1. Dosing of Porcine Surfactant: Effect on Kinetics and Gas Exchange in Respiratory
Distress Syndrome
Paola Elisa Cogo, Maddalena Facco, Manuela Simonato, Giovanna Verlato, Clementina
Rondina, Aldo Baritussio, Gianna Maria Toffolo and Virgilio Paolo Carnielli
Pediatrics 2009;124;e950-e957; originally published online Oct 12, 2009;
DOI: 10.1542/peds.2009-0126
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2. Dosing of Porcine Surfactant: Effect on Kinetics and
Gas Exchange in Respiratory Distress Syndrome
WHAT’S KNOWN ON THIS SUBJECT: Multiple surfactant doses
versus a single dose and porcine surfactant doses of 200
versus 100 mg/kg seem to be more effective in infants with
RDS. Little is known regarding surfactant pharmacokinetics in
human patients with RDS.
WHAT THIS STUDY ADDS: We report exogenous surfactant DSPC
pharmacokinetics in 61 infants who received 100 or 200 mg/kg
porcine surfactant as treatment for RDS. The dose of 200 mg/kg
was associated with a longer DSPC half-life, fewer retreatments, and
better oxygenation index values.
abstract
OBJECTIVE: The goal was to study exogenous surfactant disaturated
phosphatidylcholine (DSPC) kinetics in preterm infants with respiratory distress syndrome (RDS) who were treated with 100 or 200 mg/kg
porcine surfactant.
METHODS: Sixty-one preterm infants with RDS undergoing mechanical ventilation received, within 24 hours after birth, 100 mg/kg
(N ϭ 40) or 200 mg/kg (N ϭ 21) porcine surfactant mixed with
[U-13C]dipalmitoylphosphatidylcholine. Clinical and respiratory parameters were recorded, and DSPC half-life and pool size and endogenous DSPC synthesis rate were calculated.
RESULTS: Clinical characteristics and short-term outcomes did not
differ between groups. In the 100 mg/kg group, 28 infants (70%) received a second dose after 25 Ϯ 11 hours and 9 (22.5%) a third dose
after 41 Ϯ 11 hours; in the 200 mg/kg group, 6 infants (28.6%) received
a second dose after 33 Ϯ 8 hours and 1 a third dose. The DSPC half-life
was longer in the 200 mg/kg group (first dose: 32 Ϯ 19 vs 15 Ϯ 15
hours [P ϭ .002]; second dose: 43 Ϯ 32 vs 21 Ϯ 13 hours [P ϭ .025]).
DSPC synthesis rates and pool sizes before the first and second doses
did not differ between the groups. The 200 mg/kg group exhibited a
greater reduction in the oxygenation index than did the 100 mg/kg
group after the first (P ϭ .009) and second (P ϭ .018) doses.
AUTHORS: Paola Elisa Cogo, MD, PhD,a Maddalena Facco,
MD,a Manuela Simonato, PhD,a Giovanna Verlato, MD,
PhD,a Clementina Rondina, MD,b Aldo Baritussio, MD,c
Gianna Maria Toffolo, PhD,d and Virgilio Paolo Carnielli,
MD, PhDb
Departments of aPediatrics, cMedical and Surgical Sciences, and
dInformation Engineering, University of Padua, Padua, Italy; and
bNeonatal Division, Institute of Maternal-Infantile Sciences,
Polytechnic University of Marche and University Hospital of
Ancona, Ancona, Italy
KEY WORDS
pulmonary surfactant, isotopes, low birth weight infants,
respiratory distress syndrome
ABBREVIATIONS
DSPC— disaturated phosphatidylcholine
RDS—respiratory distress syndrome
DPPC— dipalmitoylphosphatidylcholine
FIO2—fraction of inspired oxygen
MAP—mean airway pressure
TTR—tracer/tracee ratio
www.pediatrics.org/cgi/doi/10.1542/peds.2009-0126
doi:10.1542/peds.2009-0126
Accepted for publication Jun 5, 2009
Address correspondence to Paola Elisa Cogo, MD, PhD,
Department of Pediatrics, University of Padua, Via Giustiniani 3,
Padua 35128, Italy. E-mail: cogo@pediatria.unipd.it
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2009 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Carnielli received a fee for
speaking at an educational event sponsored by Dey
Laboratories (Napa, CA) and received funds for research from
Chiesi Pharmaceuticals (Parma, Italy).
