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Acta Pdiatrica ISSN 0803-5253

REGULAR ARTICLE

Less invasive surfactant administration is associated with improved


pulmonary outcomes in spontaneously breathing preterm infants
Wolfgang Gopel (wolfgang.goepel@uksh.de)1, Angela Kribs2, Christoph Hartel1, Stefan Avenarius3, Norbert Teig4, Peter Groneck5, Dirk Olbertz6,
Claudia Roll7, Matthias Vochem8, Ursula Weller9, Axel von der Wense10, Christian Wieg11, Jurgen Wintgens12, Michael Preuss13, Andreas Ziegler13,14,
Bernhard Roth2, Egbert Herting1, for the German Neonatal Network (GNN)
beck, Lu
beck, Germany
1.Department of Pediatrics, University of Lu
2.Department of Pediatrics, University of Cologne, Cologne, Germany
3.Department of Pediatrics, University of Magdeburg, Magdeburg, Germany
4.Department of Pediatrics, University of Bochum, Bochum, Germany
5.Childrens Hospital, Leverkusen, Germany
6.Childrens Hospital, Rostock, Germany
7.Childrens Hospital, Datteln, Germany
8.Childrens Hospital, Olgahospital, Stuttgart, Germany
9.Childrens Hospital, Bielefeld, Germany
10.Childrens Hospital, Hamburg-Altona, Hamburg, Germany
11.Childrens Hospital, Aschaffenburg, Germany
nchengladbach, Germany
12.Childrens Hospital, Mo
beck, Lu
beck, Germany
13.Institute for Medical Biometry and Statistics, University of Lu
beck, Lu
beck, Germany
14. Center for Clinical Trials, University of Lu

Keywords
Bronchopulmonary dysplasia, Less invasive
surfactant administration, Mechanical ventilation,
Preterm infant, Spontaneous breathing
Correspondence
pel, MD, Department of Pediatrics, University
W Go
beck, Ratzeburger Allee 160, 23538 Lu
beck,
of Lu
Germany.
Tel: + 49 451 500 2555 |
Fax: + 49 451 500 6986 |
Email: wolfgang.goepel@uksh.de
Received
5 March 2014; revised 21 June 2014;
accepted 26 November 2014.
DOI:10.1111/apa.12883

ABSTRACT
Aim: Providing less invasive surfactant administration (LISA) to spontaneously breathing
preterm infants has been reported to reduce mechanical ventilation and
bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study
compared these outcome measures between LISA-treated infants and controls.
Methods: Infants receiving LISA, who were born before 32 gestational weeks and enrolled
in the German Neonatal Network, were matched to control infants by gestational age,
umbilical cord pH, Apgar-score at 5 min, small for gestational age status, antenatal
treatment with steroids, gender and highest supplemental oxygen during the first 12 h of
life. Outcome data were compared with chi-square and MannWhitney U-tests and
adjusted for multiple comparisons.
Results: Between 2009 and 2012, 1103 infants were treated with LISA at 37 centres. LISA
infants had lower rates of mechanical ventilation (41% versus 62%, p < 0.001), postnatal
dexamethasone treatment (2.5% versus 7%, p < 0.001), BPD (12% versus 18%,
p = 0.001) and BPD or death (14% versus 21%, p < 0.001) than the controls.
Conclusion: Surfactant treatment of spontaneously breathing infants was associated with
lower rates of mechanical ventilation and BPD. Additional large-scale randomised
controlled trials are needed to assess the possible long-term benefits of LISA.

