Effect of Minimally Invasive Surfactant Therapy on Lung Volume

and Ventilation in Preterm Infants

Pauline S. van der Burg, MD, PhD1, Frans H. de Jongh, PhD1, Martijn Miedema, MD, PhD1, Inez Frerichs, MD, PhD2,
and Anton H. van Kaam, MD, PhD1

Objective To assess the changes in (regional) lung volume and gas exchange during minimally invasive surfactant
therapy (MIST) in preterm infants with respiratory distress syndrome.
Study design In this prospective observational study, infants requiring a fraction of inspired oxygen (FiO2) $0.30
during nasal continuous positive airway pressure of 6 cmH2O were eligible for MIST. Surfactant (160-240 mg/kg)
was administered in supine position in 1-3 minutes via an umbilical catheter placed 2 cm below the vocal cords.
Changes in end-expiratory lung volume (EELV), tidal volume, and its distribution were recorded continuously
with electrical impedance tomography before and up to 60 minutes after MIST. Changes in transcutaneous oxygen
saturation (SpO2) and partial carbon dioxide pressure, FiO2, respiratory rate, and minute ventilation were recorded.
Results A total of 16 preterm infants were included. One patient did not finish study protocol because of severe
apnea 10 minutes after MIST. In the remaining infants (gestational age 29.8
2.8 weeks, body weight 1545
481 g)
EELV showed a rapid and sustained increase, starting in the dependent lung regions, followed by the nondependent
regions approximately 5 minutes later. Oxygenation, expressed as the SpO2/FiO2 ratio, increased from 233 (IQR
206-257) to 418 (IQR 356-446) after 60 minutes (P < .001). This change was significantly correlated with the change
in EELV (r = 0.70, P < .01). Tidal volume and minute volume decreased significantly after MIST, but transcutaneous
partial carbon dioxide pressure was comparable with pre-MIST values. Ventilation distribution remained un-
changed.
Conclusions MIST results in a rapid and homogeneous increase in EELV, which is associated with an improve-
ment in oxygenation. (J Pediatr 2015;-:---).

R
espiratory distress syndrome (RDS) is the most common cause of respiratory failure in preterm infants.1,2 It is
characterized by structural immaturity of the lung and a lack of endogenous surfactant.3 Treatment consists of
respiratory support and exogenous surfactant. Until recently, surfactant was administered via an endotracheal
tube during mechanical ventilation; however, this mode of respiratory support is considered an important risk factor
for developing bronchopulmonary dysplasia, and for this reason, preterm infants are managed increasingly on nasal
continuous positive airway pressure (nCPAP) directly after birth.4,5 Recent studies have therefore investigated less-
invasive methods for surfactant therapy via the use of a semirigid or flexible catheter placed just below the vocal cords
to administer surfactant during spontaneous breathing on noninvasive respiratory support.6-8 The results of this so-
called minimally invasive surfactant therapy (MIST) have been promising, demonstrating less need for mechanical venti-
lation and shorter duration of oxygen therapy.9,10
The effect of exogenous surfactant on lung function during invasive mechanical ventilation has been studied extensively in
animal models11-13 and preterm infants.14-16 The most prominent and consistent finding in these studies is a surfactant-
induced increase in end-expiratory lung volume (EELV), resulting in an improved oxygenation. Studies in animals and humans
also have shown that this increase in EELV after surfactant treatment favors the dorsal (dependent) lung regions, suggesting a
gravity-dependent distribution of exogenous surfactant.15,17 Whether these effects on EELV also are applicable to MIST
remains unclear, because to date only one study, performed in animals, has
investigated the effect of MIST on lung function, but this study did not explore
the impact on EELV.18
From the 1Department of Neonatology, Emma Children’s
Hospital, Academic Medical Center, Amsterdam, The
Netherlands; and 2Department of Anesthesiology and
Intensive Care Medicine, University Medical Center
AU Arbitrary unit nCPAP Nasal continuous positive airway Schleswig-Holstein, Campus Kiel, Kiel, Germany

EELV End-expiratory lung volume pressure Supported by Chiesi Pharmaceutical, Rijswijk, The
Netherlands. The EIT device was provided by
DEELV Relative changes in EELV RDS Respiratory distress syndrome CareFusion, Yorba Linda, CA. I.F. has received
EIT Electrical impedance tomography SpO2 Transcutaneous oxygen saturation reimbursement for congress and travel expenses and
speaking fees from Dra €ger and Swisstom. A.v.K. has
fEIT Functional electrical impedance TcPCO2 Transcutaneous partial carbon received travel expenses and speaking fees from
tomography dioxide pressure CareFusion, Yorba Linda, CA. The other authors declare
no conflicts of interest.
FiO2 Fraction of inspired oxygen DZ Impedance changes
MIST Minimally invasive surfactant 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All
therapy rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2015.11.035

