Early CPAP versus Surfactant in Extremely Preterm Infants

The n e w e ng l a n d j o u r na l of m e dic i n e
original article
Early CPAP versus Surfactant in Extremely

Preterm Infants
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD
Neonatal Research Network*
A bs t r ac t
Background
*The authors are listed in the Appendix. There are limited data to inform the choice between early treatment with continu-
The affiliations of members of the Writ- ous positive airway pressure (CPAP) and early surfactant treatment as the initial
ing Committee and other investigators
in the Surfactant, Positive Pressure, support for extremely-low-birth-weight infants.
and Pulse Oximetry Randomized Trial
(SUPPORT) Study Group of the Eunice Methods
Kennedy Shriver National Institute of
Child Health and Human Development We performed a randomized, multicenter trial, with a 2-by-2 factorial design, in-
Neonatal Research Network are listed volving infants who were born between 24 weeks 0 days and 27 weeks 6 days of
in the Appendix. Address reprint re- gestation. Infants were randomly assigned to intubation and surfactant treatment
quests to Dr. Neil N. Finer at the Uni-
versity of California at San Diego, 402 (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with
Dickinson St., MPF 1-140, San Diego, subsequent use of a protocol-driven limited ventilation strategy. Infants were also
CA 92103-8774, or at [email protected]. randomly assigned to one of two target ranges of oxygen saturation. The primary
This article (10.1056/NEJMoa0911783) was outcome was death or bronchopulmonary dysplasia as defined by the requirement
published on May 16, 2010, and updated for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemen-
June 9, 2010, at NEJM.org. tal oxygen in neonates who were receiving less than 30% oxygen).
N Engl J Med 2010;362:1970-9.
Copyright © 2010 Massachusetts Medical Society. Results
A total of 1316 infants were enrolled in the study. The rates of the primary outcome
did not differ significantly between the CPAP group and the surfactant group (47.8%
and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI],
0.85 to 1.05) after adjustment for gestational age, center, and familial clustering.
The results were similar when bronchopulmonary dysplasia was defined according
to the need for any supplemental oxygen at 36 weeks (rates of primary outcome,
48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01).
Infants who received CPAP treatment, as compared with infants who received sur-
factant treatment, less frequently required intubation or postnatal corticosteroids
for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ven-
tilation (P = 0.03), and were more likely to be alive and free from the need for me-
chanical ventilation by day 7 (P = 0.01). The rates of other adverse neonatal out-
comes did not differ significantly between the two groups.
Conclusions
The results of this study support consideration of CPAP as an alternative to intuba-
tion and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)
1970 n engl j med 362;21 nejm.org may 27, 2010
The New England Journal of Medicine

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Early CPAP vs. Surfactant and Outcomes of Prematurity
I
t has been shown that surfactant cases of pneumothorax occurred within the first
treatment at less than 2 hours of life signifi- 2 days, which is consistent with the findings of
cantly decreases the rates of death, air leak, a previous meta-analysis.13
and death or bronchopulmonary dysplasia in pre- We designed the Surfactant, Positive Pressure,
term infants.1,2 Overall, prophylactic treatment and Oxygenation Randomized Trial (SUPPORT)
with surfactant has not been shown to signifi- to compare early CPAP treatment with early sur-
cantly reduce the risk of bronchopulmonary dys- factant treatment in extremely preterm infants.
plasia alone, whereas studies comparing early Using a factorial design, we also randomly as-
with later rescue use of surfactant have shown signed infants to one of two target ranges of oxy-
that there is a decreased risk of chronic lung dis- gen saturation during their exposure to supple-
ease with early use.2 Several studies have shown mental oxygen.
that the use of surfactant does not have a sig-
nificant effect on the risk of subsequent neuro Me thods
developmental impairment,3 although a recent
follow-up assessment of infants involved in a ran- Study Design
domized trial showed that early surfactant treat- In this randomized, multicenter trial, we com-
ment (at a mean of 31 minutes of age) as compared a strategy of treatment with CPAP and
pared with later surfactant treatment (at a mean protocol-driven limited ventilation begun in the
of 202 minutes of age) was associated with a sig- delivery room and continued in the neonatal in-
nificantly higher rate of increased muscle tone in tensive care unit (NICU) with a strategy of early
the infants and a delay in the infants’ ability to intratracheal administration of surfactant (with-
roll from the supine to the prone position.4 How- in 1 hour after birth) followed by a conventional
ever, in many of the trials of surfactant treat- ventilation strategy. In a 2-by-2 factorial design,
ment, the rate of maternal corticosteroid therapy infants were also randomly assigned to one of two
before delivery — an intervention known to im- target ranges of oxygen saturation (85 to 89% or
prove neonatal survival5 and decrease the rate of 91 to 95%) until the infant was 36 weeks of age
complications — was not high, and none of the or no longer received ventilatory support or sup-
infants in the control group received early treat- plemental oxygen. The results of this portion of
ment with continuous positive airway pressure the study are discussed elsewhere in this issue of
(CPAP). There is a growing body of observational the Journal.14 Randomization was stratified ac-
evidence suggesting that in the case of very pre- cording to center and gestational-age group, with
term infants with respiratory distress who are the use of specially prepared double-sealed enve-
not treated initially with surfactant, the early use lopes, and was performed before the actual deliv-
of CPAP may decrease the need for mechanical ery. Infants who were part of multiple births were
ventilation without an increase in complica- randomly assigned to the same group. Written
tions.6-11 informed consent from a parent or guardian for
In a previous study reported in the Journal, an infant’s participation in the trial was required
610 infants, born between 25 weeks 0 days and before delivery.
28 weeks 6 days of gestation, who were able to Infants were eligible for inclusion in the study
breathe at 5 minutes of age and had evidence of if they were 24 weeks 0 days to 27 weeks 6 days
respiratory distress at that time, were randomly of gestation at birth according to the best obstet-
assigned to either intubation and ventilation or rical estimate, if they were born without known
CPAP at a pressure of 8 cm of water; infants who malformations at a participating center, if a de-
were randomly assigned to CPAP were intubated cision had been made to provide full resuscita-
if they met certain criteria for the failure of tion for them, and if written informed consent
CPAP treatment.12 There was no significant re- had been obtained from a parent or guardian.
duction in the CPAP group, as compared with the The infants were randomly assigned within each
intubated group, in the rate of death or the need center and within each gestational-age stratum
for supplemental oxygen at 36 weeks (the primary (24 weeks 0 days to 25 weeks 6 days or 26 weeks
outcome), and there was a significantly higher 0 days to 27 weeks 6 days).
rate of pneumothorax in the CPAP group than in The study was conducted as part of the Neo-
the intubated group (9.1% vs. 3.0%); most of the natal Research Network of the Eunice Kennedy
n engl j med 362;21 nejm.org may 27, 2010 1971