CONCLUSIONS: Porcine surfactant given to preterm infants with RDS
at a dose of 200 mg/kg resulted in a longer DSPC half-life, fewer retreatments, and better oxygenation index values. Pediatrics 2009;124:
e950–e957
e950
COGO et al
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3. ARTICLES
The alveolar pool of surfactant in newborns with respiratory distress syndrome (RDS) does not differ much
from the alveolar pool in adults without respiratory disease.1 Without
surfactant supplementation, however,
newborns with RDS develop severe respiratory failure, possibly through a
combination of mechanisms including
altered surfactant composition, lung
structural immaturity, and increased
surfactant inactivation.2
Dosages and modes of administration
of exogenous surfactant have been
studied mostly in animal models.3–5 For
example, in premature lambs treated
with natural sheep surfactant at doses
of 19, 53, 64, or 173 mg/kg, pressurevolume curves improved progressively
up to a dose of 64 mg/kg but no further
gain was observed with the administration of 173 mg/kg.3 Information on
the effect of exogenous surfactant dosing in human subjects is limited. In a
study by Halliday et al,6 cumulative
doses of exogenous surfactant up to
600 mg/kg were no better than 300
mg/kg. Other studies with newborn infants compared different doses of surfactant in the range of 50 to 200 mg/
kg.7–12
Four studies compared beractant
(Survanta [Abbott Laboratories, Abbott Park, IL]) administered at 100
mg/kg and poractant ␣ (Curosurf
[Chiesi Pharmaceuticals, Parma, Italy]) administered at either 100 or 200
mg/kg to infants with moderate/severe RDS.8,11,13,14 Poractant ␣ was found
to have a more-rapid onset of action
and was associated with lower neonatal mortality rates. However, the reduction in mortality rates was not statistically significant when poractant ␣
and beractant at the initial dose of 100
mg/kg were compared, which suggests that the most significant effects
on mortality rates were seen when 200
mg/kg poractant ␣ was compared
with 100 mg/kg beractant or poractant
TABLE 1 Clinical Characteristics of Study Infants
200 mg/kg
(N ϭ 21)
Birth weight, mean Ϯ SD, g
Gestational age, mean Ϯ SD, wk
Prenatal steroid treatment, n (%)
Full steroid treatment, n (%)
Delivery through cesarean section, %
Patent ductus arteriosus, %
Age at study start, mean Ϯ SD, h
FIO2 before first surfactant dose, mean Ϯ SD
MAP before first surfactant dose, mean Ϯ SD, cmH2O
Oxygenation index before first surfactant dose, mean Ϯ SD
␣.15 Data suggest that, for infants with
moderate/severe RDS, a porcine surfactant dose of 200 mg/kg may be
more effective than 100 mg/kg.8,11,13,14
After the first surfactant dose, irrespective of the amount administered,
some neonates respond to treatment
only transiently and require further
surfactant administration. A recent
meta-analysis comparing single versus multiple surfactant doses for preterm infants with established RDS
