A Randomized, Controlled Trial of Delivery-Room Respiratory Management in Very Preterm Infants

Abstract

Initial ventilation strategy may play an important role in the development of bronchopulmonary dysplasia in very preterm infants. Early nasal continuous positive airway pressure is an accepted approach, but randomized clinical trials are lacking. Our aim was to determine whether early nasal continuous positive airway pressure, preceded by a sustained inflation, is more effective and less injurious in very preterm infants than conventional intervention.
Two hundred seven very preterm infants were assigned randomly in the delivery room to either a sustained inflation through a nasopharyngeal tube followed by early nasal continuous positive airway pressure (early functional residual capacity intervention) or repeated manual inflations with a self-inflating bag and mask followed by nasal continuous positive airway pressure, if necessary, after arrival at the NICU. The primary outcome measure was intubation <72 hours of age and bronchopulmonary dysplasia at 36 weeks was used as secondary outcome. This trial was registered as an early functional residual capacity intervention trial (ISRCTN 12757724).
In the early functional residual capacity intervention group, fewer infants were intubated at <72 hours of age or received >1 dose of surfactant, and the average duration of ventilatory support was less. Infants in the early functional residual capacity intervention group developed bronchopulmonary dysplasia less frequently.
A sustained inflation followed by early nasal continuous positive airway pressure, delivered through a nasopharyngeal tube, is a more efficient strategy than repeated manual inflations with a self-inflating bag and mask followed by nasal continuous positive airway pressure on admission to the NICU.

Full text

DOI: 10.1542/peds.2007-0114
2007;120;322Pediatrics
Arjan B. te Pas and Frans J. Walther
Very Preterm Infants
A Randomized, Controlled Trial of Delivery-Room Respiratory Management in
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ARTICLE
A Randomized, Controlled Trial of Delivery-Room
Respiratory Management in Very Preterm Infants
Arjan B. te Pas, MD, Frans J. Walther, MD, PhD
Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
BACKGROUND. Initial ventilation strategy may play an important role in the develop-
ment of bronchopulmonary dysplasia in very preterm infants. Early nasal contin-
uous positive airway pressure is an accepted approach, but randomized clinical
trials are lacking. Our aim was to determine whether early nasal continuous
positive airway pressure, preceded by a sustained inflation, is more effective and
less injurious in very preterm infants than conventional intervention.
METHODS. Two hundred seven very preterm infants were assigned randomly in the
delivery room to either a sustained inflation through a nasopharyngeal tube
followed by early nasal continuous positive airway pressure (early functional
residual capacity intervention) or repeated manual inflations with a self-inflating
bag and mask followed by nasal continuous positive airway pressure, if necessary,
after arrival at the NICU. The primary outcome measure was intubation ⬍72 hours
of age and bronchopulmonary dysplasia at 36 weeks was used as secondary
outcome. This trial was registered as an early functional residual capacity inter-
vention trial (ISRCTN 12757724).
RESULTS. In the early functional residual capacity intervention group, fewer infants
were intubated at ⬍72 hours of age or received ⬎1 dose of surfactant, and the
average duration of ventilatory support was less. Infants in the early functional
residual capacity intervention group developed bronchopulmonary dysplasia less
frequently.
CONCLUSIONS. A sustained inflation followed by early nasal continuous positive air-
way pressure, delivered through a nasopharyngeal tube, is a more efficient strat-
egy than repeated manual inflations with a self-inflating bag and mask followed by
nasal continuous positive airway pressure on admission to the NICU.
www.pediatrics.org/cgi/doi/10.1542/
peds.2007-0014
doi:10.1542/peds.2007-0114
Both authors have contributed to the
manuscript and have seen and approved
the final version.
Dr te Pas had primary responsibility for
protocol development, patient screening,
enrollment, outcome assessment and
writing of the manuscript. Dr Walther
contributed to protocol development and
writing of the manuscript.