1
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Therefore, we measured the changes in lung volume and its
distribution before, during, and after MIST in preterm in-
fants with RDS, using electrical impedance tomography
(EIT). EIT is a noninvasive, radiation-free tool that measures
(regional) changes in impedance in a cross-sectional slice of
the lung, which correlate well with actual changes in aeration
and are representative for the changes in the whole lung in
preterm infants.19,20 We hypothesized that MIST would
lead to an increase in EELV favoring the more dependent
lung regions.
Methods
The prospective observational study was performed in the
level III neonatal intensive care unit of the Emma Children’s
Hospital, Academic Medical Center (Amsterdam, The
Netherlands). Preterm infants were considered eligible for
MIST if they fulfilled all of the following criteria: (1) gesta-
tional age $26 weeks; (2) birth weight of $750 g; (3) fraction
of inspired oxygen (FiO2) $0.30 while supported with a
nCPAP of 6 cmH2O; (4) clinical and radiological signs of
RDS; and (5) adequate respiratory drive. All infants with a
gestational age <28 weeks received prophylactic caffeine
treatment started within the first hour after life. Infants
receiving MIST were included in the study if the procedure
was performed within 72 hours after birth and written
informed consent was obtained from both parents. The study
was approved by the institutional review board.
The protocol was based on the MIST procedure described
by G€ opel et al.9 Infants were placed in supine position. With
the use of a laryngoscope and a Magill forceps, a marked 3.5-5
Fr catheter was placed 2 cm below the vocal cords and, based
on the whole content of a vial, a dose of 160-240 mg/kg
porcine-derived surfactant (Curosurf; Chiesi Pharmaceuti-
cals, Parma, Italy) was administered slowly (1-3 minutes).
During the pilot phase of implementation, a considerable
proportion of infants showed loss of surfactant via the nose
and mouth. For this reason, we decided to administer surfac-
tant under continuing visual inspection of the vocal cords to
avoid reflux of surfactant as much as possible. nCPAP was
continued during this procedure. After surfactant adminis-
tration, the infants were placed in supine 12 reverse Trende-
lenburg position for 60 minutes. Transcutaneous oxygen
saturation (SpO2) values were targeted between 86% and
94% throughout the study.
Patient characteristics, including gestational age, birth
weight, Apgar scores, and postnatal age at MIST, were
collected. In addition, nCPAP settings, FiO2, heart rate,
SpO2, and transcutaneous partial carbon dioxide pressure
levels (TcPCO2) were recorded throughout the study.
Lung impedance changes (DZ) were measured continu-
ously from 10 minutes before until 60 minutes after the
MIST procedure. Sixteen hand-trimmed electrodes (Blue
Sensor, BRS-50-K; Ambu Inc, Linthicum Heights, Mary-
land) were placed equidistantly on the thorax circumfer-
2 van der Burg et al
Vol. -, No. -
ence, just above nipple line and connected to the
Goettingen Goe-MF II EIT system (CareFusion, Yorba
Linda, California). Repetitive electrical currents (5 mA,
100 kHz) were injected cyclically (scan rate 13 Hz) through
adjacent electrode pairs. Voltage changes were registered in
all other passive electrode pairs. A back-projection algo-
rithm generated a series of 32  32-pixel matrices of relative
DZ by comparing these voltage changes to a reference
period. DZ values were recorded with a custom-designed
Polybench-based software package (Applied Biosignals,
Weener, Germany).
Analyses
EIT data analysis was performed off-line with AUSPEX
version 1.6 (VUmc, Amsterdam, The Netherlands). The
change in EELV was calculated by selecting a stable 30-
second period just before the start of the MIST procedure,
which was used as reference. Next, the relative DZ at the
troughs of the breaths in the stable 30-second was used
to calculate the relative changes in EELV (DEELV) in arbi-
trary units (AUs) after MIST, by comparing it with the
average DZ at the troughs at 5-minute intervals during
the first 60 minutes after surfactant administration. The
DEELV were then normalized for body weight, expressed
in AU/kg.
The same 30-second recordings used for DEELV analysis
also were used for calculating changes in EIT-derived tidal
volume; however, tidal volume changes at each time point
were now referenced to the average DZ in that same interval.
The EIT waveforms of relative DZ values were band-pass
filtered in the band of spontaneous breathing rate (10/min
below the actual breathing frequency and 10/min above its
second harmonic). The peak and trough signal values were
identified and averaged over the selected period. The average
amplitude was normalized for body weight.
Regional (tidal) ventilation distribution of the sponta-
neous breaths was assessed by means of functional EIT
(fEIT) images. fEIT images were generated by calculating
the SD of the impedance waveforms in each individual pixel
within the 32  32-pixel matrix. A ventilation profile was
derived from each fEIT image showing the distribution of
ventilation in 32 anteroposterior slices, as described previ-
ously.11 Subsequently, the areas under the curve for the ante-
rior (slice 1-16) and posterior (slice 17-32) regions were
calculated. Finally, the geometrical center of ventilation was
determined as an additional measure describing the ventila-
tion distribution in relation to the ventral-to-dorsal chest
diameter, as described previously.11,21
Statistical analysis was performed with GraphPad Prism
5.0 (GraphPad Software Inc, San Diego, California) and
SPSS version 20.0 (SPSS Inc, Chicago, Illinois). Data were ex-
pressed as mean with SD or median with IQR, as appropriate.
Comparative analysis was performed with the Friedman test
for repeated measures for skewed data and one-way ANOVA
for repeated measures for normally distributed data, followed
by post hoc testing. Correlations were expressed as Spearman
- 2015 ORIGINAL ARTICLES