Shriver National Institute of Child Health and amplitude of less than twice the mean airway pres-
Human Development. The study was approved by sure if high-frequency ventilation was being used,
the human subjects committee at each participat- hemodynamic stability, and the absence of clini-
ing site and at RTI International, which is the cally significant patent ductus arteriosus. Crite-
data center for the Neonatal Research Network. ria for reintubation were the same as those for
Data collected at participating sites were trans- initial intubation. After three intubations, infants
mitted to RTI International, which stored, man- in the CPAP group received treatment according to
aged, and analyzed the data for this study. the standard practice in the NICU to which they
had been admitted.
CPAP Group
In the delivery room, CPAP was administered by Surfactant Group
means of a T-piece resuscitator, a neonatal venti- All the infants in the surfactant group were to be
lator, or an equivalent device. CPAP or ventilation intubated in the delivery room and were to receive
with positive end-expiratory pressure (PEEP) (at a surfactant within 1 hour after birth with contin-
recommended pressure of 5 cm of water) was used ued ventilation thereafter. The infants were to be
if the infant received positive-pressure ventilation extubated within 24 hours after meeting all of the
during resuscitation. CPAP was continued until following criteria: a PaCO2 of less than 50 mm Hg
the infant’s admission to the NICU. Intubation was and a pH higher than 7.30, an FiO2 of 0.35 or less
not performed for the sole purpose of surfactant with an SpO2 of 88% or higher, a mean airway
administration in infants who were randomly as- pressure of 8 cm of water or less, a ventilator rate
signed to the CPAP group, but infants who re- of 20 breaths per minute or less, an amplitude of
quired intubation for resuscitation on the basis less than twice the mean airway pressure if high-
of standard indications specified in the Neonatal frequency ventilation was being used, and hemo-
Resuscitation Program guidelines15 were given dynamic stability without evidence of clinically
surfactant within 60 minutes after birth. significant patent ductus arteriosus. Once the in-
In the NICU, infants who were randomly as- fants were extubated, they were treated according
signed to CPAP could be intubated if they met any to the standard practice in the NICU to which they
of the following criteria: a fraction of inspired had been admitted.
oxygen(FiO2) greater than 0.50 required to main- The criteria for both groups were in effect for
tain an indicated saturation of peripheral oxygen the infants’ first 14 days of life, after which the
(SpO2) at or above 88% for 1 hour; a partial pres- infants were treated according to the standard
sure of arterial carbon dioxide (PaCO2) greater practice in the NICU to which they had been ad-
than 65 mm Hg, documented by a single measure- mitted. In the case of both groups, intubation
ment of blood gases within 1 hour before intu- could be performed at any time if there was an
bation; or hemodynamic instability, defined as a episode of repetitive apnea requiring bag-and-
blood pressure that was low for gestational age, mask ventilation, clinical shock, or sepsis, or if
poor perfusion, or both, requiring volume or surgery was required.
pressor support for a period of 4 hours or more.
Infants who were intubated within the first 48 Outcomes
hours after birth were to receive surfactant. After The primary outcome was death or bronchopul-
an infant’s admission to the NICU, the unit used monary dysplasia. Bronchopulmonary dysplasia
its standard method for the delivery of CPAP — was defined according to the physiological defi-
that is, a ventilator, a purpose-built flow driver, nition, as the receipt of more than 30% supple-
or a bubble CPAP circuit. mental oxygen at 36 weeks or the need for posi-
Extubation of an infant in the CPAP group was tive-pressure support or, in the case of infants
to be attempted within 24 hours after the infant requiring less than 30% oxygen, the need for any
met all of the following criteria: a PaCO2 below supplemental oxygen at 36 weeks after an attempt
65 mm Hg with a pH higher than 7.20, an SpO2 at withdrawal of oxygen.16,17 Prespecified second-
above 88% with an FiO2 below 0.50, a mean air- ary outcomes included bronchopulmonary dys-
way pressure of less than 10 cm of water, a venti- plasia as defined by the receipt of any supple-
lator rate of less than 20 breaths per minute, an mental oxygen at 36 weeks. Prespecified safety