Key Words
early nasal continuous positive airway
pressure, resuscitation, preterm infants,
respiratory distress syndrome,
bronchopulmonary dysplasia
Abbreviations
BPD— bronchopulmonary dysplasia
NCPAP—nasal continuous positive airway
pressure
F
IO
2
—fraction of inspired oxygen
ENCPAP— early nasal continuous positive
airway pressure
RDS—respiratory distress syndrome
EFURCI— early functional respiratory
capacity intervention
PIP—peak inspiratory pressure
PEEP—positive end-expiratory pressure
IVH—intraventricular hemorrhage
IQR—interquartile range
OR— odds ratio
CI— confidence interval
Accepted for publication Mar 19, 2007
Address correspondence to Arjan B. te Pas,
MD, Department of Pediatrics, Leiden
University Medical Center, J6-S, Box 9600,
2300 RC Leiden, Netherlands. E-mail: a.b.
te㛭pas@lumc.nl
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics
322 te PAS, WALTHER
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T
HE PATHOGENESIS OF bronchopulmonary dysplasia
(BPD) or chronic lung disease in very preterm in-
fants is multifactorial, but ventilator-induced lung injury
plays a major contributing role.
1
Various new ventilation
strategies have been introduced, but this has not reduced
the incidence of BPD.
2
Early respiratory management,
that is, ventilatory support from birth during the first
days of life, may influence pulmonary outcome, but,
because of lack of data, there is no consensus on the
early ventilatory management of preterm infants.
3
Ret-
rospective cohort and experimental studies suggest that
the initial ventilation strategy may play an important
role in the development of BPD.
4–9
The most effective
and least injurious way to recruit the lung in very pre-
mature neonates at birth may be a combination of a
sustained inflation and early nasal continuous positive
airway pressure (ENCPAP). This attempt to avoid intu-
bation and mechanical ventilation may reduce lung in-
jury and BPD in preterm infants as suggested in a retro-
spective study by Lindner et al
10
A trial of ENCPAP at
birth seems justified in infants at risk of respiratory dis-
tress syndrome (RDS), providing early surfactant rescue
is given if required.
11,12
We performed a randomized,
controlled trial and compared the traditional ventilatory
approach with a new method that combined a number
of techniques, which theoretically could improve the
respiratory outcome of preterm infants. We hypothe-
sized that a sustained inflation followed by ENCPAP,
using a pressure-limited mechanical device, is a more
effective and less injurious management strategy in pre-
term infants than conventional intervention.
PATIENTS AND METHODS
The limits of viability in the Netherlands are set at 25
weeks’ gestation. All very preterm infants ⬍33 weeks’
gestation who were born in the Leiden University Med-
ical Center were eligible for this study if they were free
from known major congenital anomalies. The study was
approved by the ethics review committee of the hospital.
Patients were included before birth, and informed con-
sent was obtained from the infant’s parents or legal
guardian. Before birth, patients were assigned randomly
to early functional residual capacity intervention
(EFURCI) or conventional intervention by using sealed
envelopes. Blocked randomization and stratification for
each week of gestational age were used to ensure treat-
ment balance between the 2 arms.
EFURCI Approach
After oropharyngeal and nasal suctioning (time ⫽ 0 –30
seconds), and if breathing was insufficient (ie, no signs of
spontaneous breathing or spontaneous breathing
present, but signs of poor air entry [severe retractions,
nasal flaring]), a pressure-controlled (20 cm H
2
O) infla-
tion was sustained for 10 seconds, using a nasopharyn-
geal tube and a T-piece ventilator (Neopuff Infant Re-
suscitator; Fisher and Paykel, Auckland, New Zealand)
(time ⫽ 30 – 45 seconds). This T-piece ventilator is a
pressure-limited mechanical device that supplies a con-
sistent peak inspiratory pressure (PIP) and positive end-
expiratory pressure (PEEP) and is capable of delivering a
sustained inflation.
13–16
Use of a sustained inflation re-
duces the need for higher initial airway pressures. To
avoid PEEP leakage, a nasopharyngeal tube was used as
interface.
17
Nasopharyngeal tubes with a diameter of 2.5
to 4.0 mm were used, according to gestational age/birth
weight. The length of the tube was cut down to 6 cm.
The mouth and other nostril were held closed manually
during the inflation. This procedure was repeated (time
⫽ 50 – 65 seconds) with an increased pressure (25
cm H
2
O) if breathing remained insufficient and/or the
heart rate was ⬍100 beats per minute and/or the infant
was cyanotic. After the initial inflation, ENCPAP at 5 to
6cmH
2
O was started. If breathing was sufficient, the
patient was observed in the delivery room before trans-
portation to the NICU. If there was improvement (heart
rate ⬎100 beats per minute and pink color, but apnea or
insufficient breathing), intermittent ventilation with a
PIP of 20 to 25 cm H
2
O and a rate of 60 per minute was
delivered through the nasopharyngeal tube for several
minutes until the infant improved (heart rate ⬎100
beats per minute, pink color, and spontaneous breath-
ing). Endotracheal intubation and mechanical ventila-
tion was initiated if the heart rate did not increase
above 100 beats per minute, the infant remained cya-
nosed, breathing was absent, or marked dyspnea oc-
curred (time ⫽ 90 seconds to 5 minutes). Patients were
transferred to the NICU with ENCPAP or intermittent
mandatory ventilation.
