Targeted Oxygen in the Resuscitation of Preterm Infants, a ...

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.


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.


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.



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

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ay b

e >

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use

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bed

.


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.



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.


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.


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.


OEI et al

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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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DOI: 10.1542/peds.2016-1452; originally published online December 29, 2016; 2017;139;Pediatrics

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,

TrialTargeted Oxygen in the Resuscitation of Preterm Infants, a Randomized Clinical

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DOI: 10.1542/peds.2016-1452; originally published online December 29, 2016; 2017;139;Pediatrics

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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