correlation coefficient (r). A P value of <.05 was considered TcPCO2 slowly decreased, reaching presurfactant values at
statistically significant. t = 30 minutes (Table II). The regional distribution of
(tidal) ventilation was more anteriorly oriented as
indicated by the area under the curve of the anterior lung
Results region and geometric center of ventilations, and this did
not change after MIST (Table II).
We included 16 patients in the study; 1 patient did not com-
plete the study protocol because of severe apnea 10 minutes
after MIST (Table I). All patients received a nCPAP of 6 Discussion
cmH2O at the start of the MIST procedure, and this
remained unchanged during the study period. MIST results in a rapid improvement of the EELV, starting
EELV showed a rapid increase after MIST (Figure 1, A). in the dependent lung regions and thereafter spreading to
At a regional level, the increase in EELV first started in the nondependent regions. Furthermore, this increase in
the dorsal dependent lung regions followed by the ventral EELV is associated with a significant increase in oxygena-
non-dependent regions approximately 5 minutes later tion. The effect of surfactant administration via an endotra-
(Figure 1, B). Although the median increase in EELV after cheal tube during both conventional and high-frequency
60 minutes was greater in the dorsal (22.9, IQR 7.2-25.7 AU/ ventilation on EELV has been studied extensively in preterm
kg) compared with the ventral regions (12.5, 5.9-24.7 AU/ infants. Surfactant increases EELV and, furthermore, this ef-
kg), this difference was no longer statistically significant. fect is most prominent in the dependent lung regions, sug-
There were no significant differences between DEELV in the gesting a gravity-dependent distribution15,23; however,
right and the left lungs (data not shown). there are fundamental differences between MIST and surfac-
The rapid increase in EELV was accompanied by a rapid tant treatment during mechanical ventilation, such as a
and significant decrease in FiO2 from a median value of slower rate of surfactant infusion and the absence of positive
0.40 (0.35-0.45) before to 0.21 (0.21-0.24) after MIST pressure inflations during MIST, which may impact surfac-
(Table II). SpO2 was stable throughout this first hour, and tant distribution and its effect on EELV.24 The present study
the SpO2/FiO2 ratio22 improved significantly starting shows that MIST also leads to an increase in EELV, starting
5 minutes after surfactant administration (Figure 2, A). At at the time of surfactant infusion and stabilization within
the time of the most pronounced improvement in 5 minutes after administration. This improvement in
oxygenation (t = 5 min), the SpO2/FiO2 ratio and global EELV is very similar to surfactant administration via an
impedance signal were strongly correlated (r: 0.70, P < .01; endotracheal tube during mechanical ventilation.15 EIT
Figure 2, B). Regional tidal volume showed a rapid also allowed us to determine the regional changes in EELV
decrease immediately after surfactant administration, and during MIST, showing that the increase in EELV initially
respiratory rate remained stable. This resulted in a starts in the dependent dorsal lung regions. This finding sug-
significant decrease in minute volume and a concomitant gests a gravity-dependent distribution of surfactant during
increase in the TcPCO2 (Table II). During the remaining MIST, which is, again, comparable with a report on surfac-
60 minutes after surfactant administration both tidal tant treatment during mechanical ventilation15; however, in
volume and minute volume remained stable, but the contrast to this report, EELV also increased in the nonde-
pendent ventral lung regions, lagging approximately 5 mi-
nutes behind the dorsal lung regions. This resulted in a
relatively homogeneous effect of MIST on EELV 60 minutes
Table I. Patient characteristics after surfactant administration.
It is unclear why the effect of surfactant on EELV seems to
Subject no. GA, wk BW, g 5-min Apgar score Age, h
be more homogeneous during MIST compared with admin-
1 29.9 1335 9 6 istration via an endotracheal tube during mechanical ventila-
2 28.1 1325 8 3
3 28.0 1150 8 13 tion. Possible factors that may play a role in explaining this
4 29.0 1385 8 5 difference are the presence of spontaneous negative pressure
5 28.1 1055 8 4 breathing and the slow infusion rate of surfactant during
6 29.4 1465 7 7
7 31.7 1730 9 24 MIST, although studies in animals suggest that the latter
8 31.7 1735 9 26 will only worsen and not improve surfactant distribution24;
9 29.9 1295 8 7 however, it is important to realize that the animals in these
10 36.4 2636 9 13
11 25.6 925 8 54 studies were mechanically ventilated and not spontaneously
12 33.7 2425 9 10 breathing as during MIST. The authors of an animal-based
13 32.0 1965 6 5 study assessed surfactant distribution more directly
14 29.0 1358 8 9
15 27.6 1390 7 3 by administering labeled surfactant during both MIST and
Median 29.4 1385 8 7 conventional ventilation.18 Unfortunately, this study only re-
IQR 28.1-29.7 1310-1732 8-9 5-13 ported the distributions between the right and left lungs
BW, body weight; GA, gestational age. across the craniocaudal axis and not the gravity-dependent

