the higher SpO2 range was mainly attributable
to the difference between groups in the risk of death. The
lower target range did not reduce bronchopulmonary dys-
plasia or severe visual impairment, but it did increase the risk
of necrotizing enterocolitis requiring surgery or causing
death. The trials provide no reason to prefer SpO2 targets
2016 S. Karger AG, Basel
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www.karger.com/neo
Published online: June 3, 2016
below 90% and indicate the importance of more trials to see
if a further survival advantage can be identified. The safety
of targets above 95% has not been evaluated. The five trials
were designed to be similar to facilitate an individual patient
data meta-analysis, and this Neonatal Oxygen Prospective
Meta-Analysis (NeOProM) may provide further insights.
2016 S. Karger AG, Basel
Historical Evidence
Prior to the recent randomized controlled trials of low-
er versus higher oxygen saturation (SpO2) target ranges,
the evidence base to guide oxygen therapy in extremely
preterm infants was very weak. When oxygen therapy was
first introduced into neonatal care, there was no way to
measure arterial oxygen levels. Oxygen was administered
to preterm infants at high inspired percentages for long
periods according to clinical judgements and it was in this
context that retinopathy of prematurity (ROP) was linked
with prolonged exposure to high inspired oxygen (FiO2).
Trials conducted without measurements of oxygenation
demonstrated that a restrictive approach to oxygen sup-
plementation could reduce the number of infants with
retinopathy [13], but the oxygen restriction that fol-
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Univ. of California Santa Barbara
Ben J. Stenson
Neonatal Unit, Royal Infirmary of Edinburgh
51 Little France Crescent, Old Dalkeith Road
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Edinburgh EH16 4SA (UK)
E-Mail ben.stenson@luht.scot.nhs.uk
lowed came with a cost of increased mortality and cere-
bral palsy [48].
When it became possible to measure oxygen tension,
first by intermittent arterial puncture and then by mea-
surement of transcutaneous oxygen tension (PO2), con-
trolled oxygen therapy began. Oxygen was titrated to
achieve various PO2 ranges, but there were no trials to
determine the upper and lower PO2 limits associated with
the best outcomes.
A trial published in 1987 aimed to show whether using
continuous transcutaneous PO2 monitoring, in addition
to intermittent arterial sampling, would improve out-
comes in comparison with intermittent arterial sampling
alone [9]. PO2 targets of 5070 mm Hg (6.79.3 kPa) were
used in both groups. There were 296 infants with birth
weight <1,300 g randomized. The addition of transcuta-
neous monitoring was associated with an 8% decrease in
all stages of ROP (51 vs. 59%). However, there was no dif-
ference in more concerning severe retinopathy. There
were 8% more deaths in the transcutaneous monitoring
group (32 vs. 24%). These differences were not statisti-
cally significant and may be chance findings, but in retro-
spect they may represent further early evidence that tight-
ening up the control of oxygen administration reduced
retinopathy at a cost of increased mortality. In a later
analysis of the same study, ROP was associated with PO2
levels greater than 80 mm Hg (10.7 kPa) [10]. The Amer-
ican Academy of Pediatrics recommended a PO2 target
range of 5080 mm Hg (6.710.7 kPa) [11].
Pulse oximetry gradually became the most widely used
monitoring method, probably because of its ease of ap-
plication and not because of its demonstrated superiority
in optimizing clinical outcomes. There were no trials to
determine that using SpO2 monitoring improved out-
comes when compared with transcutaneous PO2 moni-
toring. It remains an open question whether oxygen ten-
sion or oxygen saturation represents the safer measure for
guiding oxygen treatment in preterm infants. A small
crossover study suggested that transcutaneous monitor-
ing may facilitate avoidance of high and low oxygen ten-
sion more effectively than saturation monitoring [12].
In the absence of trials to determine the optimal satura-
tion target range for preterm infants there was widespread
variation in practice. A survey of practice in UK neonatal
units interested in participating in the BOOST-II UK trial