outcomes included death, pneumothorax, intra- times. Lan–DeMets spending functions with Po-
ventricular hemorrhage, and the need for chest cock and O’Brien–Fleming boundaries were used
compressions or epinephrine during resuscitation. to determine stopping rules for interim safety and
efficacy monitoring, respectively.
Statistical Analysis For the 46 planned analyses of secondary out-
The sample-size calculations were based on data comes according to treatment, we would expect
from the Neonatal Research Network from the no more than 3 tests to have P values of less than
year 2000, which showed that the rate of death or 0.05 on the basis of chance alone. Subgroup
survival with bronchopulmonary dysplasia at 36 analyses were conducted within prespecified ges-
weeks was 67% and the rate of death or survival tational-age strata for 36 predefined outcomes.
with neurodevelopmental impairment at 18 to 22 Although these tests have not been adjusted for
months was 61%. We hypothesized that with early multiple comparisons, we would expect no more
CPAP there would be a reduction of 10% in the than 2 tests per stratum to have P values of less
incidence of these complications. We increased than 0.05 on the basis of chance alone.
the sample size by a factor of 1.12 to allow for
infants in multiple births to be randomly as- R e sult s
signed to the same treatment, because this intro-
duced a clustering effect into the design, and we Characteristics of the Study Sample
increased the sample sizes by an additional 17% From February 2005 through February 2009, a
to adjust for loss to follow-up after discharge. We total of 1316 infants were enrolled, of whom 565
increased the sample size further to minimize were in the lower gestational-age stratum (24
type I error with the use of a conservative 2% weeks 0 days to 25 weeks 6 days) and 751 were in
level of significance. The result was a target sam- the higher stratum (26 weeks 0 days to 27 weeks
ple of 1310 infants. We planned to test for an 6 days) (Fig. 1). There were no significant differ-
interaction between the two factorial parts of the ences between the two treatment groups with re-
study, but the study was not powered for that spect to sex, birth weight, or race or ethnic group
analysis. (Table 1).
Analyses were performed according to the in- Delivery room interventions in the two groups
tention-to-treat principle. The denominator that are summarized in Table 2. The rates of intuba-
was used to calculate the rate of each outcome tion in the delivery room and of the use of pos-
was the number of infants for whom that out- itive-pressure ventilation or epinephrine to treat
come was known. The primary analyses focused persistent bradycardia were significantly lower
on the percentage of infants in each group who among infants randomly assigned to CPAP than
survived to 36 weeks of postmenstrual age with- among those assigned to surfactant treatment.
out bronchopulmonary dysplasia. Analysis of this Overall, 32.9% of the infants in the CPAP group
and all other categorical outcomes was performed did not receive surfactant during their hospital-
with the use of robust Poisson regression in a ization.
generalized-estimating-equation model to obtain
adjusted relative risks with 95% confidence inter- Primary Outcome
vals. Continuous outcomes were analyzed with the After adjustment for gestational age, center, and
use of mixed-effects linear models to obtain ad- familial clustering, the rates of the primary out-
justed means and standard errors. come of death or bronchopulmonary dysplasia as
In the analysis of all outcomes, the results were assessed according to the physiological defini-
adjusted, as prespecified, for gestational-age strata, tion did not differ significantly between the two
center, and familial clustering. Two-sided P val- groups. The results were similar when bronchopul-
ues of less than 0.05 were considered to indicate monary dysplasia was defined according to the
statistical significance, and no adjustments have need for any supplemental oxygen at 36 weeks.
been made for multiple comparisons. An indepen- When components of this composite outcome were
dent data and safety monitoring committee re- analyzed separately, there was no significant be-
viewed the interim safety and efficacy results — tween-group difference in the rate of death or the
including those related to adverse outcomes — four rate of bronchopulmonary dysplasia (Table 3).

1974
3546 Infants were assessed for eligibility
(3127 pregnancies)
2230 Were excluded

235 Did not meet eligibility criteria
125 Did not have personnel or equipment available
699 Were eligible, but consent was not sought
344 Were excluded because parent or guardian was unavailable
748 Had consent denied by parent or guardian
11 Had other reasons
68 Had consent provided but did not undergo randomization
The
1316 Underwent randomization
654 Were assigned to target 662 Were assigned to target

oxygen saturation of 85–89% oxygen saturation of 91–95%
n engl j med 362;21

nejm.org
n e w e ng l a n d j o u r na l

336 Were assigned to 318 Were assigned to 327 Were assigned to 335 Were assigned to
of
receive early CPAP receive early surfactant receive early CPAP receive early surfactant
may 27, 2010