Conventional Intervention Group
In this group, a self-inflating bag and mask with a
built-in pressure limitation (Ambu Infant R Resuscita-
tors, Ambu, Ballerup, Denmark) and an oxygen reser-
voir were used after birth. A manometer was attached to
monitor the pressures given. The mask and bag deliver
inconsistent PIP and minimal PEEP and are unable to
deliver a sustained inflation.
14,18,19
With this approach, a
higher initial pressure is used to open the lung, and
ENCPAP was only given on arrival in the NICU if
needed. Mask and bag ventilation was administered dur-
ing 30 seconds if breathing was insufficient after oropha-
ryngeal and nasal suctioning (time ⫽ 30 – 60 seconds).
Initial inflation pressures of 30 to 40 cm H
2
O were used;
after that not ⬎20 cm H
2
O was allowed.
3
If breathing
remained insufficient, or the heart rate was ⬍ 100 beats
per minute, or the infant remained cyanotic, or inflation
was not possible, endotracheal intubation and mechan-
ical ventilation were performed (time ⫽ 60–90 seconds).
If bag and mask resuscitation was successful and breath-
ing was sufficient (spontaneous breathing, normal chest
movements, no cyanosis, heart rate ⬎100 beats per
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minute), the infant was observed in the delivery room
and transferred to the NICU. Nonintubated infants were
transferred with oxygen monitored by measuring oxy-
gen saturation.
In Both Groups
One hundred percent oxygen was initially used and
weaned down as quickly as possible depending on the
infants’ response, color, and heart rate. Pulse oximetry
was started immediately after resuscitation. If no respi-
ratory support in the delivery room was needed, the
infant was observed and transferred to the NICU. Nasal
continuous positive airway pressure (NCPAP) was
started if there were signs of respiratory distress or the
fraction of inspired oxygen (F
IO
2
) was ⬎0.3. Infants on
ENCPAP or NCPAP were placed on an Infant Flow De-
vice (EME Tricomed, Brighton, United Kingdom) or In-
fant Star ventilator (Infrasonics Inc, San Diego, CA) with
Hudson prongs (Hudson-RCI, Temecula, CA). The level
of pressure was titrated from 5 to 8 cm H
2
O according to
the degree of respiratory distress, assessed by observing
chest retractions, effort of breathing, chest radiograph,
and oxygen requirement (Pa
O
2
⬎50 mm Hg, while pH
⬎7.20 and Pa
CO
2
⬍60 mm Hg).
Caffeine or theophylline were given as soon as pos-
sible after birth to infants ⬍30 weeks’ gestation and in
more mature infants if they had apnea. Arterial and
transcutaneous partial pressures of oxygen and carbon
dioxide and oxygen saturation were monitored. RDS
was defined in the presence of clinical features (need of
supplemental oxygen, sternal retraction, intercostal and
subcostal recession, grunting and tachypnea) and radio-
logic finding of poor lung expansion. Chest radiographs
were used to assess the severity of RDS and lung expan-
sion. Chest radiographs were reviewed by a radiologist,
and the reading was recorded in the database. The radi-
ologist did not participate in this trial, only the usual
clinical information was given, and he/she was not
aware of the treatment assignment. Intubation and me-
chanical ventilation were initiated either when the ar-
terial oxygen saturation values were ⬍88% or Pa
O
2
ⱕ50
mm Hg while receiving F
IO
2
ⱖ0.40 (corresponding with
an alveolar-arterial oxygen tension difference of ⬍0.22),
or the Pa
CO
2
was ⬎60 mm Hg, with a pH ⬍7.20, or there
were ⬎4 apneic episodes in 1 hour or the infant needed
⬎2 episodes of bagging per hour. These criteria were
agreed on by participating clinicians before the study
started and were applied rigorously. The decision was
made by clinicians other than the investigators. When-
ever 1 of the investigators was supervising the NICU, 1 of
their colleagues (fellows) made the decision to intubate
or not intubate the infants included in the study. Sur-
factant (Curosurf, Chiesi, Italy) was given at 12-hour
intervals when on mechanical ventilation with a mean
airway pressure ⫻ F
IO
2
ratio ⬎2. All infants intubated in
the delivery room received surfactant shortly after ar-
rival in the NICU, if required. All infants intubated later
on in the NICU received surfactant shortly after intuba-
tion if required. Neonates were extubated as soon as the
F
IO
2
was ⬍0.3 and the mean airway pressure ⬍7
cm H
2
O. Immediately after extubation, NCPAP was
started. NCPAP was discontinued when the neonate re-
mained stable with a capillary P
CO
2
⬍60 mm Hg and
oxygen saturation ⬎92% without supplementary O
2
.