suggested that a SpO2 range of 8595% was broadly rep-
resentative of practice before the recent trials; however,
some units were using higher or lower limits [unpubl.
data]. The relationship between PO2 and saturation varies
within and between infants, and the range of possible PO2
Oxygen Saturation Targets for Extremely
Preterm Infants
values at any individual SpO2 is wide. The 95% confidence
intervals for PO2 in oxygen-dependent preterm infants for
the SpO2 range 8595% in the first week after birth include
a PO2 range of 2967 mm Hg (3.88.9 kPa) [13]. In other
words, the shift to SpO2 monitoring with a range of 85
95% from transcutaneous PO2 monitoring was associated
with an unevaluated and substantial shift downwards in
the permitted range of PO2 values that preterm infants
were being targeted to from previous limits of 5080 mm
Hg (6.710.7 kPa) to a range of around 2967 mm Hg
(3.88.9 kPa). Encouragingly, observational studies sug-
gested the possibility that targeting lower SpO2 values
might allow a reduction in ROP and bronchopulmonary
dysplasia (BPD), without an increase in the risk of mortal-
ity or disability [1417], giving rise to wide interest in the
evaluation of different SpO2 targets.
Recent Trial Evidence
Five randomized controlled trials have now been un-
dertaken since 2005 to compare the outcomes of infants
targeted to lower (8589%) versus higher (9195%) SpO2
targets [1821]. These trials were conducted as separately
funded and managed components of a prospective indi-
vidual patient data meta-analysis known as the Neonatal
Oxygen Prospective Meta-Analysis (NeOProM) Collabo-
ration [22]. The trials used Masimo Radical oximeters
(Masimo Corporation, Irvine, Calif., USA) that were in
widespread use clinically at the time. In order to mask the
group allocation from the caregivers, the trial oximeters
were offset to read either 3 percentage points higher or
lower than the underlying true SpO2 reading in the range
8595%, so that in the lower SpO2 target group a SpO2
reading of 90% would be displayed at an underlying SpO2
of 87% and in the higher target group a SpO2 reading of
90% would be displayed at an underlying SpO2 of 93%. If
nursing staff targeted the displayed SpO2 range 8892%,
this was expected to achieve the intended ranges of 85
89% and 9195% in the two randomization groups, re-
spectively, and in the middle of the target ranges there was
expected to be a 6% difference between groups in mean
SpO2. In order that clinical staff could be confident that
they were not allowing what they might consider clini-
cally significant hypoxia or hyperoxia at SpO2 above 95 or
below 85%, the oximeter transitioned back to displaying
the underlying true reading. An oximeter offset of plus or
minus 2% was effective in achieving separation in SpO2
distributions between randomization groups in the first
BOOST trial in 2003 [23].
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DOI: 10.1159/000444913
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 A relevant factor for the interpretation of the trials was
the discovery by the UK trial team that the Masimo Rad-
ical pulse oximeters used for the trials had an artefact in
their calibration [24]. This was a feature of Masimo ox-
imeters in general use at the time and was not specific to
the trial oximeters. The oximeter returned fewer values
than expected in the SpO2 range 8790% and shifted val-
ues above 87 upwards by 12%. This affected the higher
and lower SpO2 target ranges in the trials, but particu-
larly the lower target range. The Masimo Corporation
provided revised calibration software for the oximeters
which eliminated the issue and the revised oximeters re-
turned saturation distributions that were similar to in-
struments from other manufacturers [24]. Revised oxim-
eters were introduced into the UK and Australian
BOOST-II trials and into the Canadian Oxygen Trial
(COT) during enrollment. Therefore, these three trials
each have populations of infants treated with the original
and the revised oximeters. The UK trial was at an earlier
stage in its intended enrollment than the other trials when
the issue was identified and decided to make infants treat-
ed with the revised oximeters its primary analysis popula-
tion. Data from the UK, Australian and New Zealand
BOOST-II trials showed consistently that the oximeter
artefact affected the achieved SpO2 distributions in both