INTRODUCTION
Providing less invasive surfactant administration (LISA) to
spontaneously breathing infants via a thin catheter has been
associated with improved pulmonary outcomes in observational studies (16). In addition, two randomised controlled
trials (RCTs), the Avoidance of Mechanical Ventilation
study (7) and the Take Care study (8), reported a reduced
rate of mechanical ventilation and bronchopulmonary
dysplasia (BPD), respectively, in infants who were treated
with LISA.
Additional RCTs using this new technique of surfactant
administration have been completed, but the total number
of infants taking part in RCTs is still small, and this means
that the side effects of the procedure might not be observed.
Furthermore, improvements observed in RCTs in selected

Key notes


2014 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 241246

Providing less invasive surfactant administration (LISA)


to spontaneously breathing preterm infants has been
reported to reduce mechanical ventilation and bronchopulmonary dysplasia in randomised controlled trials.
Our large-scale study showed that the 1103 infants
who were treated with LISA had lower rates of
mechanical ventilation and bronchopulmonary dysplasia than the 1103 matched controls.
Additional studies are needed to assess the possible
benefits of LISA with regard to long-term outcomes.

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pel et al.
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Less invasive surfactant administration and preterm infants

centres can be less obvious if a new method is used in a high


number of neonatal intensive care units (NICUs).
We carried out a matched-pair analysis of a large cohort
study to increase the number of infants analysed. Infants
were matched for known risk factors of respiratory distress
syndrome (RDS). Outcomes for the RDS risk groups were
analysed separately to identify subgroups of infants who
might not benefit from the procedure.
Table 1 Clinical data on the first day of life

Gestational age*
(weeks, median, IQR)
Birthweight
(grams, median, IQR)
Male gender*
(%, n/n)
Multiples
(%, n/n)
Umbilical cord pH < 7.1*
(%, n/n)
APGAR at 5 min < 7*
(%, n/n)
Small for gestational age*
[%, n/n]
Inborn
(%, n/n)
No antenatal steroids*
(%, n/n)
Peak fraction of inspired
oxygen during the first 12 h
of life* (Median, IQR)

Matched controls
(n = 1103)

LISA-treated
infants (n = 1103)

28.0
26.729.4
1020
8161240
53
583/1103
37
409/1100
2
20/1024
11
121/1078
11
1.22/1103
98
1011/1034
9
95/1101
0.35
0.260.45

28.0
26.729.4
985
7901220
53
584/1103
34
373/1103
2
21/1024
11
119/1077
11
125/1103
99
1084/1099
8
90/1099
0.35
0.270.50

Matching criteria are marked with an asterisk.


LISA = Less invasive surfactant administration.

Restricted to 966 control infants and 963 LISA infants with data.

PATIENTS AND METHODS


Patients
The German Neonatal Network (GNN) is an ongoing
prospective cohort study focussed on the long-term development of very low birthweight infants. Patients with a
birthweight of below 1500 g and a gestational age of below
37 + 0 weeks were enrolled by participating NICUs. Regular on-site data monitoring was carried out by physicians
beck.
at the central GNN office at the University of Lu
Clinical data were coded and entered into a central
database. Written parental consent was obtained from
parents or carers. The GNN study was approved by the
ethics committees of the participating centres.
LISA was prospectively recorded in the GNN, which
started enrolling patients on January 1, 2009. We screened
the GNN database for preterm infants with a gestational
age of below 32 weeks who were treated with LISA
between January 2009 and December 2012. Infants who
were enrolled in the Avoidance of Mechanical Ventilation
trial (7) or the randomised Non-Intubated Surfactant
Application trial (ISRCTN64011614) were excluded, as
were infants receiving comfort care. The indication for
LISA was not recorded. However, most centres provided
LISA in response to the clinical condition of the infant,
such as respiratory distress. A video of the LISA method
is available at https://www.youtube.com/watch?v=OU
vgJ57FQR8.
Matching procedure
Low gestational age is the most important risk factor for
RDS. Additional independent risk factors are severe perinatal depression, defined as an umbilical cord pH of below
7.1, or moderate perinatal depression, defined as a five
minute APGAR score of below seven (9). Further risk
factors include birthweight below the 10th percentile (10),
no antenatal treatment with steroids (11) and male gender