When taken off NCPAP, infants were given supplemen-
tal oxygen using low flow nasal cannulae if saturation
was ⬍92%. If oxygen requirements exceeded 30% (ef-
fective F
IO
2
20
), NCPAP was restarted.
All infants had cerebral ultrasounds performed at
least 3 times in the first week and weekly thereafter.
The primary outcome measure was the percentage of
infants intubated within 72 hours of age. Secondary
outcome measures were intubation in the delivery
room, the need for mechanical ventilation and surfac-
tant treatment, death during admission or BPD based on
the National Institute of Child Health and Human De-
velopment definition,
21
intraventricular hemorrhage
(IVH), periventricular leucomalacia, retinopathy of pre-
maturity, persistent ductus arteriosus, and necrotizing
enterocolitis.
Data are reported as means and SDs or as medians
and interquartile range (IQR) if appropriate. Sample size
analysis showed that to detect a reduction in intubation
and mechanical ventilation from 60% to 40%, with a
power of 80% and an
␣
error of 5% (2-tailed test), 97
infants were required for each arm of the study. Because
our center admits ⬃200 eligible newborns per year and
we expected 20% of the parents to refuse consent, the
duration of the study was estimated at 1 year and 3
months. All analyses were performed on an intention-
to-treat principle. The baseline characteristics and out-
come parameters in the 2 treatment groups were com-
pared using Student’s t test for parametric and the
Mann-Whitney U test for nonparametric comparisons
for continuous variables, and the
␹
2
test for categorical
variables. Reported P values are 2-sided, and P ⬍ .05 was
considered statistically significant. The presented odds
ratio (OR) with the corresponding 95% confidence in-
terval (CI) is an approximation to the relative risk.
This study was approved by the Leiden University
Medical Center Ethics Review Committee.
RESULTS
A total of 217 inborn very preterm infants (gestational
age: 25–32 weeks) were admitted to the NICU between
April 1, 2005, and July 12, 2006. Five infants were
excluded because of severe cardiac or respiratory anom-
alies or syndromes incompatible with survival. Five were
not included because their parents did not consent an-
tenatally. The early respiratory management of the 207
infants is shown in Fig 1. The demographic characteris-
tics of both groups are presented in Table 1.
324 te PAS, WALTHER
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Fewer infants in the EFURCI group were intubated
within 72 hours of age (38 [37%] of 104 vs 52 [51%] of
103; P ⫽ .04; OR: 0.57 (95% CI: 0.32– 0.98). In the
EFURCI group, 73 (70%) of 104 infants needed a pro-
longed inflation, 44 (60%) of 73 infants could be stabi-
lized after inflation of 20 cm H
2
O, 29 (40%) of 73
needed a second inflation of 25 cm H
2
O, and 18 of these
29 (62%) infants also needed intubation. Nasal intermit-
tent positive pressure ventilation optional after sustained
inflation in case of absent/insufficient breathing was
used in 15 (14%) of 104 infants. Almost all of these
infants (13 of 15) had to be intubated in the delivery
room.
Secondary outcomes are shown in Table 2. The du-
ration of ventilatory support (including NCPAP) was
shorter in infants in the EFURCI group compared with
those in the conventional group (median days [IQR]: 2.7
[0.5–10] vs 4.3 [0.5–20]; P ⫽ .01) In the subgroup of
infants ventilated within 72 hours of age, total time of
ventilatory support (including NCPAP) was less in in-
fants in the EFURCI than in the conventional group
(median days [IQR]: 10 [4 –19.5] vs 15 [5.6 –36.3]; P ⫽
.04). The first pH, Pa
CO
2
, and FIO
2
on arrival in the NICU
and maximum of F
IO
2
used were similar in both groups
(pH 7.23 ⫾ 0.1 in both groups; Pa
CO
2
6.9 ⫾ 1.4 vs 6.8 ⫾
1.6 kPa; F
IO
2
0.32 ⫾ 0.17 vs 0.32 ⫾ 0.19; maximum FIO
2
used 0.4 ⫾ 0.25 vs 0.36 ⫾ 0.19). The incidence of RDS
was less in infants in the EFURCI group compared with
those in the conventional group (39 [38%] of 104 vs 56
[54%] of 103; P ⫽ .015; OR: 0.50 [95% CI: 0.29 – 0.88]).