Effect of Minimally Invasive Surfactant Therapy on Lung Volume and Ventilation in Preterm Infants 3
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. -, No. -

Figure 1. EELV changes directly after surfactant administration is completed (End SF) and at time points 1, 5, 30, and 60 minutes
after the end of surfactant administration, relative to before MIST. A, Global DEELV and B, DEELV in ventral (striped boxes) and
dorsal (dotted boxes) lung regions. The median, 25th and 75th percentiles, and minimum and maximum values are shown.
*
P < .05, **P < .001, ***P < .0001. SF, surfactant.

ventral-to-dorsal axis, which makes it difficult to compare
these results with the present study in preterm infants.
The rapid improvement in oxygenation after MIST
is consistent with previous studies in animals and
humans.7,8,10,18 To explore the hypothesis that this improve-
ment in oxygenation was, in part, mediated through the in-
crease in EELV, we determined the correlation between
these 2 variables at the time point when the relative changes
were most pronounced. The significant correlation supports
this hypothesis.
The regional tidal volume immediately after MIST was
lower compared with before surfactant administration.
This also resulted in a reduced minute volume and an in-
crease in TcPCO2. This reduction in ventilation is probably
caused by accumulation of a relatively high dose of surfactant
in the airways, resulting in an increased resistance and a sub-
sequent decrease in tidal volume. Moreover, because of con-
stant visualization of the glottis during the procedure, the
transmission of nasal pressure to the distal airways might
have been reduced. Surprisingly, the tidal volume and minute
volume 60 minutes after MIST also were significantly lower
than presurfactant values.
Several studies have shown that surfactant treatment
during mechanical ventilation results in an improved
compliance of the respiratory system.14,15,25-27 Assuming
this is also the case during MIST, one might expect an in-
crease rather than a decrease in tidal and minute volume.
However, it is important to realize that infants subjected to
MIST are spontaneously breathing and therefore in full
control of ventilation. The fact that CO2 returned to pre-
surfactant values 30 minutes after MIST, and tidal and
minute volumes were significantly lower, suggests that
alveolar ventilation improved after MIST. In response to
this improvement infants may have reduced their tidal
and minute volume by generating less (negative) transpul-
monary pressures.
Before MIST, the distribution of (tidal) ventilation along
the anteroposterior axis was more prominent in the ventral
(nondependent) than the dorsal (dependent) lung regions.
This finding is consistent with other studies investigating
preterm infants in their acute phase of RDS.15,22 MIST did
not change this ventilation distribution pattern suggesting,
similar to the EELV findings, a relatively homogeneous dis-
tribution of surfactant in the lungs.