showed greater improvements in
oxygenation and ventilatory requirements, a decreased risk of pneumothorax, and a trend toward improved
survival rates for infants who received
multiple surfactant doses.16 When the
retreatment should be performed is
still unclear. In clinical practice, some
neonatologists prefer to retreat their
patients after a fixed time, whereas
others choose to retreat them if their
respiratory function deteriorates.17
It is likely that better knowledge of the
pharmacokinetic features of exogenous surfactant in RDS could help to
optimize the treatment of preterm infants. Few studies, with small numbers
of infants, have been published.18–20
In this study, we administered to newborns with RDS 100 or 200 mg/kg porcine surfactant mixed with 13C-labeled
dipalmitoylphosphatidylcholine (DPPC),
and we measured exogenous surfactant kinetics by analyzing the isotopic
enrichment of disaturated phosphatidylcholine (DSPC) isolated from tra-
100 mg/kg
(N ϭ 40)
P
1058 Ϯ 413
28.4 Ϯ 2.6
17 (80.9)
10 (47.6)
61.9
73.7
3.7 Ϯ 2.9
0.50 Ϯ 0.20
8.5 Ϯ 2.5
9.2 Ϯ 7.0
1110 Ϯ 429
28.9 Ϯ 2.7
27 (67.5)
19 (47.5)
72.5
75.0
6.0 Ϯ 5.8
0.54 Ϯ 0.20
8.2 Ϯ 2.1
9.5 Ϯ 6.6
.65
.46
.45
.93
.40
.36
.09
.45
.58
.86
cheal aspirates.16–18 Apart from their
safety,21 stable isotopes have the advantage that their enrichment is not
affected by sample dilution. From the
enrichment curves, we derived the
surfactant pool size at the time of dosing, the rate of endogenous surfactant
synthesis, and the half-life of administered exogenous surfactant.
METHODS
Patients and Study Design
We studied 61 newborn infants with
RDS who were admitted to the NICU of
the Department of Pediatrics, University of Padua, or the Division of Neonatology of the Polytechnic University of
Marche (Ancona, Italy). Infants were
recruited if they required synchronized intermittent mandatory ventilation and received exogenous surfactant within the first 24 hours of life. The
study protocol was approved by the
ethics committees of both institutions,
and written informed consent was obtained from both parents. The study
lasted from 2000 to 2004.
Newborns with congenital malformations, sepsis, or renal or liver failure
were excluded from the study. The diagnosis of RDS was based on clinical
data and on chest radiograms,22 after
exclusion of infections. All infants,
whose clinical characteristics are reported in Table 1, received either 100
or 200 mg/kg porcine surfactant (Curosurf [Chiesi]) as rescue treatment
for RDS. Administered surfactant
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e951

4. doses were labeled with 2.5 mg/kg
[U-13C-palmitic acid]DPPC (Martek Biosciences, Columbia, MD) per dose as
tracer. [U-13C-palmitic acid]DPPC was
suspended in normal saline solution23
and was mixed with the exogenous
surfactant during surfactant preparation. The choice of surfactant dosing
was at the discretion of the attending
neonatologists, who were blinded to
laboratory and kinetic results.