randomization groups and that the oximeter revision rec-
tified this, allowing clearer separation between groups in
saturation patterns and resulting in the infants allocated
to the lower SpO2 target range spending more time in
their intended target range [21]. It was therefore feasible
to consider that if SpO2 ranges affect clinical outcome that
the oximeter revision could have an important effect on
the trial outcomes. Masimo eliminated the calibration ar-
tefact from oximeters sold after it was identified. The is-
sue does not invalidate the trial data gathered using the
original oximeters. The original oximeters performed
within the required standards of accuracy and allowed
infants to be managed with higher or lower SpO2, albeit
with less separation between groups. It is reasonable to
pool data that were gathered using oximeters of both
types, but as the revised oximeters allowed greater separa-
tion of the groups in saturation patterns and returned sat-
uration distributions more like those obtained with ox-
imeters from other manufacturers, the trial data gathered
using the revised oximeters may be more generalizable to
current practice, making it important also to consider
them separately.
The NeOProM trials recruited infants born before 28
weeks gestation within 24 h of birth. The intervention
was continued until 36 weeks postmenstrual age as long
354 Neonatology 2016;109:352358
DOI: 10.1159/000444913
as the infants still needed supplemental oxygen and were
being monitored. Conducting these trials with such a
lengthy intervention was a major logistical challenge.
There were some differences among the trials. In the
SUPPORT trial [18] consent was obtained before deliv-
ery, the infants were randomized from birth and outborn
infants were not included. Infants from multiple births
received the same intervention. The SUPPORT trial did
not enroll infants born before 24 weeks gestation. In the
other trials [1921] randomization took place in the first
24 h after birth, infants were not enrolled if they were al-
ready considered to be unlikely to survive and outborn
infants were enrolled. Infants from multiple births were
randomized individually. Infants born before 24 weeks
gestation were eligible for inclusion.
All of the trials targeted the same SpO2 ranges, but
they varied in their approaches to the application of
alarm limits, in the amount of detail gathered about oxy-
gen administration and in the detail that has been re-
ported about their achieved SpO2 distributions. Follow-
up assessments of cognitive function in the SUPPORT
trial [18] and COT [19] used only Bayley-III assessments.
In the UK, Australian and New Zealand BOOST-II trials
the Bayley-III was used in the majority of cases but, blind
to trial group allocation, some alternative measures of
cognitive function were substituted in infants when a
Bayley-III examination could not be achieved in order to
avoid post-randomization exclusions from missing data
[21, 25].
The trials overlapped one another in terms of their en-
rollment periods, but were not completed simultaneous-
ly. The first trial to report outcomes was the SUPPORT
trial [18], which showed an increased risk of mortality in
infants randomized to the lower SpO2 target range. At
this time, recruitment to the New Zealand BOOST-II tri-
al [20] and COT [19] was almost complete, but the UK
and Australian BOOST-II Trials [21] had longer to run.
In response to the SUPPORT trial findings and in keeping
with the trial protocols, their data monitoring commit-
tees undertook a pooled safety analysis combining mor-
tality data from the SUPPORT trial with data from the
UK, Australian and New Zealand BOOST-II trials. When
this analysis showed an increased risk of death in infants
targeted to the SpO2 range 8589% that was statistically
significant at the pre-specified 99.73% level of statistical
confidence, the results were revealed to the investigators.
The UK and Australian trial investigators considered the
mortality risk to be beyond reasonable doubt and the
BOOST-II UK and Australian trials were stopped early
[26].
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Stenson
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 Study or subgroup Lower SpO2 Higher SpO2 Weight, RR RR
% Mantel-Haenszel, Mantel-Haenszel,
events total events total fixed (95% CI), year fixed (95% CI)