The incidence of pneumothoraces was not significant
different between the groups (1 [1%] of 104 vs 7 [7%]
of 103; P ⫽ .069; OR: 0.13 [95% CI: 0.02–1.10]).
Posthoc analysis of gestational-age subgroups (Fig 2)
showed that the greatest effect was at 28 to 30 weeks’
gestation (intubation ⬍72 hours: 16 [32%] of 50 vs 27
[59%] of 47; P ⫽ .01; OR: 0.33 [95% CI: 0.14 – 0.76]. In
the subgroup ⬍28 weeks’ gestation, fewer infants were
intubated in the delivery room (8 [40%] of 20 vs 15
[79%] of 19; P ⫽ .022; OR: 0.178 [95% CI: 0.043–
207 very
preterm
neonates
included
Conventional 103
EFURCI 104
37
intubation
66
M+B
37
none
18
intubation
73
neopuff + ENCPAP
31
none
16
none
21
NCPAP
21
NCPAP
8
none
13110
Total 52
17
none
14
NCPAP
0
5
15
Total 38
DR
management
NICU
management
Intubation <
72 h
FIGURE 1
Early respiratory management of the 2 trial groups. DR indicates delivery room; M⫹B, mask and bag.
TABLE 1 Demographic Characteristics
Characteristic EFURCI
(N ⫽ 104)
Conventional
(N ⫽ 103)
Birth weight, mean (SD), g 1311 (403) 1290 (392)
Gestational age, mean (SD), wk 29.4 (1.9) 29.5 (1.9)
Male gender, n (%) 56 (54) 57 (55)
Umbilical arterial pH, mean (SD) 7.25 (0.09) 7.25 (0.10)
Prenatal steroids, n (%) 85 (82) 83 (81)
Chorioamnionitis, n (%) 12 (12) 8 (8)
PPROM, n (%) 21 (20) 28 (27)
(Pre)eclampsia, n (%) 23 (22) 26 (25)
Fetal distress, n (%) 23 (22) 15 (15)
IUGR, n (%) 16 (15) 19 (18)
Cesarean section, n (%) 48 (46) 38 (37)
5-min Apgar score, median (IQR) 9 (8–9) 8 (7–9)
Singletons, n (%) 36 (35) 47 (46)
Chorioamnionitis is defined as maternal fever with at least 1 of the following symptoms: leu-
kocytosis, tenderness of the uterus, fetal tachycardia, foul-smelling amniotic fluid. Antenatal
steroids are any number of doses of steroids for induction of fetal lung maturation. PPROM
indicates preterm premature rupture of the membranes; IUGR, intrauterine growth retardation.
PEDIATRICS Volume 120, Number 2, August 2007 325
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0.736]), but there was no significant difference in intu-
bation ⬍72 hours (13 [65%] of 20 vs 15 [79%] of 19;
not significant).
DISCUSSION
This randomized, controlled trial shows that very pre-
term infants need less intubation, mechanical ventila-
FIGURE 2
Number of infants intubated in the delivery room and at ⬍72 hours of age in subgroups with gestational ages of ⬍28, 28 to 30, and ⬎30 weeks. White bars, EFURCI; black bars,
conventional intervention. DR indicates delivery room.
TABLE 2 Secondary Outcomes
Secondary Outcomes EFURCI
(N ⫽ 104)
Conventional
(N ⫽ 103)
Univariate
Analysis, P
OR (95% CI)
Intubation delivery room, n (%) 18 (17) 37 (36) .002 0.37 (0.20–0.70)
Total period of mechanical ventilation of intubated infants
⬍72 h of age, median (IQR), d 关n兴
2.5 (1–8.3)关38兴 4.5 (2–11.5)关52兴 .2
Total period of NCPAP of total group, median (IQR), d 2 (0.3–8) 2 (0–11) .038
Surfactant doses, mean (SD) 0.4 (0.8) 0.6 (1.0) .3
Surfactant ⬎1 dose, n (%) 10/103 (10) 22/104 (21) .02 0.39 (0.18–0.88)
Mortality, n (%) 2 (2) 4 (4) .4
BPD
total
, n (%)
a
22 (22
a
) 34 (34
a
) .05
BPD
moderate-severe
, n (%)
a
9(9
a
) 19 (19
a
) .04 0.41 (0.18–0.96)
PDA needing treatment, n (%) 21 (20) 16 (16) .4
NEC at least stage 2, n (%) 0 (0) 1 (1) .5
ROP above grade 3, n (%) 0 (0) 1 (1) .5
IVH grade 3 ⫹ 4, n (%) 7 (7) 3 (3) .3
Cystic PVL, n (%) 2 (2) 5 (5) .4
PDA indicates patent ductus arteriosus; NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; PVL, periventricular leucomalacia.