The indications for surfactant treatment were a fraction of inspired oxygen (FIO2) of Ͼ0.40 and a mean airway
pressure (MAP) of Ͼ7.5 cm H2O. Surfactant was administered as a bolus
through a small catheter inserted
through the endotracheal tube. After
the procedure, the neonates were reconnected to the mechanical ventilator at pretreatment settings. The mode
of ventilation at the beginning of the
study period was standardized, with
an inspiratory time of 0.3 to 0.5 seconds, an initial respiratory rate of 50 to
65 breaths per minute, and a positive
end expiratory pressure of 3 to 4
cm H2O. Peak inspiratory pressure and
FIO2 were adjusted so that PaO2 was between 50 and 70 mm Hg, oxygen saturation was Ͼ88% but Ͻ96%, and PaCO2
was between 40 and 50 mm Hg. Ventilatory parameters were recorded before the start of the study and then every 6 hours. The oxygenation index was
calculated as follows: oxygenation index ϭ [(MAP ϫ FIO2)/PaO2] ϫ 100. Tracheal aspirations were performed as
described previously,20 and samples
were collected before administration
of the first dose of surfactant (time 0),
every 6 hours until 72 hours, and then
every 12 hours until extubation. Patients received additional surfactant
doses if FIO2 returned to Ͼ0.35 and
MAP was Ն7.5 cm H2O. On the basis of
our previous work20 and the policy of
the 2 participating neonatal units, retreatment was not given earlier than
18 hours after the previous dose une952
less there was a high index of suspicion regarding surfactant maldistribution, on the basis of clinical evidence or
radiologic findings.24
Analytical Methods
Lipids from tracheal aspirates and from
exogenous surfactant were extracted
according to the method described by
Bligh and Dyer,25 after addition of the
internal standard heptadecanoylphosphatidylcholine. One third of the extract
was oxidized with osmium tetroxide.26
DSPC was isolated from the lipid extract through thin-layer chromatography, after oxidation with osmium
tetroxide.26 DSPC fatty acids were derivatized27 as pentafluorobenzyl derivatives, extracted with hexane, and
stored at Ϫ20°C. A half-spot of exogenous surfactant DSPC was derivatized
as the methyl ester,28 and the amount
of DSPC was measured through gas
chromatography, as described previously.20 Tracheal aspirates with visible
blood were discarded.
The enrichment of [U-13C-palmitic acid]
DPPC from the tracheal aspirates was
measured through gas chromatographymass spectrometry in negative ionization mode, and results were expressed
in mole percent excess.20 The mole percent excess represents the increase in
the mole percentage of [U-13C]palmitic
acid above the baseline value obtained
at time 0 of the study.
Calculations
Data were analyzed under the following assumptions: (1) exogenous surfactant DSPC is distributed in the
alveolar pool and subsequently internalized and recycled by the type II cells;
(2) endogenous DSPC is synthesized by
lung parenchyma, secreted in the alveoli, and recycled before degradation;
(3) exogenous surfactant DSPC is distributed homogeneously in the lungs,
and the system is at steady state; and
(4) DSPC kinetics are linear. Under
these assumptions, DSPC kinetics can
be modeled conveniently on the basis
of the tracer/tracee ratio (TTR), that is,
the ratio of exogenous (tracer) to endogenous (tracee) DSPC.29,30 This variable is different from enrichment,
which measures the ratio of the labeled component of exogenous surfactant to unlabeled DSPC, originating
from both exogenous and endogenous
sources. Therefore, enrichment (E)
measured at time t was converted to
TTR by using the following formula (derived in the Appendix): TTR(t) ϭ E(t)[(EI ϩ
1)/[EI Ϫ E(t)]], where EI is the percentage of [U-13C-palmitic acid]DPPC with
respect to unlabeled DSPC in the administered surfactant dose, equal to
7 Ϯ 3%, on average. TTR data were fitted
to either a monoexponential or biexponential decay model (Fig 1), and DSPC
kinetic parameters were calculated as
follows. In the monoexponential model,
that is, TTR(t) ϭ AeϪKt, the DSPC halflife (in hours) is ln(2)/k, the DSPC pool
size (in milligrams per kilogram) is
dose/A, and the DSPC synthesis rate (in
milligrams per day per kilogram) is
(DSPC pool size ϫ k ϫ 24) ϭ [dose/(A/
k) ϫ 24]. In the biexponential model,
that is, TTR(t) ϭ A1eϪk1t ϩ A2eϪk2t,
the DSPC half-life (in hours) is ln(2)/k2,
the DSPC pool size (in milligrams per
kilogram) is dose/(A1 ϩ A2), and the
DSPC synthesis rate (in milligrams per
day per kilogram) is [dose/[A1/k1 ϩ
A2/k2]] ϫ 24. Dose (in milligrams per
kilogram) is the administered surfactant
DSPC dose, t is time (in hours), and, for
the biexponential model, k2 indicates
the rate constant of the slower component, responsible for the late portion
of TTR decay.