Table 2 Treatment data


Matched controls
(n = 1103)
Surfactant treatment
(%, n/n)
Surfactant doses
(Total number, median, IQR)
Mechanical ventilation
(%, n/n)
Days on mechanical ventilation
(Total number, median, IQR)
Dexamethasone treatment
(%, n/n)
Any postnatal steroid treatment
(%, n/n)
Treatment with analgesics or sedatives
(%, n/n)

61
672/1103
1101
1, 01
62
684/1103
9394
2, 07
7
66/955
17
165/959
45
487/1080

LISA-treated infants
(n = 1103)
100
1003/1003
1506
1, 12
41
453/1103
5420
0, 05
2.5
24/948
11
109/952
37
407/1083

Nominal
p

Adjusted p

<10

30

<0.001

<10

30

<0.001

<10

30

<0.001

6.4 9 10

19

<0.001

7 9 10

<0.001

3.3 9 10

0.005

3.9 9 10

0.006

MannWhitney U-test for surfactant doses and days on mechanical ventilation, chi-square test for all other variables. Nominal p-values are given as exact values
(e.g.: 3.9 9 10 4 = 0.00039). Adjusted p-values were corrected for 16 comparisons.

242

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(12). The need for high oxygen supplementation during the


first 24 h of life is known to be a direct indicator for severe
RDS.
Each infant receiving LISA was matched with one
infant not treated with LISA. As far as possible, the LISA
and non-LISA infants were matched by gestational age
and by the same yes or no answers to the following
questions: umbilical cord pH below 7.1, 5-min APGAR
score below seven, birthweight below the 10th percentile
according to Voigt (13) and antenatal treatment of the
mother with steroids. The other factors included whether
they were male or female and the highest percentage of
supplemental oxygen during the first 24 h of life. If more
than one infant fulfilled the matching criteria, that one was
randomly selected. If matching criteria information was
missing for the LISA-treated infants, such as umbilical
cord pH, they were matched to controls with identical
missing data. If complete matching was not possible,
infants were selected due to the ranking described above:
firstly by gestational age, secondly by umbilical cord pH
and so on. Complete matches were identified with the
SPSS programme.

Less invasive surfactant administration and preterm infants

Treatment data
We compared the number of infants treated with surfactant,
the median number of surfactant doses and the number and
duration of episodes of mechanical ventilation, which was
defined as ventilation via an endotracheal tube. We also
compared the frequency of any treatment with dexamethasone, steroids and sedatives and analgesics.
Endpoints analysed
Pneumothorax was defined as any pneumothorax with
intrapleural drainage. Bronchopulmonary dysplasia was
defined as the need for supplemental oxygen or continuous
positive airway pressure at 36 weeks of postmenstrual age
(14). We also analysed the combined endpoint of BPD or
death and complications which were defined as serious in
the Avoidance of Mechanical Ventilation Trial (7). These
were intraventricular haemorrhage (IVH) grade III or IV
(according to Papile), periventricular leukomalacia, surgical
treatment of necrotising enterocolitis or focal intestinal
perforation, laser or cryotherapy of retinopathy of prematurity and death and a combination of any of these
complications.
Statistics
We used the chi-square test to compare dichotomous
variables and the MannWhitney U-test to compare continuous variables. The global significance level was set to
0.05. Adjustments for multiple testing were carried out
using Bonferroni correction for 16 comparisons involving
all matched pairs, and thus the nominal p-value was 0.003.
For descriptive comparisons of subgroups with a high risk
of RDS, only nominal p-values were analysed. All p-values
were two-sided. Analyses were performed with the SPSS
statistics software version 20.0 (IBM, New York, NY,
USA).

Figure 1 Infants treated with less invasive surfactant administration (LISA)


compared to matched controls and stratified for gestational age. Large
differences with regard to mechanical ventilation were observed in infants
between 25 and 30 weeks of gestational age (A). LISA-treated infants with a
gestational age of below 28 weeks had low rates for bronchopulmonary
dysplasia (B).