54 Died 60 Died 40 Died 54 Died

m e dic i n e
282 Survived to 36 wk 258 Survived to 36 wk 287 Survived to 36 wk 281 Survived to 36 wk

postmenstrual age postmenstrual age postmenstrual age postmenstrual age
103 Had BPD 179 Did not have BPD 102 Had BPD 156 Did not have BPD 120 Had BPD 167 Did not have BPD 117 Had BPD 164 Did not have BPD
Figure 1 (facing page). Screening, Randomization, Table 1. Demographic and Clinical Characteristics of the Study Participants.*
and Primary Outcome.
The numbers in the figure exclude infants of women CPAP Surfactant
Variable (N = 663) (N = 653)
who were screened during pregnancy but whose babies
were not subsequently born at a study center between Gestational age — no. (%)
24 weeks 0 days and 27 weeks 6 days of gestation. 24 wk 0 days–25 wk 6 days 285 (43.0) 280 (42.9)
Postmenstrual age is defined as the gestational age
plus the postnatal age. BPD denotes bronchopulmo- 26 wk 0 days–27 wk 6 days 378 (57.0) 373 (57.1)
nary dysplasia according to the physiological definition Assignment to low target oxygen-saturation
(receipt of more than 30% supplemental oxygen at 36 range in 2-by-2 factorial design —
weeks, the need for positive-pressure support, or in no./total no. (%)
the case of infants requiring less than 30% oxygen, the Gestational age of 24–25 wk 142/285 (49.8) 134/280 (47.9)
need for any supplemental oxygen at 36 weeks after an
attempt at withdrawal of oxygen).16,17 Gestational age of 26–27 wk 194/378 (51.3) 184/373 (49.3)
Male sex — no. (%) 342 (51.6) 370 (56.7)
Race or ethnic group — no. (%)†
There was no significant interaction between
Non-Hispanic black 254 (38.3) 235 (36.0)
the two interventions assessed in the trial with
respect to the primary outcome of death or bron- Non-Hispanic white 250 (37.7) 271 (41.5)
chopulmonary dysplasia as assessed either accord- Hispanic 138 (20.8) 121 (18.5)
ing to the physiological definition (P = 0.59) or Other or unknown 21 (3.2) 26 (4.0)
according to the need for any supplemental oxy- Birth weight — g 834.6±188.2 825.5±198.1
gen at 36 weeks (P = 0.53). There was no signifi- Gestational age at birth — wk 26.2±1.1 26.2±1.1
cant interaction between gestational-age stratum
Maternal use of antenatal corticosteroids
and treatment strategy with respect to the primary — no./total no. (%)
outcome (P = 0.84 with the physiological defini- Any 642/663 (96.8) 623/652 (95.6)
tion of bronchopulmonary dysplasia and P = 0.44
Full course 486/660 (73.6) 453/649 (69.8)
with bronchopulmonary dysplasia defined accord-
ing to the need for any supplemental oxygen at Death of infant in the delivery room — 1 (0.2) 5 (0.8)
no. (%)
36 weeks), and there was no significant between-
group difference in the rate of the primary out- * Plus–minus values are means ±SD. None of the differences between groups
come (with either definition of bronchopulmo- were significant. CPAP denotes continuous positive airway pressure.
† Race or ethnic group was reported by the mother or guardian of each child.
nary dysplasia) in either gestational-age stratum.
Secondary Outcomes
More infants in the CPAP group than in the sur- was not intubated; 83.1% of the infants in the
factant group were alive and free from the need CPAP group were intubated (P<0.001). The rate
for mechanical ventilation by day 7 (P = 0.01), and of use of postnatal corticosteroids to treat bron-
infants in the CPAP group required fewer days chopulmonary dysplasia was lower in the CPAP
of ventilation than did those in the surfactant group than in the surfactant group (P<0.001) (Ta-
group (P = 0.03). There were no significant be- ble 3). The other secondary outcomes are shown
tween-group differences in the rates of air leak in Table 3.
in the first 14 days, pneumothorax during the In post hoc stratified analyses of secondary
hospital stay, necrotizing enterocolitis requiring outcomes, among infants who were born between
medical or surgical treatment, patent ductus ar- 24 weeks 0 days and 25 weeks 6 days of gestation,
teriosus requiring surgery, severe intraventricu- the rates of death during hospitalization and at
lar hemorrhage, or severe retinopathy of prema- 36 weeks were significantly lower in the CPAP
turity, as defined according to the new type 1 group than in the surfactant group (rate of death
threshold in the Early Treatment for Retinopa- during hospitalization: 23.9% vs. 32.1%; relative
thy of Prematurity study (ETROP; ClinicalTrials risk with CPAP, 0.74; 95% confidence interval [CI],
.gov number, NCT00027222)18 or according to 0.57 to 0.98; P = 0.03; rate of death at 36 weeks:
the need for surgical intervention among survi- 20.0% vs. 29.3%; relative risk, 0.68; 95% CI, 0.5 to
vors. One infant in the surfactant group died in 0.92; P = 0.01 [see Table A1 in the Supplementary
the delivery room at 21 minutes after birth and Appendix, available with the full text of this ar-

Table 2. Apgar Scores of Newborns and Interventions in the Delivery Room and NICU.*
CPAP Surfactant Relative Risk with Adjusted