When data collected after administration of the second dose were analyzed,
equations were modified to account
for the contribution of the first dose.
For example, for the monoexponential
model, DSPC pool size is dose/(A Ϫ
COGO et al
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5. ARTICLES
A
3
2
First dose
Second dose
ln, TTR
1
0
0
24
48
72
96
120
144
168
-1
y = -0.0388x + 2.2823
R2 = 0.989
-2
-3
-4
B
Time, h
3
2
Second dose
First dose
ln, TTR
1
0
0
24
48
72
96
y = -0.0706x + 3.0278
R2 = 0.8891
-1
120
144
168
y = -0.0525x + 6.1915
R2 = 0.9767
-2
-3
C
Time, h
2
1
ln, TTR
0
-1
y = 2.9e-0.07x + 1.2e -0.02x- - 0.8
-2
-3
-4
-5
0
24
48
72
96
120
144
168
Time, h
FIGURE 1
Three typical surfactant DSPC kinetic patterns (semilogarithmic plots). A, The half-life of the first dose was not computable (Ͻ3 samples available before
the second dose). B, DSPC disappeared from the airways monoexponentially after 2 surfactant doses but with different slopes. C, DSPC disappeared from
the airways according to a biexponential decay.
TTRpre), where TTRpre is the TTR value
immediately before administration of
the second dose.
The derived DSPC pool size is an estimate of the amount of tracee (ie,
endogenous DSPC) present in the air-
ways during each surfactant administration and is designated as the DSPC
pool. DSPC kinetic parameters were
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e953

6. missing when DSPC decay curves had
Ͻ3 enrichment points, that is, too few
points for calculation of DSPC kinetics
(Fig 1A).
Data were expressed as mean Ϯ SD or
median and interquartile range, according to variable distribution, and
they were compared with independent
t tests or Mann-Whitney U tests for continuous variables and ␹2 tests for binary data. Statistical analyses were
performed with SPSS for Windows XP
15.00 (SPSS, Chicago, IL).
RESULTS
Surfactant DSPC pharmacokinetics
could be calculated reliably after 74
surfactant administrations to 61 infants who received Ն1 dose of exogenous surfactant. Forty infants were
treated with 100 mg/kg surfactant
(100 mg/kg group) and 21 with 200
mg/kg surfactant (200 mg/kg group),
at the discretion of the attending neonatologist. All first doses were administered within 24 hours after birth. The
2 groups were similar with regard to
all recorded clinical variables (Table
1). The study was conducted in 2 neonatal units, and the proportions of 200
mg/kg doses were 35% and 27% (not
significant). The average ventilator settings, including inspiratory time, did
not differ between the 2 units or between infants receiving 100 versus 200
mg/kg doses of exogenous surfactant.
In the 100 mg/kg group, a second surfactant dose was administered to 28 infants
(70.0%) after 25 Ϯ 11 hours, and a third
dose was administered to 9 infants
(22.5%) 41 Ϯ 11 hours after the second
dose. In the 200 mg/kg group, 6 infants
(28.6%) received a second dose after
33 Ϯ 8 hours, and only 1 received a third
dose. The interval between the first and
second doses tended to be longer in the
200 mg/kg group than in the 100 mg/kg
group, but the difference did not reach
statistical significance (Table 1). After
the first and second doses, infants ase954
TABLE 2 Surfactant Dose Effects on Oxygenation and Outcome Parameters
200 mg/kg
(N ϭ 21)
.59
.44
.81
Ͻ.01
.02
Ͻ.01
6.0 Ϯ 2.6
.02
33 Ϯ 8
DSPC enrichment could be measured in
all tracheal aspirates, but decay curves
with Ͼ2 enrichment points were obtained for 74 of the 99 surfactant doses.