a
Percentage of survivors.
326 te PAS, WALTHER
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tion, days on NCPAP, and had less RDS, air leaks, and
moderate-to-severe BPD when a prolonged inflation
through a nasal tube, immediately followed by nasal
CPAP (EFURCI) is used instead of bag and mask venti-
lation and CPAP on admission to the NICU. Treatment
with surfactant was not different, but fewer infants re-
ceived ⬎1 dose in the EFURCI group. These data suggest
that this lung recruitment maneuver (sustained inflation
followed by NCPAP) is a more effective management
strategy for ventilation of very preterm infants in the
delivery room.
This is the first randomized, controlled trial, to our
knowledge, in which the EFURCI ventilation strategy is
compared with bag and mask ventilation advised by
international neonatal resuscitation guidelines.
3
Our re-
sults are consistent with the findings in the retrospective
report of Lindner et al
10
, who compared the same lung
recruitment maneuver and ENCPAP in 1996 with elec-
tive intubation as historical control in 1994. Their study
group consisted of smaller infants (mean gestational age
of 26.9 weeks and birth weight of 739 g in the interven-
tion group), but their intubation rate in the delivery
room decreased from 84% to 40% (P ⬍ .001), and 7%
were never intubated in the 1994 group compared with
25% in 1996 (P ⬍ .01). The rate of moderate-to-severe
BPD decreased from 32% to 12% (P ⬍ .05).
10
Consistent
with our results, no harmful effects of their new ap-
proach were found; for example, there were no in-
creased rates of IVH or pneumothorax.
Our trial showed that the EFURCI approach allows
more infants to breathe during the first days with
ENCPAP alone. ENCPAP and selective surfactant treat-
ment is an accepted alternative, and retrospective studies
have shown less morbidity when ENCPAP is used in the
delivery room to avoid intubation, even if ENCPAP fails
later on and intubation follows.
1,4,22–24
More prospective
trials are under way, but there is currently insufficient
information to evaluate the effectiveness of prophylactic
(early) NCPAP in very preterm infants.
25
Finer et al
26
found, in a feasibility study among infants ⬍28 weeks’
gestation receiving CPAP/PEEP or not in the delivery
room, no differences in intubation rate or surfactant use.
Animal studies have shown that an inflammatory
process can be initiated with the first large manual
breaths during resuscitation and may ultimately lead to
BPD.
5–9
Very preterm infants may not be able to generate
high enough inspiratory pressures to achieve effective
lung expansion and, therefore, need ventilatory sup-
port.
27,28
A prolonged inflation time, used if spontaneous
breathing is inadequate, may help the preterm infant to
overcome the long time constant of a fluid-filled lung
and prevent the use of potentially dangerous high in-
spiratory pressures.
29,30
The beneficial effects of a sustained inflation were not
confirmed in recent randomized, controlled trials.
31,32
Lindner et al
31
compared a 15-second inflation to inter-
mittent mandatory ventilation in infants ⬍29 weeks’
gestation. Consistent with our findings, there was no
difference regarding the intubation rate ⬍72 hours in
this group of infants. Harling et al
32
used a different
method by comparing a sustained inflation of 5 seconds
with a conventional inflation of 2 seconds. Both studies
lacked power because of small sample sizes. To maintain
an adequate lung volume after inflation and to prevent
atelectrauma, application of PEEP/CPAP is necessary.
33–35
Starting time of ENCPAP is important, because a non-
compliant, surfactant-deficient lung has a tendency to
collapse and lung volume is not maintained if CPAP/
PEEP is not given immediately to keep the lung open.
Self-inflating bags may deliver insufficient or excessively
high PIP and minimal PEEP, leading to volutrauma and
atelectrauma, even when a manometer is incorporat-
ed.