Variable (N = 663) (N = 653) CPAP (95% CI) P Value
no./total no. (%)
Apgar score <3
At 1 min 154/661 (23.3) 167/653 (25.6) 0.92 (0.76–1.11) 0.38
At 5 min 26/663 (3.9) 32/653 (4.9) 0.82 (0.5–1.34) 0.43
PPV in the delivery room 435/662 (65.7) 606/652 (92.9) 0.71 (0.67–0.75) <0.001
CPAP in the delivery room 538/663 (81.1) 146/653 (22.4) 3.66 (3.16–4.25) <0.001
Intubation in the delivery room
For any reason 227/660 (34.4) 609/652 (93.4) 0.37 (0.34–0.42) <0.001
For resuscitation 215/660 (32.6) 176/652 (27.0) 1.21 (1.02–1.43) 0.02
Surfactant treatment
In the delivery room 93/660 (14.1) 335/652 (51.4) 0.28 (0.23–0.34) <0.001
In the delivery room or NICU 443/660 (67.1) 646/653 (98.9) 0.67 (0.64–0.71) <0.001
Chest compressions in the delivery 36/660 (5.5) 40/653 (6.1) 0.86 (0.57–1.31) 0.48
room
Epinephrine in the delivery room 13/660 (2.0) 27/653 (4.1) 0.48 (0.25–0.91) 0.02
* CI denotes confidence interval, CPAP continuous positive airway pressure, NICU neonatal intensive care unit, and PPV
positive-pressure ventilation.
ticle at NEJM.org]); in contrast, there was no sig- dysplasia in the CPAP group that was between 85
nificant between-group difference in the rate of and 105% of that in the surfactant group. The
death during hospitalization or at 36 weeks results were similar in secondary analyses in which
among the infants who were born between 26 bronchopulmonary dysplasia was defined accord-
weeks 0 days and 27 weeks 6 days of gestation ing to the use of any supplemental oxygen at 36
(rate of death during hospitalization: 10.8% and weeks.
10.2%, respectively; rate of death at 36 weeks: We did not include infants who were born at
9.8% and 8.6%, respectively) (see Tables A1 and a gestational age of less than 24 weeks, since the
A3 in the Supplementary Appendix). results of a pilot trial showed that 100% of such
infants required intubation in the delivery room.19
Discussion A retrospective study showed that some infants
in this gestational-age group can be treated suc-
In this multicenter, randomized trial involving cessfully with early CPAP, but the majority re-
extremely preterm infants, there was no signifi- quire intubation.20
cant difference between a strategy of early CPAP There was a high rate of intubation and sur-
and limited ventilation and a strategy of early factant treatment among infants assigned to CPAP,
intubation and surfactant administration within but this was anticipated, given the design of the
1 hour after birth with respect to the rate of the study, which was to test an initial strategy of early
composite primary outcome of death or bron- CPAP as compared with early intubation and sur-
chopulmonary dysplasia. We used the physiolog- factant, with crossover planned for ethical rea-
ical definition of bronchopulmonary dysplasia, sons in the case of infants in whom CPAP treat-
since it includes as a specification an attempt to ment was not successful. Our trial differs from
withdraw supplemental oxygen from infants re- the trial of Morley et al.12 in that we randomly
ceiving less than 30% oxygen at 36 weeks, in or- assigned all eligible preterm infants to a treatment
der to confirm their need for supplemental oxy- group, irrespective of whether they were breath-
gen.16,17 Plausible results, on the basis of the 95% ing spontaneously or whether they had respira-
confidence intervals for the relative-risk estimates, tory distress that warranted intervention, and in
included a risk of death or bronchopulmonary that we included infants who were born as early

Table 3. Selected Prespecified Outcomes.*
CPAP Surfactant Relative Risk Difference in Means Adjusted