In most cases, decay curves were monoexponential (Fig 1). Biexponential decay
was more frequent in the 200 mg/kg
group, without reaching statistical significance (43% vs 29% after the first
dose [P ϭ .3] and 43% vs 13% after the
second dose [P ϭ .15]). In the 200 mg/kg
group, DSPC kinetics were calculated for
10 Ϯ 10
82.5
44.1
70.0
192 Ϯ 73
6.9 Ϯ 5.4
3.2 Ϯ 1.5
signed to the 200 mg/kg group showed a
better oxygenation index, compared with
the 100 mg/kg group (Table 2). The 2
groups were not statistically different
with respect to duration of mechanical
ventilation, survival rates, rates of bronchopulmonary dysplasia (defined as oxygen dependency at 36 weeks), or rates
of the combination of death and bronchopulmonary dysplasia (P ϭ .860)
(Table 2).
P
12 Ϯ 13
90.0
52.9
28.6
250 Ϯ 89
4.0 Ϯ 1.9
Conventional ventilation, mean Ϯ SD, d
Survival, %
Bronchopulmonary dysplasia at 36 wk, %
Ͼ1 surfactant dose, %
Total surfactant dose, mean Ϯ SD, mg/kg
Oxygenation index after first surfactant dose,
mean Ϯ SD
Oxygenation index after second surfactant
dose, mean Ϯ SD
Interval between first and second doses,
mean Ϯ SD, h
100 mg/kg
(N ϭ 40)
25 Ϯ 11
.09
15 infants (71.4%) after the first dose
and 5 (83.3%) after the second dose. In
the 100 mg/kg group, DSPC kinetics were
calculated for 31 infants (77.5%) after
the first dose and 23 (82.1%) after the
second dose.
The DSPC pool sizes were similar in the
100 and 200 mg/kg groups during the
first and second surfactant administrations (Table 3). The DSPC half-life
was significantly longer in the 200
mg/kg group after both the first and
second doses, whereas endogenous
surfactant DSPC synthesis rates
were similar in the 2 groups (Table
3). DSPC kinetic variables did not
seem to be influenced by the mode of
TTR decay (ie, monoexponential versus biexponential).
DISCUSSION
Exogenous surfactant therapy is a cornerstone of modern neonatology, be-
TABLE 3 DSPC Half-Life, Endogenous DSPC Pool Size, and Synthesis Rate for Preterm Newborns
Treated With 200 or 100 mg/kg Porcine Surfactant Extract
200 mg/kg (N ϭ 21)
DSPC half-life, mean Ϯ SD, h
First dose
Second dose
Third dose
Endogenous DSPC pool size, median
(interquartile range), mg/kg
First dose
Second dose
DSPC synthesis, median (interquartile range),
mg/kg per d
First dose
Second dose
100 mg/kg (N ϭ 40)
P
32 Ϯ 19 (n ϭ 15)
43 Ϯ 32 (n ϭ 5)
15 Ϯ 15 (n ϭ 31)
21 Ϯ 13 (n ϭ 23)
17 Ϯ 7 (n ϭ 7)
Ͻ.01
.02
5.3 (1–12.7) (n ϭ 15)
2.6 (0.7–18.5) (n ϭ 5)
2.5 (0.5–6.8) (n ϭ 31)
4.4 (1.2–16.1) (n ϭ 23)
.32
.67
4.8 (0.1–14.4) (n ϭ 15)
2.4 (1.7–5.8) (n ϭ 5)
7.2 (3.8–10.8) (n ϭ 31)
4.8 (2.2–13.4) (n ϭ 23)
.80
.35
COGO et al
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7. ARTICLES
cause it reduces mortality and morbidity rates for neonates with RDS.24
Current treatment schemes are derived from human and animal studies with very high doses of surfactant.3,5,7,8,11–13,17,31 Studies performed
with different animal species showed
that the amount of surfactant present
in the airways at birth is correlated
with the severity of RDS and that administered surfactant disappears with
a half-life of 4 to 12 hours.32–35 Little is
known about surfactant turnover in
premature newborns, and studies
measuring surfactant pools in this
population are limited.18–20 Furthermore, most clinical trials have been
performed with intention-to-treat analyses, and the effectiveness of different
dosing schemes remains unclear.