SUPPORT 140 633 118 648 27.9 1.21 (0.981.51), 2012

COT 97 585 88 577 21.2 1.09 (0.831.42), 2013
BOOST-II New Zealand 25 170 27 170 6.5 0.93 (0.561.53), 2014
BOOST-II UK 122 484 98 483 23.5 1.24 (0.981.57), 2015
BOOST-II Australia 100 561 87 562 20.8 1.15 (0.891.50), 2015

Total (95% CI) 2,433 2,440 100.0 1.16 (1.031.31)

Total events 484 418
Heterogeneity: 2 = 1.51, d.f. = 4 (p = 0.83), I2 = 0%
0.2 0.5 1 2 5
Test for overall effect: Z = 2.50 (p = 0.01)
Favours Favours
lower SpO2 higher SpO2

Fig. 1. Meta-analysis of mortality at 1824 months for all infants reported, using both the original and revised
oximeters. Analysed using RevMan version 5.3, Cochrane Collaboration.

Summary Outcomes
A meta-analysis of some of the outcomes from the 5
NeOProM trials was published in 2014 [27]. At this time
the UK, Australian and New Zealand BOOST-II trials had
reported their outcomes to hospital discharge, but their
2-year outcome data were not available. The 2014 meta-
analysis reported data for 4,911 infants. The analyses
showed that there was a lower risk of severe ROP in infants
targeted to lower SpO2 (10.7%) compared to the higher
SpO2 (14.5%), with a relative risk (RR) of 0.74 and 95%
confidence interval (CI) of 0.590.92. Infants randomized
to the lower SpO2 range had a higher risk of necrotizing
enterocolitis (11.2 vs. 9.0%; RR 1.25, 95% CI 1.051.49).
There was no significant difference between groups in in-
cidence of BPD when this was defined physiologically or
as severe disease (37.6 vs. 39.7%; RR 0.95, 95% CI 0.86
1.04). There was no significant difference between groups
in brain injury (14.2 vs. 14.1%; RR 1.02, 95% CI 0.881.19)
or in treatment for patent ductus arteriosus (49.2 vs. 49%;
RR 1.10, 95% CI 0.951.08). There was no heterogeneity
between trials for any of these outcomes.
Data on outcomes to 1824 months have now been
reported for all 5 trials [19, 20, 25, 28]. Data are available
for the composite outcome of death or disability in 4,751
infants, 2,379 who were treated with the lower SpO2 tar-
get and 2,372 who were treated with the higher SpO2 tar-
get. A fixed effects meta-analysis of the 5 trials combining
the results of infants who were treated with the original
and the revised oximeters shows that the composite out-
come of death or disability occurred in 1,040/2,379
(43.7%) infants in the low SpO2 target group versus
967/2,372 (40.8%) infants in the high target group (RR
1.07, 95% CI 1.001.14; p = 0.04). When this analysis is
restricted to infants treated with the revised oximeters,
death or disability occurred in 430/852 (50.5%) low target
group infants versus 372/829 (44.9%) high target infants
(RR 1.13, 95% CI 1.021.24; p = 0.02). A test for interac-
tion was not statistically significant for the 2 different ox-
imeter types for this composite outcome (p = 0.24).
Considering the components of the primary outcome
separately, death before 1824 months occurred in
484/2,433 (19.9%) low target infants and 418/2,440
(17.1%) of high target infants (RR 1.16, 95% CI 1.031.31;
p = 0.01; fig.1). When this analysis was restricted to the
results obtained using the revised oximeters, death before
1824 months occurred in 190/860 (22.1%) low target in-
fants versus 137/856 (16.0%) high target infants (RR 1.38,
95% CI 1.131.68; p = 0.001). A test for interaction showed
that the results obtained using the revised oximeters were
significantly different from those obtained with the orig-
inal oximeters (p = 0.009). The effect of the change in ox-
imeters on mortality was similar in all 3 trials which
changed to the revised oximeters during enrollment
(fig.2).
There was no significant difference between groups in
the composite measure of disability. One or more of the
measures of disability was identified in 566/1,895 (29.9%)
infants randomized to the low SpO2 target and 539/1,954
(28.1%) infants randomized to the high SpO2 target (RR
1.04, 95% CI 0.941.14). The results were similar when
the analysis was restricted to the infants treated with re-
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Oxygen Saturation Targets for Extremely Neonatology 2016;109:352358 355

Preterm Infants DOI: 10.1159/000444913
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 Study or subgroup Lower SpO2 Higher SpO2 Weight, RR RR
% Mantel-Haenszel, Mantel-Haenszel,
events total events total fixed (95% CI) fixed (95% CI)

1.6.1 Original oximeters

COT 49 281 48 268 18.0 0.97 (0.681.40)
BOOST-II UK 21 113 29 114 10.6 0.73 (0.441.20)
BOOST-II Australia 57 345 57 345 20.9 1.00 (0.721.40)

Subtotal (95% CI) 739 727 49.6 0.93 (0.751.16)

Total events 127 134
Heterogeneity: 2 = 1.15, d.f. = 2 (p = 0.56), I2 = 0%
Test for overall effect: Z = 0.62 (p = 0.54)

1.6.2 Revised oximeters

COT 46 273 38 270 14.0 1.20 (0.811.78)
BOOST-II UK 101 371 69 369 25.4 1.46 (1.111.91)
BOOST-II Australia 43 216 30 217 11.0 1.44 (0.942.21)

Subtotal (95% CI) 860 856 50.4 1.38 (1.131.68)

Total events 190 137
Heterogeneity: 2 = 0.69, d.f. = 2 (p = 0.71), I2 = 0%
Test for overall effect: Z = 3.20 (p = 0.001)

Total (95% CI) 1,599 1,583 100.0 1.16 (1.001.34)