14,18,19
A pressure-limited mechanical device with a
T-piece delivers more consistent PIP and PEEP and is
better able to deliver a sustained inflation compared
with a self-inflating bag.
13–16
Another advantage is that it
is easy to use and thereby increases the chance of effec-
tive ventilation, even in the hands of inexperienced
physicians.
14
It is difficult to deliver PEEP with a face
mask because the seal can break very easily.
15,36
To avoid
this PEEP leakage, a nasopharyngeal tube is used as
interface. Data are limited, but a randomized trial
showed significantly less intubations in neonates with
moderate asphyxia.
17
Another advantage of using a na-
sopharyngeal tube as interface is that CPAP/PEEP can be
continued very easily and directly after resuscitation.
There was a significant decrease of RDS in infants in
the EFURCI group. A possible explanation for this is that
the EFURCI intervention was effective in preserving sur-
factant. During initial assessment of a very preterm in-
fant in the delivery room, it is difficult to differentiate
between respiratory distress attributable to transitional
problems or RDS, and a trial of ENCPAP provides time to
solve this problem. In the conventional group, some
preterm neonates who were intubated and ventilated in
the delivery room may have had transitional problems,
but developed RDS secondary to lung injury.
Some very preterm infants failed ENCPAP later on,
especially infants ⬍28 weeks’ gestation with RDS. The
maximum level of ENCPAP used was 8 cm H
2
O, and a
higher level of CPAP or a recruitment maneuver during
CPAP might have reduced later treatment failure. An-
other explanation for ENCPAP failure may have been
the low threshold for intubation and surfactant treat-
ment at our institution (F
IO
2
⬎40% or PaCO
2
⬎8.0 kPa).
This low threshold was chosen to prevent the disadvan-
tageous and deleterious effects of a late rescue with
surfactant treatment (F
IO
2
ⱖ0.6) in infants who are
quickly deteriorating because of RDS.
11,37
Prophylactic or
early surfactant treatment of neonates requiring me-
chanical ventilation is more effective than late rescue
treatment
38,39
but has the potential disadvantage that
PEDIATRICS Volume 120, Number 2, August 2007 327
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some preterm neonates are treated who are surfactant
sufficient and will not develop RDS.
There are limitations of this randomized, controlled
trial. To reach the most effective application of an open
lung strategy, we combined several techniques (me-
chanical pressure-limited device, prolonged inflation,
nasopharyngeal tube as interface, and direct ENCPAP in
the delivery room). This makes it impossible to deter-
mine which factor contributes most to the final result. In
the conventional method, a higher pressure is used ini-
tially to open the lung. Although this technique is in
agreement with the international guidelines, this could
have contributed to the poorer outcome. Biases in the
management could have occurred because the study was
not blinded, and the staff performing the study also took
care of the infants later on. However, the decision to
intubate was made by clinicians other than the investi-
gators. Whenever 1 of the investigators was supervising,
1 of their colleagues (fellow) made the decision to intu-
bate or not in the infants included in the study. We tried
to minimize these biases by maintaining strict criteria
and definitions during the trial. This trial was performed
in a single center with experienced neonatologists,
trained in the techniques of EFURCI, and it is possible
that others might not get the same results.
Limits of viability in the Netherlands are set at 25
weeks’ gestation, thus the results of this study cannot be
applied to infants ⬍25 weeks’ gestation. We detected
little effect of the EFURCI approach in infants ⬍28
weeks’ gestation, but this trial was not designed and
powered to detect a difference in this subgroup.
Whether the EFURCI approach is more efficient and less
injurious among the most vulnerable preterm infants,
that is, those with a gestational age of 23 to 27 weeks,
needs additional evaluation.
CONCLUSIONS
This randomized, controlled trial comparing 2 ventila-
tory approaches showed that the combination of a sus-
tained inflation breath and ENCPAP supplied by a me-
chanical pressure-limited device and a nasopharyngeal
tube as interface is a more efficient strategy than re-
peated manual inflations with a self-inflating bag and
mask for the early respiratory management of very pre-
term infants in the delivery room. ENCPAP also buys
time to differentiate between RDS and transition prob-
lems and reduces the number of preterm infants intu-
bated unnecessarily. More investigation is needed to
determine which part of the EFURCI approach contrib-
uted the most. Although this trial has shown the impor-
tance of early respiratory management for pulmonary
outcome (BPD) in preterm infants, more randomized
trials, especially in infants ⬍28 weeks’ gestation, are
needed to develop an optimal strategy for extremely
preterm infants.
