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REGULAR ARTICLE
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
241
pel et al.
Go
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
Restricted to 966 control infants and 963 LISA infants with data.
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
2014 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 241246
pel et al.
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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).
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
2014 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 241246
243
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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.
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,
2014 Foundation Acta Pdiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 241246
pel et al.
Go
ACKNOWLEDGEMENTS
The authors of this paper acknowledge the contributions of
all the other members of the German Neonatal Network.
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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