Outcome (N = 663) (N = 653) with CPAP (95% CI) (95% CI) P Value
BPD or death by 36 wk of postmenstrual age
— no. (%)
Physiological definition of BPD† 317 (47.8) 333 (51.0) 0.95 (0.85 to 1.05) 0.30
BPD defined by need for supplemental 323 (48.7) 353 (54.1) 0.91 (0.83 to 1.01) 0.07
oxygen
BPD by 36 wk of postmenstrual age — no./
total no. (%)
Physiological definition of BPD† 223/569 (39.2) 219/539 (40.6) 0.99 (0.87 to 1.14) 0.92
BPD defined by need for supplemental 229/569 (40.2) 239/539 (44.3) 0.94 (0.82 to 1.06) 0.32
oxygen
Death by 36 wk of postmenstrual age — 94 (14.2) 114 (17.5) 0.81 (0.63 to 1.03) 0.09
no. (%)
Need for supplemental oxygen — no. of 0.12
days‡
Adjusted mean 62.2±1.6 65.3±1.6 −3.1 (−7.1 to 0.8)
Unadjusted median 52 56
Interquartile range 20 to 86 27 to 91
Need for mechanical ventilation — no. of 0.03
days‡§
Adjusted mean 24.8±1.0 27.7±1.1 −3.0 (−5.6 to −0.3)
Unadjusted median 10 13
Interquartile range 2 to 32 2 to 36
Survival without need for high-frequency or 362/655 (55.3) 318/652 (48.8) 1.14 (1.03 to 1.25) 0.01
conventional ventilation at 7 days —
no./total no. (%)
Any air leak in first 14 days — no. (%) 45 (6.8) 48 (7.4) 0.89 (0.6 to 1.32) 0.56
Necrotizing enterocolitis requiring medical 83/654 (12.7) 63/636 (9.9) 1.25 (0.92 to 1.71) 0.15
or surgical treatment — no./total
no. (%)
Intraventricular hemorrhage grade 3 or 4 — 92/642 (14.3) 72/628 (11.5) 1.26 (0.94 to 1.68) 0.12
no./total no. (%)¶
Postnatal corticosteroid therapy for BPD — 47/649 (7.2) 83/631 (13.2) 0.57 (0.41 to 0.78) <0.001
no./total no. (%)
Severe retinopathy of prematurity among 67/511 (13.1) 65/473 (13.7) 0.94 (0.69 to 1.28) 0.71
survivors — no./total no. (%)
* Plus–minus values are means ±SD. BPD denotes bronchopulmonary dysplasia, CI confidence interval, and CPAP continuous positive airway
pressure.
† The physiological definition of BPD includes, as a criterion, the receipt of more than 30% supplemental oxygen at 36 weeks, the need for
positive-pressure support, or in the case of infants requiring less than 30% oxygen, the need for any supplemental oxygen at 36 weeks after
an attempt at withdrawal of supplemental oxygen.16,17
‡ Data are for 1098 infants who survived to discharge, transfer, or 120 days; the maximum follow-up was 120 days.
§ This variable includes high-frequency ventilation and conventional ventilation.
¶ There are four grades of intraventricular hemorrhage; higher grades indicate more severe bleeding.
as 24 weeks of gestation. In the study by Morley Neonatal Research Network sites that had the
et al., surfactant was not administered routinely most experience with CPAP also used a higher
in the intubation group. Our protocol, which threshold for intubation and the initiation of me-
called for early CPAP and a determination of the chanical ventilation than did sites with less ex-
need for intubation, was based on the findings perience.4-6 The infants who were randomly as-
of previous observational studies showing that signed to surfactant treatment in our trial were