This report describes pharmacokinetics and clinical outcomes after the administration of 100 or 200 mg/kg poractant ␣ to preterm infants with
moderate/severe RDS. Stable-isotope
DSPC labeling of the administered surfactant dose allowed us to trace exogenous surfactant DSPC and to calculate the TTR, that is, the exogenous
(tracer)/endogenous (tracee) surfactant DSPC ratio. This variable is the most
convenient way to express data from experiments with stable isotopes. Pharmacokinetic parameters such as DSPC halflife, pool size (estimation of the alveolar
DSPC pool size), and synthesis rate can
be estimated easily by fitting a multiexponential model to TTR data and then
applying simple formulas to the model
parameters.
The main clinical findings of this study
were that the larger dose had a longer
half-life and that newborns receiving it
needed fewer additional doses and
had better oxygenation index values.
There were no differences in durations
of mechanical ventilation, mortality
rates, or development of bronchopulmonary dysplasia. The cumulative
dose of exogenous surfactant was sig-
nificantly greater in the 200 mg/kg
group, but the 100 mg/kg group required more redosing, in agreement
with data by Ramanathan et al.11 In
both groups, the alveolar surfactant
DSPC level was on the order of 2.5 to 5
mg/kg, which is markedly lower than
that found in mature newborns.36 The
DSPC pool in preterm newborns with
RDS during the first day of life ranged
from 1 to 15 mg/kg,20 whereas term
infants without RDS have 3 times that
value.36 In this study, for both groups of
newborns, the pool of DSPC was Ͻ6
mg/kg (median) before the first dose
and Ͻ5 mg/kg before the second dose.
Therefore, patients who needed a second dose had endogenous surfactant
DSPC pool values similar to those
found before the first dose, which suggests incomplete retention of the first
dose, high catabolic rates, or insufficient endogenous synthesis. Infants
who required a second dose had surfactant deficiency and were at risk of
mechanical and alveolar instability.31,37
Endogenous DSPC synthesis rates
were not different between our study
groups. It must be noted that this kinetic parameter represents only the
surfactant DSPC synthesized de novo,
is not affected by surfactant recycling,
and does not reflect other DSPC synthetic pathways. Among our infants,
the DSPC synthesis rates ranged between 2.4 and 7.2 mg/kg per day, which
suggests that preterm infants with
RDS need at least 3 or 4 days to accumulate adequate amounts of surfactant in their airways. These findings
are in agreement with previous estimates of DSPC synthesis obtained
through intravenous administration of
stable-isotope glucose and palmitate.
In those studies, the DSPC synthesis
rates ranged between 2.7 and 4.8
mg/kg per day among preterm infants
with respiratory failure who required
no surfactant or Ն1 dose of exogenous surfactant.38,39 Therefore, in RDS,
surfactant administration is needed to
compensate for slow de novo synthesis and to substitute for surfactant degraded or lost through the conducting
airways.
Little is known regarding exogenous
surfactant turnover in human RDS18–20
and, to the best of our knowledge, this
is the first time the half-life of exogenous surfactant has been measured in
preterm infants with RDS receiving 100
or 200 mg/kg doses of exogenous surfactant. We found that, after administration of 200 mg/kg, the half-life of administered surfactant was longer. This
difference is unlikely to be attributable
to heterogeneity of the study groups,
because all infants had received a single mode of ventilation (synchronized
intermittent mandatory ventilation)
from birth and patients with signs of
infection, such as increased white
blood cell and neutrophil counts, increased C-reactive protein levels, and
temperature instability, were excluded
prospectively from analyses.40
An interesting finding is that administered surfactant left the airways monoexponentially most of the time and
in a biexponential mode only in some
cases (Fig 1). This might have happened through several mechanisms.