Total events 317 271
Heterogeneity: 2 = 8.70, d.f. = 5 (p = 0.12), I2 = 43% 0.2 0.5 1 2 5
Test for overall effect: Z = 1.97 (p = 0.05)
Favours Favours
Test for subgroup differences: 2 = 6.75, d.f. = 1 (p = 0.009), I2 = 85.2%
lower SpO2 higher SpO2

Fig. 2. Meta-analysis of mortality at 1824 months in the BOOST-II UK and Australian trials and COT, sub-
grouped according to whether infants were treated with the original or the revised oximeters. Analysed using
RevMan version 5.3, Cochrane Collaboration.

vised oximeters (RR 1.06, 95% CI 0.921.23). Disability
outcomes for COT are not in the trial outcomes paper and
were estimated by subtracting the number of infants who
died from the published results for death or disability.
Severe visual impairment was present in 25/1,910 in-
fants targeted to lower SpO2 and 24/1,965 infants targeted
to higher SpO2 (RR 1.13, 95% CI 0.651.97). Most of the
trials did not report blindness due to retinal damage sep-
arately to that resulting from cortical visual impairment.
In the BOOST-II UK trial [25] there were 4 infants (2 in
each group) whose severe visual impairment was due to
retinal damage from a total of 18 cases (12 cortical, 4 ret-
inal, 2 unknown).
Discussion
The recent oxygen trials took place in a developed world
setting where SpO2 monitoring is universally available and
ROP screening and treatment is carefully organized. In
that context, targeting SpO2 below 90% significantly in-
creased mortality and necrotizing enterocolitis. There was
no reduction in BPD with lower SpO2 targets. Although
there were fewer infants treated for ROP with lower SpO2
targets, ROP treatment is usually successful and there was
no long-term difference in severe visual impairment or any
other disability between groups. The hope that lower SpO2
targets might reduce ROP and BPD without any conse-
quence was not fulfilled. The fact that higher SpO2 targets
increased survival without increasing morbidity should be
considered quite exciting. At least in a developed world set-
ting, there is no longer (as there was in the past) a trade-off
between mortality and blindness from ROP only between
mortality and a need for ROP treatment. This should not
be a difficult choice given the success of ROP treatment.
The advantage of higher SpO2 targets is clear. The message
is similar when the data from all oximeters combined are
considered and when the analysis is restricted to the re-
vised oximeters; however, the difference in mortality ob-
served after the oximeters were revised was greater.
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356 Neonatology 2016;109:352358 Stenson