RESULTS
Between January 2009 and December 2012, 46 NICUs
enrolled infants in the GNN study. A total of 1103 infants
were treated with LISA in 37 centres, with a median of 15
infants per centre and an interquartile range (IQR) of seven
to 21 infants per centre. Matched controls were selected
from 4048 infants treated in 46 NICUs. The median number
of selected controls was 18 infants per centre, with an IQR
of nine to 30 infants per centre. Complete matching was
achieved for 777 LISA-treated infants and incomplete
matching for a further 326 infants. Clinical baseline data
were not different between LISA-treated infants and
matched controls (Table 1).
Treatment data are given in Table 2. As expected, the
number of surfactant treated infants was significantly
higher in the LISA group. These 1103 infants received

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Less invasive surfactant administration and preterm infants

Table 3 Outcome data

Pneumothorax
(%, n/n)
Bronchopulmonary dysplasia
(%, n/n)
Bronchopulmonary dysplasia or death (%, n/n)
IVH grade III or IV
(%, n/n)
Periventricular leukomalacia (%, n/n)
Surgery for necrotising enterocolitis or
focal intestinal perforation (%, n/n)
Laser or cryotherapy for retinopathy of prematurity (%, n/n)
Severe complications
(%, n/n)
Death
(%, n/n)

Matched controls
(n = 1103)

LISA-treated infants
(n = 1103)

7
70/1077
18
200/1098
21
232/1103
6
64/1097
4
38/1077
5
50/1090
4
38/1098
16
171/1103
4
43/1103

6
61/1101
12
134/1101
14
157/1103
5
55/1092
3
27/1084
6
60/1098
2
22/1101
12
137/1103
3
31/1103

Nominal p*

Adjusted p

0.34

7.9 9 10

0.001

2.8 9 10

<0.001

0.41

0.15

0.34

0.035

0.56

0.037

0.59

0.15

Nominal p-values are given as exact values (e.g.: 3.9 9 10 4 = 0.00039). Adjusted p-values were corrected for 16 comparisons.
*Chi-square test.

Severe complications were defined as IVH grade III or IV, periventricular leukomalacia, surgical treatment of necrotising enterocolitis or focal intestinal perforation,
laser or cryotherapy of retinopathy of prematurity, death and a combination of any of these complications.

more than 400 additional surfactant doses than the


matched controls. Of the LISA-treated infants, 41%
received mechanical ventilation, compared to 62% of the
matched controls. This was expected as well, because
intubation and mechanical ventilation was the only way
surfactant could be administered in the control group, as
the intubation surfactant extubation procedure was rarely
used in German NICUs. Large differences in mechanical
ventilation were observed for infants between 25 and
30 weeks of gestation (Fig. 1A). Postnatal treatment with
dexamethasone, other steroids and analgesics or sedatives
was significantly more frequent in the matched control
group. Outcome data are given in Table 3. We observed a
significantly lower rate of BPD and BPD or death, which
was due to differences in infants with a gestational age of
below 28 weeks. In infants at, or above, 28 weeks of
gestation, the frequency of death and BPD was below 10%
(Fig. 1B). A tendency towards lower rates for laser or
cryotherapy for retinopathy of prematurity and the
combined endpoint of severe complications or death were
also observed for LISA infants. However, this difference
was no longer significant after adjusting for multiple
comparisons (Table 3).
As anticipated, all predefined RDS risk groups had higher
rates of mechanical ventilation and complications. With the
exception of infants who were severely depressed at birth,
all LISA subgroups had at least some favourable outcome
parameters when compared with matched controls.
LISA-treated infants did not have higher rates of adverse
outcomes in any of the subgroups.