For example, a slow rate of uptake of
administered material or a low rate of
de novo synthesis might have favored
a biexponential mode of decay. On the
whole, however, it seems that the kinetic differences between the 100
mg/kg group and the 200 mg/kg group
were not attributable to differences in
data fitting, because the distributions
of decay modes did not differ significantly between the 2 groups.
The major limitation of the present
study was that patients were not assigned randomly to the treatment
groups, because of different orientations regarding surfactant administration among attending neonatologists.
However, the 2 groups were well
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e955

8. matched with respect to all clinical parameters, respiratory disease severity, and DSPC pool sizes during the first
and second doses. Furthermore, to obtain reliable kinetic measurements,
we needed to collect tracheal aspirates for at least 18 to 24 hours. Therefore, our design might have favored
the selection of preterm infants with
intermediate to severe RDS. Studies
are needed to analyze DSPC kinetics in
infants with less-severe respiratory
failure and those receiving different
types of ventilatory support.
CONCLUSIONS
The present study compared the pharmacokinetics of different doses of porcine surfactant (100 or 200 mg/kg) in
preterm infants with moderate/severe
RDS. We found that, after administration of 200 mg/kg, the half-life of administered surfactant was longer, oxygenation was better, and the need for
redosing was reduced. Further studies
E͑t͒ ϭ
APPENDIX
The calculation of TTR from enrichment (E) measurements is described.
At any time t, the following equations
express TTR and E as functions of
[U-13C-palmitic acid]DPPC levels, coming from the surfactant dose (q), unlabeled DSPC levels, also coming from
the surfactant dose (Qexo), and endogenous unlabeled DSPC levels (Qendo):
q͑t͒ ϩ Q exo͑t͒
TTR͑t͒ ϭ
Q endo͑t͒
(2)
Dividing the left sides of eqs 1 and 2 by
Qexo(t) yields
TTR͑t͒ ϭ
EI ϩ 1
q͑t͒/Q exo͑t͒ ϩ 1
ϭ
Q endo͑t͒/Q exo͑t͒
Q endo͑t͒/Q exo͑t͒
(3)
EI
1 ϩ Q endo͑t͒/Q exo͑t͒
(4)
In eq 4, the result given in ref 29 was
used, namely, that the percentage of
[U-13C-palmitic acid]DPPC (q) with respect to exogenous DSPC (Qexo) remains constant in the system and
equal to the percentage (EI) of [U-13Cpalmitic acid]DPPC with respect to
DSPC in the administered surfactant
dose. Solving eq 4 for Qendo(t)/Qexo(t)
and substituting into eq 3 yields
TTR͑t͒ ϭ E͑t͒
(1)
q͑t͒
E͑t͒ ϭ
Q exo͑t͒ ϩ Q endo͑t͒
q͑t͒/Q exo͑t͒
1 ϩ Q endo͑t͒/Q exo͑t͒
ϭ
are in progress to explore the possibility that the higher dose also might lead
to earlier extubations and/or fewer
reintubations.
EI ϩ 1
E I Ϫ E͑t͒
(5)
which is the desired expression for TTR
in terms of E.
ACKNOWLEDGMENTS
This study was supported by laboratory core funds and by the Department
of Pediatrics, University of Padua, for 1
doctoral salary.
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e957

10. Dosing of Porcine Surfactant: Effect on Kinetics and Gas Exchange in Respiratory
Distress Syndrome
Paola Elisa Cogo, Maddalena Facco, Manuela Simonato, Giovanna Verlato, Clementina
Rondina, Aldo Baritussio, Gianna Maria Toffolo and Virgilio Paolo Carnielli
Pediatrics 2009;124;e950-e957; originally published online Oct 12, 2009;
DOI: 10.1542/peds.2009-0126
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