DOI: 10.1159/000444913
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 Individual patient data meta-analysis of the trials will
allow further useful subgroup analyses to evaluate the ef-
fects of other characteristics on outcomes, such as gender,
gestation, antenatal steroid exposure, intrauterine growth
restriction and multiple births.
A meta-analysis of the NeOProM trials published in
2015 [29] prior to the availability of the follow-up out-
comes of the UK and Australian BOOST-II trials down-
graded the quality of the evidence on the basis that the
mortality data available at the time were assessed at dis-
charge from hospital and this was not pre-specified, the
difference in saturation patterns between the trials was
less than expected, and because there were concerns
about the oximeters. The mortality data to 2 years were
pre-specified and are now available. The finding of sig-
nificant differences in mortality between groups despite
smaller than expected separation in saturation patterns
does not downgrade the evidence, but instead gives rise
to a concern that a bigger difference in mortality may
have been observed if there had been more success in
keeping the low target group in their intended range. The
mortality effect of targeting lower SpO2 is apparent when
the results from all oximeters are considered and becomes
stronger when the analysis is restricted to the infants
treated with oximeters with the revised calibration algo-
rithm. A strikingly similar effect was observed in all 3 tri-
als that changed their oximeters, despite these trials being
conducted independently on 3 different continents.
There can be little doubt that correcting the oximeter al-
gorithm strengthened the results. The UK and Australian
trials were stopped early because of an extremely strong
mortality signal. Trials of interventions that influence
mortality are likely to be stopped early if they are showing
a statistically strong effect because of the gravity of the
outcome. Conversely, trials showing smaller effects are
less likely to be stopped. It is important to consider all of
the evidence in reaching conclusions.
It is clear that small differences in oxygen saturation
patterns in preterm infants influence major clinical out-
comes. This emphasizes the need for more studies to de-
termine whether there is a further survival advantage to
be identified. It should also give clinicians pause in using
untested saturation targets outside of clinical trials, par-
ticularly if they include values below 90%. Analyses of the
saturation patterns associated with morbidity and mor-
tality will be important to inform the design of future
studies. Testing a higher saturation range may be impor-
tant, but may also be difficult because of the possibility of
high PO2 values at higher saturations in infants receiving
supplemental oxygen, and future studies may need to in-
Oxygen Saturation Targets for Extremely
Preterm Infants
corporate some transcutaneous PO2 monitoring. Servo-
controlled systems are increasingly being demonstrated
to enable improved oxygen saturation targeting with re-
duced time outside the target range and can operate with
quite narrow targets [30]. As these devices become more
widespread, it may be possible to conduct future trials of
different target ranges with improved protocol compli-
ance, greater discriminatory power and enhanced patient
safety.
Conclusions
In trials conducted in a developed world setting with
continuous SpO2 monitoring and protocols for screening
for and treating ROP, targeting SpO2 below 90% in ex-
tremely preterm infants increased mortality and did not
reduce the risk of blindness or other disabilities and can-
not be recommended.
Acknowledgment
I am grateful to Andy King for advice about the statistical anal-
yses.
Disclosure Statement
Ben Stenson is an investigator on the BOOST-II UK trial. This
commissioned article represents his individual views and has been
written without input from the trial group or from the members of
the NeOProM Collaboration.
References 1 Lanman JT, Guy LP, Dancis J: Retrolental fi-
broplasia and oxygen therapy. JAMA 1954;
155:223226.
2 Patz A: Oxygen studies in retrolental fibropla-
sia. IV. Clinical and experimental observa-
tions. Am J Ophthalmol 1954;38:291308.
3 Kinsey VE: Retrolental fibroplasia; coopera-
tive study of retrolental fibroplasia and the use
of oxygen. AMA Arch Ophthalmol 1956; 56:
481543.
4 Avery ME: Recent increase in mortality from
hyaline membrane disease. J Pediatr 1960;57:
553559.
5 McDonald AD: Oxygen treatment of prema-
ture babies and cerebral palsy. Dev Med Child
Neurol 1964;6:313314.
6 Cross KW: Cost of preventing retrolental fi-
broplasia? Lancet 1973;2:954956.
128.111.121.42 - 6/9/2016 6:22:01 AM
Univ. of California Santa Barbara
Neonatology 2016;109:352358 357
DOI: 10.1159/000444913
Downloaded by:
 7 Bolton DP, Cross KW: Further observations
on cost of preventing retrolental fibroplasia.
Lancet 1974;1:445448.