ACKNOWLEDGMENT
We thank Professor Colin J. Morley for critical review of
this manuscript.
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OXYCONTIN MAKER PLEADS GUILTY: PAYS $634.5 MILLION SETTLEMENT FOR HIDING
ADDICTION RISK
“In one of the largest drug company criminal settlements, the maker of
narcotic painkiller OxyContin will pay $634.5 million after guilty pleas by
Purdue Frederick Co and three of its executives. The company pleaded guilty
to misbranding the drug with the intent to defraud and mislead the public
about its addictive qualities. The three executives pleaded guilty to misbrand-
ing the drug. . . . The company trained its sales force to falsely inform
health-care providers that it was difficult to extract oxycodone, the drug’s
active ingredient, from the drug for purposes of abuse. . . . The company . . .
encouraged physicians to prescribe the drug for use every eight hours instead
of every 12 hours, as approved by the US Food and Drug Administration.”
Tesoriero HW. Wall Street Journal. May 11, 2007
Editorial Comment: It sounds like a big fine—$635 million— but because this
was/is a “billion dollar” a year drug since 2003, it’s small. Why no jail time?
Noted by JFL, MD
PEDIATRICS Volume 120, Number 2, August 2007 329
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te Pas AB, Walther FJ. A Randomized, Controlled Trial of
Delivery-Room Respiratory Management in Very Preterm Infants.
PEDIATRICS 2007;120:322–329.
An error occurred in the article by te Pas and Walther, titled “A Randomized,
Controlled Trial of Delivery-Room Respiratory Management in Very Preterm
Infants,” published in the August 2007 issue of Pediatrics (doi:10.1542/peds.
2007-0114). On page 323, under the heading “EFURCI Approach,” lines
38 – 40, the authors wrote: “Patients were transferred to the NICU with
ENCPAP or synchronized intermittent mandatory ventilation.” This should
read: “Patients were transferred to the NICU with ENCPAP or intermittent
mandatory ventilation.”
doi:10.1542/peds.2007-2440
Lindstro¨ m K, Winbladh B, Haglund B, Hjern A. Preterm Infants as
Young Adults: A Swedish National Cohort Study. PEDIATRICS
2007;120:70 –77.
An error occurred in the article by Lindstro¨ m et al, titled “Preterm Infants as
Young Adults: A Swedish National Cohort Study,” published in the July
2007 issue of Pediatrics (doi:10.1542/peds.2006-3260). On page 70, in the
Results section of the Abstract, lines 2–5, the authors wrote: “A total of
13.2% of children born at 24 to 28 weeks’ gestation and 5.6% born at 29 to
32 weeks’ gestation received economic assistance from society because of
handicap or persistent illness compared with those born at term after ad-
justment for socioeconomic and perinatal confounders.” This should read: ”A
total of 13.2% of children born at 24 to 28 weeks’ gestation and 5.6% born
at 29 to 32 weeks’ gestation received economic assistance from society
because of handicap or persistent illness, which is equivalent to nearly 4
times the risk of those born at term after adjustment for socioeconomic and
perinatal confounders.⬙
doi:10.1542/peds.2007-2439
Maegawa GHB, Stockley T, Tropak M, et al. The Natural History of
Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and
Literature Review of 134 Previously Reported. PEDIATRICS 2006;
118:e1550 – e1562.
Errors occurred in the article by Maegawa et al, titled “The Natural History
of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature
Review of 134 Previously Reported,” published in the November 2006 issue
of Pediatrics Electronic Pages (doi:10.1542/peds.2006-0588). In Table 3 on page
e1554, “Diarrhea/constipation” row, column 5, footnote “a” is misplaced; it
should apply to “5 (18.5).” In the “Behavioral and psychiatric problems”
row, column 3, footnote “a” is misplaced; it should apply to “6 (100).” In the
“Sleep problems” row, column 5, footnote “b” is misplaced; it should apply
to “5 (18.5).” In the “Acroparestesia and/or neuropathy” row, column 3,
footnote “a” is misplaced; it should apply to “2 (33.3).”
doi:10.1542/peds.2007-0343
936 ERRATUM
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DOI: 10.1542/peds.2007-0114
2007;120;322Pediatrics
Arjan B. te Pas and Frans J. Walther
Very Preterm Infants
A Randomized, Controlled Trial of Delivery-Room Respiratory Management in
Services
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