treated with a ventilation approach that was used further testing should be performed in this im-
by a majority of the Neonatal Research Network mature population.
sites before the trial began. We believed that com- In summary, we found no significant differ-
paring these two methods would provide more ence in the primary outcome of death or bron-
clinically relevant results. Data are currently be- chopulmonary dysplasia between infants randomly
ing collected to assess survival without neurode- assigned to early CPAP and those assigned to
velopmental impairment at 18 to 22 months. early surfactant treatment. In secondary analyses,
We found no significant between-group dif- the CPAP strategy, as compared with early sur-
ferences in the rates of pneumothorax, intraven- factant treatment, resulted in a lower rate of in-
tricular hemorrhage, or the need for chest com- tubation (both in the delivery room and in the
pressions or epinephrine in the delivery room, and NICU), a reduced rate of postnatal corticosteroid
the rates were similar to those among infants in use, and a shorter duration of ventilation with-
the Neonatal Research Network population who out an increased risk of any adverse neonatal out-
were born between 2000 and 2004 at similar come. These data support consideration of CPAP
gestational ages. The rate of air leaks in the first as an alternative to routine intubation and sur-
14 days of life was not increased with the use of factant administration in preterm infants.
early CPAP at a pressure of 5 cm of water, as Supported by grants (U10 HD21364, U10 HD21373, U10
compared with the use of early surfactant. HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10
In secondary analyses stratified according to HD27856, U10 HD27880, U10 HD27871, U10 HD27904, U10
HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10
gestational age at birth, there was a significant HD40498, U10 HD40521, U10 HD40689, U10 HD53089, U10
reduction in the risk of death in the CPAP group, HD53109, U10 HD53119, U10 HD53124) from the Eunice Kennedy
as compared with the early-intubation group, Shriver National Institute of Child Health and Human Develop-
ment, cofunding from the National Heart, Lung, and Blood Insti-
among infants born between 24 weeks 0 days tute, and grants (M01 RR30, M01 RR32, M01 RR39, M01 RR44,
and 25 weeks 6 days of gestation but not among M01 RR54, M01 RR59, M01 RR64, M01 RR70, M01 RR80, MO1
infants who were born at a later gestational age. RR125, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01
RR7122, M01 RR8084, M01 RR16587, UL1 RR25008, UL1
Given the fact that there was no significant in- RR24139, UL1 RR24979, UL1 RR25744) from the National Insti-
teraction between the intervention and gestational tutes of Health.
age, the post hoc nature of these analyses, and Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
the number of secondary analyses performed, this We thank our medical and nursing colleagues and the infants
observation must be interpreted with caution, and and their parents who agreed to take part in this study.
Appendix
The authors are as follows: Neil N. Finer, M.D., Waldemar A. Carlo, M.D., Michele C. Walsh, M.D., Wade Rich, R.R.T., C.C.R.C.,
Marie G. Gantz, Ph.D., Abbot R. Laptook, M.D., Bradley A. Yoder, M.D., Roger G. Faix, M.D., Abhik Das, Ph.D., W. Kenneth Poole,
Ph.D., Edward F. Donovan, M.D., Nancy S. Newman, R.N., Namasivayam Ambalavanan, M.D., Ivan D. Frantz III, M.D., Susie Buchter,
M.D., Pablo J. Sánchez, M.D., Kathleen A. Kennedy, M.D., M.P.H., Nirupama Laroia, M.D., Brenda B. Poindexter, M.D., C. Michael
Cotten, M.D., M.H.S., Krisa P. Van Meurs, M.D., Shahnaz Duara, M.D., Vivek Narendran, M.D., M.R.C.P., Beena G. Sood, M.D., T. Mi-
chael O’Shea, M.D., M.P.H., Edward F. Bell, M.D., Vineet Bhandari, M.D., D.M., Kristi L. Watterberg, M.D., and Rosemary D. Higgins,
M.D., for the NICHD Neonatal Research Network and the SUPPORT Study Group.
The following are the authors’ affiliations: the Division of Neonatology, University of California at San Diego, San Diego (N.N.F.,
W.R.); the Division of Neonatology, University of Alabama at Birmingham, Birmingham (W.A.C., N.A.); the Department of Pediatrics,
Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland (M.C.W., N.S.N.); Statistics and Epidemiology Unit,
RTI International, Research Triangle Park (M.G.G., W.K.P.), the Department of Pediatrics, Duke University, Durham (C.M.C.), and
Wake Forest University School of Medicine, Winston-Salem (T.M.O.) — all in North Carolina; the Department of Pediatrics, Women
and Infants Hospital, Brown University, Providence, RI (A.R.L.); the Department of Pediatrics, Division of Neonatology, University of
Utah School of Medicine, Salt Lake City (B.A.Y., R.G.F.); Statistics and Epidemiology Unit, RTI International, Rockville (A.D.), and the
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda (R.D.H.)
— both in Maryland; the Department of Pediatrics, University of Cincinnati, Cincinnati (E.F.D., V.N.); the Department of Pediatrics,
Division of Newborn Medicine, Floating Hospital for Children, Tufts Medical Center, Boston (I.D.F.); the Department of Pediatrics,
University of Texas Southwestern Medical Center, Dallas (P.J.S.); the Department of Pediatrics, Emory University School of Medicine,
and Children’s Healthcare of Atlanta — both in Atlanta (S.B.); the Department of Pediatrics, University of Texas Medical School at
Houston, Houston (K.A.K.); University of Rochester School of Medicine and Dentistry, Rochester, NY (N.L.); the Department of Pedi-
atrics, Indiana University School of Medicine, Indianapolis (B.B.P.); the Department of Pediatrics, Stanford University School of Medi-
cine, Palo Alto, CA (K.P.V.M.); the Department of Pediatrics, Wayne State University, Detroit (B.G.S.); University of Miami Miller School
of Medicine, Miami (S.D.); the Department of Pediatrics, University of Iowa, Iowa City (E.F.B.); the Department of Pediatrics, Yale
University School of Medicine, New Haven, CT (V.B.); and the University of New Mexico Health Sciences Center, Albuquerque
(K.L.W.).
The following investigators, in addition to those listed as authors, participated in this study: Neonatal Research Network Steering Com-
mittee Chairs: A.H. Jobe (University of Cincinnati, Cincinnati [2003–2006]), M.S. Caplan (University of Chicago, Pritzker School of Medi-
cine, Chicago [2006–present]); Alpert Medical School of Brown University and Women and Infants Hospital — both in Providence, RI: W. Oh, A.M.