8 Silverman WA: A cautionary tale about sup-
plemental oxygen: the albatross of neonatal 17
medicine. Pediatrics 2004;113:394396.
9 Bancalari E, Flynn J, Goldberg RN, Bawol R,
Cassady J, Schiffman J, et al: Influence of
transcutaneous oxygen monitoring on the in- 18
cidence of retinopathy of prematurity. Pediat-
rics 1987;79:663669.
10 Flynn JT, Bancalari E, Snyder ES, Goldberg
RN, Feuer W, Cassady J, et al: A cohort study 19
of transcutaneous oxygen tension and the in-
cidence and severity of retinopathy of prema-
turity. N Engl J Med 1992;326:10501054.
11 American College of Obstetricians and Gyne-
cologists: Guidelines for Perinatal Care, ed 2.
Elk Grove Village, American Academy of Pe-
diatrics, 1988. 20
12 Quine D, Stenson BJ: Does the monitoring
method influence stability of oxygenation in
preterm infants? A randomised crossover
study of saturation versus transcutaneous
monitoring. Arch Dis Child Fetal Neonatal
Ed 2008;93:F347F350.
13 Quine D, Stenson BJ: Arterial oxygen tension 21
(PaO2) values in infants <29 weeks of gesta-
tion at currently targeted saturations. Arch
Dis Child Fetal Neonatal Ed 2009; 94:F51
F53.
14 Tin W, Milligan DW, Pennefather P, Hey E:
Pulse oximetry, severe retinopathy, and out-
come at one year in babies of less than 28
weeks gestation. Arch Dis Child Fetal Neona-
tal Ed 2001;84:F106F110. 22
15 Sun SC: Relation of target SpO2 levels and
clinical outcome in ELBW infants on supple-
mental oxygen. Pediatr Res 2002;51:350a.
16 Chow LC, Wright KW, Sola A; CSMC Oxy-
gen Administration Study Group: Can chang-
358 Neonatology 2016;109:352358
DOI: 10.1159/000444913
es in clinical practice decrease the incidence
of severe retinopathy of prematurity in very
low birth weight infants? Pediatrics 2003;111:
339345.
Anderson CG, Benitz WE, Madan A: Reti-
nopathy of prematurity and pulse oximetry: a
national survey of recent practices. J Perinatol
2004;24:164168.
Carlo WA, Finer NN, Walsh MC, Rich W,
Gantz MG, Laptook AR, et al: Target ranges
of oxygen saturation in extremely preterm in-
fants. N Engl J Med 2010;362:19591969.
Schmidt B, Whyte RK, Asztalos EV, Mod-
demann D, Poets C, Rabi Y, et al; Canadian
Oxygen Trial (COT) Group: Effects of target-
ing higher vs lower arterial oxygen satura-
tions on death or disability in extremely pre-
term infants: a randomized clinical trial.
JAMA 2013;309:21112120.
Darlow BA, Marschner S, Donoghoe M, Bat-
tin MR, Broadbent RS, Elder MJ, et al; Bene-
fits of Oxygen Saturation Targeting-New
Zealand (BOOST-NZ) Collaborative Group:
Randomized controlled trial of oxygen satu-
ration targets in very preterm infants: two
year outcomes. J Pediatr 2014;165:3035.
BOOST II United Kingdom Collaborative
Group; BOOST II Australia Collaborative
Group;BOOST II New Zealand Collaborative
Group, Stenson BJ, Tarnow-Mordi WO, Dar-
low BA, Simes J, Juszczak E, Askie L, et al; for
the Boost II United Kingdom, Australian and
New Zealand Collaborative Groups: Oxygen
saturation and outcomes in preterm infants.
N Engl J Med 2013;368:20942104.
Askie LM, Brocklehurst P, Darlow BA, Finer
N, Schmidt B, Tarnow-Mordi W; NeOProM
Collaborative Group: NeOProM: Neonatal
Oxygenation Prospective Meta-analysis Col-
laboration study protocol. BMC Pediatr 2011;
11:6.
23 Askie LM, Henderson-Smart DJ, Irwig L,
Simpson JM: Oxygen-saturation targets and
outcomes in extremely preterm infants. N
Engl J Med 2003;349:959967.
24 Johnston ED, Boyle B, Juszczak E, King A,
Brocklehurst P, Stenson BJ: Oxygen targeting
in preterm infants using the Masimo SET
Radical pulse oximeter. Arch Dis Child Fetal
Neonatal Ed 2011;96:F429F433.
25 The BOOST-II Australia and United King-
dom Collaborative Groups: Outcomes of two
trials of oxygen-saturation targets in preterm
infants. N Engl J Med 2016;374:749760.
26 Stenson B, Brocklehurst P, Tarnow-Mordi W;
UK BOOST II trial; Australian BOOST II tri-
al; New Zealand BOOST II trial: Increased 36-
week survival with high oxygen saturation
target in extremely preterm infants. N Engl J
Med 2011;364:16801682.
27 Saugstad OD, Aune D: Optimal oxygenation
of extremely low birth weight infants: a meta-
analysis and systematic review of the oxygen
saturation target studies. Neonatology 2014;
105:5563.
28 Vaucher YE, Peralta-Carcelen M, Finer NN,
Carlo WA, Gantz MG, Walsh MC, et al; SUP-
PORT Study Group of the Eunice Kennedy
Shriver NICHD Neonatal Research Network:
Neurodevelopmental outcomes in the early
CPAP and pulse oximetry trial. N Engl J Med
2012;367:24952504.
29 Manja V, Lakshminrusimha S, Cook DJ: Oxy-
gen saturation target range for extremely pre-
term infants: a systematic review and meta-
analysis. JAMA Pediatr 2015;169:332340.
30 Wilinska M, Bachman T, Swietlinski J, Kostro
M, Twardoch-Drozd M: Automated FiO2-
SpO2 control system in neonates requiring re-
spiratory support: a comparison of a standard
to a narrow SpO2 control range. BMC Pediatr
2014;14:130.
128.111.121.42 - 6/9/2016 6:22:01 AM
Univ. of California Santa Barbara
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