244

DISCUSSION
The lungs of preterm infants are extremely vulnerable and
even a short period of mechanical ventilation might affect
the normal process of pulmonary microvascular growth and
alveolarisation (15). In addition, recent research indicates
that mechanical ventilation can induce systemic inflammation by releasing molecular patterns, which are associated
with damage activate pattern recognition receptors and
release proinflammatory cytokines and chemokines (16,17).
Therefore, reducing the number of ventilator days or
completely avoiding mechanical ventilation might be beneficial for the patients lungs (18) and other vulnerable
organs like the brain, which might be injured by systemic
inflammation.
Over the last few years, surfactant administration to
spontaneously breathing infants has been reported by a
number of groups from different countries (16,19,20). Two
randomised trials reported reduced mechanical ventilation
and BPD rates in infants receiving LISA. However, the total
number of LISA-treated infants in these trials were only 65
and 100, respectively (7,8).
With regard to the beneficial outcomes reported in the
Avoidance of Mechanical Ventilation trial (7) and the Take
Care trial (8), we were able to confirm these data by our
matched-pair analysis. LISA-treated infants needed less
mechanical ventilation and had lower rates of BPD and
death compared to carefully matched control infants. It
should be noted that achievable benefits were closely related
to gestational age. Infants of 28 weeks of gestational age and
above might benefit with regard to mechanical ventilation,

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pel et al.
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whereas ventilation rates in infants with a gestational age of


below 25 weeks are similar, regardless of LISA treatment.
However, these infants had lower rates of the much more
important endpoint, which was BPD or death. LISA-treated
infants from 25 to 27 weeks of gestational age had lower
measures for both outcomes. The mean gestational age of
our analysis was similar to the Take Care trial (8). However,
LISA-treated infants only had a 7% lower rate of BPD or
death compared to the 10% recorded in the Take Care trial.
Dexamethasone treatment reduces the rate of BPD, but
has severe side effects with regard to long-term neurological
outcome. A lower rate of dexamethasone treatment in infants
receiving LISA was observed. An interesting finding of our
analysis was the tendency towards lower rates of severe
complications in LISA-treated infants. Although this endpoint was no longer significant after adjusting for multiple
testing, low rates of severe complications in LISA-treated
infants in the Avoidance of Mechanical Ventilation trial (7)
and several observational studies (1,19) have indicated that
combined risks of severe complications should be defined, at
least as secondary endpoints, in ongoing and future RCTs
testing LISA. Subgroup analyses were carried out to rule out
the possibility that specific subgroups suffer increased incidences of severe side effects if treated with LISA.
The major limitation of our study was the matched pair
design. Although we tried to select perfect matches with
regard to factors influencing the severity of RDS, we could
not rule out the possibility that unrecognised confounders,
such as centre-specific treatment strategies, approaches to
neonatal resuscitation or persistent ductus arteriosus management, might bias the results of our analysis. Furthermore,
it is possible that positive effects observed in infants with
LISA were due to the higher rate of surfactant treatment in
this group. Finally, we were not able to analyse long-term
follow-up data, because standardised follow-up of GNN
infants is carried out at the age of five. The strengths of our
study were the high sample size, prospectively recorded data
sets and the high number of centres using LISA.
Our data add information about the safety assessment of
the LISA procedure, indicating that this method of surfactant
administration can be used in the majority of preterm infants
below 32 weeks of gestation. However, it should be noted
that only physicians who are proficient in endotracheal
intubation should use this new technique. We retested
mechanical ventilation and BPD as endpoints, as these were
reported to be improved by LISA in RCTs. Our data support
the view that the LISA technique was not only beneficial
when it was used in randomised trials carried out at single or
selected centres, it was also beneficial when it was introduced
into daily clinical practice in many NICUs. However,
additional well-designed RCTs will be necessary to explore
the possible benefits of the LISA method with regard to
severe complications of prematurity and long-term outcome.

ACKNOWLEDGEMENTS
The authors of this paper acknowledge the contributions of
all the other members of the German Neonatal Network.

Less invasive surfactant administration and preterm infants

We are grateful to the infants, parents and healthcare


providers who supported our study.

FUNDING
This study was supported by the German Ministry for
Education and Research (BMBF-grant-No: 01ER0805).

CONFLICT OF INTEREST
Dr. Herting and Dr. Groneck have worked on advisory
boards for surfactant-producing companies and companies
working in the field of neonatal ventilation. The other
authors have no conflict of interests to disclose.

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