Hensman, D. Gingras, S. Barnett, S. Lillie, K. Francis, D. Andrews, K. Angela; Case Western Reserve University and Rainbow Babies and Children’s
Hospital — both in Cleveland: A.A. Fanaroff, B.S. Siner; Cincinnati Children’s Hospital Medical Center, University of Cincinnati Hospital, and Good Sa-
maritan Hospital — all in Cincinnati: K. Schibler, K. Bridges, B. Alexander, C. Grisby, M.W. Mersmann, H.L. Mincey, J. Hessling; Duke Uni-
versity School of Medicine University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital — all in Durham, NC: R.N. Goldberg, K.J.
Auten, K.A. Fisher, K.A. Foy, G. Siaw; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory Crawford Long Hospital
— all in Atlanta: B.J. Stoll, A. Piazza, D.P. Carlton, E.C. Hale; Eunice Kennedy Shriver National Institute of Child Health and Human Development,
Bethesda, MD: S.W. Archer; Indiana University, Indiana University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services
— all in Indianapolis: J.A. Lemons, F. Hamer, D.E. Herron, L.C. Miller, L.D. Wilson; National Heart, Lung, and Blood Institute, Bethesda, MD: M.A.
Berberich, C.J. Blaisdell, D.B. Gail, J.P. Kiley; RTI International, Research Triangle Park, NC: M. Cunningham, B.K. Hastings, A.R. Irene,
J. O’Donnell Auman, C.P. Huitema, J.W. Pickett II, D. Wallace, K.M. Zaterka-Baxter; Stanford University Lucile Packard Children’s Hospital, Palo
Alto, CA: D.K. Stevenson, M.B. Ball, M.S. Proud; Tufts Medical Center Floating Hospital for Children, Boston: J.M. Fiascone, B.L. MacKinnon, E.
Nylen, A. Furey; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama — both in Birmingham: M.V. Collins, S.S.
Cosby, V.A. Phillips; University of California at San Diego Medical Center and Sharp Mary Birch Hospital for Women — both in San Diego: M.R. Rasmus-
sen, P.R. Wozniak, K. Arnell, R. Bridge, C. Demetrio; University of Iowa Children’s Hospital, Iowa City: J.A. Widness, J.M. Klein, K.J. Johnson;
University of Miami Holtz Children’s Hospital, Miami: R. Everett-Thomas; University of New Mexico Health Sciences Center, Albuquerque: R.K. Ohls,
J. Rohr, C.B. Lacy; University of Rochester Medical Center Golisano Children’s Hospital, Rochester, NY: D.L. Phelps, L.J. Reubens, E. Burnell; University
of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children’s Medical Center — all in Dallas: C.R. Rosenfeld, W.A.
Salhab, J. Allen, A. Guzman, G. Hensley, M.H. Lepps, M. Martin, N.A. Miller, A. Solls, D.M. Vasil, K. Wilder; University of Texas Health Science
Center at Houston Medical School and Children’s Memorial Hermann Hospital — both in Houston: B.H. Morris, J.E. Tyson, B.F. Harris, A.E. Lis,
S. Martin, G.E. McDavid, P.L. Tate, S.L. Wright; University of Utah University Hospital, Intermountain Medical Center, LDS Hospital, and Primary
Children’s Medical Center — all in Salt Lake City: J. Burnett, J.J. Jensen, K.A. Osborne, C. Spencer, K. Weaver-Lewis; Wake Forest University Baptist
Medical Center Brenner Children’s Hospital and Forsyth Medical Center — both in Winston-Salem, NC: N.J. Peters; Wayne State University Hutzel Women’s
Hospital and Children’s Hospital of Michigan — both in Detroit: S. Shankaran, R. Bara, E. Billian, M. Johnson; Yale University and Yale–New Haven
Children’s Hospital, New Haven, and Bridgeport Hospital, Bridgeport — all in Connecticut: R.A. Ehrenkranz, H.C. Jacobs, P. Cervone, P. Gettner, M.
Konstantino, J. Poulsen, J. Taft. Data and Safety Monitoring Committee — G. Avery (chair), Children’s National Medical Center, Washing-
ton, DC; C.A. Gleason (chair), University of Washington, Seattle; M.C. Allen, Johns Hopkins University School of Medicine, Baltimore; S.I.
Bangdiwala, University of North Carolina, Chapel Hill; C.J. Blaisdell, D.B. Gail, C. Hunt, National Heart, Lung, and Blood Institute,
Bethesda, MD; R.J. Boyle, University of Virginia Health System, Charlottesville; T. Clemons, EMMES Corporation, Rockville, MD; M.E.
D’Alton, Columbia University, New York; A. Das (ex officio) RTI International, Rockville, MD; W.K. Poole (ex officio), RTI International,
Research Triangle Park, NC; M. Keszler, Georgetown University Hospital, Washington, DC; C.K. Redmond, University of Pittsburgh,
Pittsburgh; M.G. Ross, UCLA School of Medicine and Public Health, Los Angeles; M.A. Thomson, Hammersmith Hospital, London; S.J.
Weiner, George Washington University, Washington, DC; M. Willinger (ex officio), Eunice Kennedy Shriver National Institute of Child
Health and Human Development, Bethesda, MD. Retinopathy of Prematurity Adjudication Committee — G.D. Markowitz, University of
Rochester, Rochester, NY; A.K. Hutchinson, Emory University, Atlanta; D.K. Wallace, S.F. Freedman, Duke University, Durham, NC.
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Early CPAP versus Surfactant in Extremely Preterm Infants

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The n e w e ng l a n d j o u r na l of m e dic i n e

Early CPAP versus Surfactant in Extremely

1970 n engl j med 362;21 nejm.org may 27, 2010

The New England Journal of Medicine

n engl j med 362;21 nejm.org may 27, 2010 1971

1972 n engl j med 362;21 nejm.org may 27, 2010

The New England Journal of Medicine

n engl j med 362;21 nejm.org may 27, 2010 1973

2230 Were excluded

1316 Underwent randomization

654 Were assigned to target 662 Were assigned to target

n engl j med 362;21

The New England Journal of Medicine

may 27, 2010

Copyright © 2010 Massachusetts Medical Society. All rights reserved.

282 Survived to 36 wk 258 Survived to 36 wk 287 Survived to 36 wk 281 Survived to 36 wk

n engl j med 362;21 nejm.org may 27, 2010 1975

CPAP Surfactant Relative Risk with Adjusted

1976 n engl j med 362;21 nejm.org may 27, 2010

The New England Journal of Medicine

Table 3. Selected Prespecified Outcomes.*

CPAP Surfactant Relative Risk Difference in Means Adjusted

n engl j med 362;21 nejm.org may 27, 2010 1977

1978 n engl j med 362;21 nejm.org may 27, 2010

The New England Journal of Medicine

n engl j med 362;21 nejm.org may 27, 2010 1979

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