Table II. Ventilation and oxygenation parameters

Before SF End SF t = 30 min t = 60 min
1
RR, min 71
16 73
34 67
19 77
16
VT, AU/kg* 6.4 (3.9-9.0) 3.3 (2.3-9.8) 3.4 (2.5-6.7)† 3.5 (2.8-5.0)†
MV (AU/kg/min)* 434 (297-562) 300 (161-494) 259 (200-329)z 256 (227-384)†
SpO2, %* 92 (89-95) 97 (89-99) 93 (89-95) 92 (88-95)
FiO2, %* 0.40 (0.35-0.45) 0.53 (0.43-0.76) 0.25 (0.22-0.29)† 0.21 (0.21-0.24)z
TcPCO2, kPa 7.8
1.3 8.8
1.9† 7.9
1.6 7.5
1.7
AUCant, % 55.5
7.7 58.3
10.1 57.5
9.0 54.6
8.0
CoV, % 47.1
4.6 45.0
6.6 46.0
4.9 47.7
4.4

AUCant, area under the curve of the anterior lung region; Before SF, time point before SF administration is started; CoV, geometric center of ventilations; End SF, time point when SF administration is
completed; MV, minute volume; RR, respiratory rate; SF, surfactant; t = 30 min, time point 30 minutes after SF administration is completed; VT, tidal volume.
Data are presented as mean
SD or median (IQR 25-75) when stated differently (*). Comparative analyses between groups are performed with one-way ANOVA for repeated measures or Friedman
test for repeated measures when appropriate.
†Indicates a significant change compared to Before SF, P < .05.
zIndicates a significant change compared to Before SF, P < .001.

4 van der Burg et al

- 2015 ORIGINAL ARTICLES

Figure 2. A, SpO2/FiO2 directly after surfactant administration is completed (End SF) and at time points 1, 5, 30, and 60 minutes
after the end of surfactant administration, relative to before MIST. B, Correlation between changes in SpO2/FiO2 and DEELV at
t = 5 minutes after surfactant administration is completed, Spearman correlation coefficient (r) is shown. Median, 25th and 75th
percentiles, and minimum and maximum values are shown. *P < .01, ***P < .0001.

This study has several limitations. First, we did not
include a control group not treated with MIST. We there-
fore cannot exclude the possibility that the changes in
EELV and oxygenation are the result of spontaneous
improvement in lung condition over time. However, we
feel this is very unlikely considering the age of the infants
at the time of MIST and the rapid and acute onset of lung
distribution compared with surfactant administration via
an endotracheal tube. However, this needs be confirmed by
studies performing a direct comparison between these 2
modes of surfactant delivery. n
Submitted for publication Aug 20, 2015; last revision received Oct 12, 2015;
accepted Nov 11, 2015.

volume changes after MIST. Because our study also did
not include a control group receiving surfactant via an
endotracheal tube, we were only able to compare our re-
sults with a previous study in a similar population
receiving exogenous surfactant via an endotracheal tube.
Second, this study only included preterm infants with a
gestational age >26 weeks. At the time of implementation,
the efficacy of MIST was only proven in this population.9
Although unlikely, we cannot rule out that the results of
our study might be different in preterm infants with a
gestational age <26 weeks. Third, EIT only measures rela-
tive and not absolute changes in lung volumes because
calibration in spontaneously breathing preterm infants
on nCPAP is not feasible; however, this does not compro-
mise the validity of our findings, because the focus of this
study was not on the absolute but on the relative changes
in lung volumes. Furthermore, the concomitant improve-
ment in oxygenation clearly indicates that the changes in
EELV were clinically relevant. Finally, minor variation in
how the MIST procedure is performed, may impact the
magnitude of the treatment effects reported in this study.
This study provides information on the physiological ef-
fects of MIST on lung volumes and gas exchange. The clini-
cian can use this knowledge to assess the effect of MIST and
to adjust the level of respiratory support. Second, it provides
convincing arguments that, from a physiological standpoint,
MIST is a good alternative to conventional surfactant treat-
ment during mechanical ventilation. It even suggests that
MIST might result in a more homogenous surfactant
Reprint requests: Pauline S. van der Burg, MD, PhD, Department of
Neonatology (H3-146), Emma Children’s Hospital AMC, P.O. Box 22660, 1100
DD Amsterdam, The Netherlands. E-mail: p.s.burgvander@amc.uva.nl
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