Keywords
dosage - preterm babies - respiratory distress syndrome - surfactant
Surfactant is the cornerstone of the treatment of respiratory distress syndrome (RDS)
in preterm infants. Treatment with surfactant has been shown to reduce the risk of
pulmonary morbidity (pneumothorax and pulmonary interstitial emphysema) and neonatal
mortality.[1]
[2]
[3] Mechanical ventilation is considered the single most important risk factor for the
development of bronchopulmonary dysplasia (BPD).[4] The clinical focus on avoiding mechanical ventilation and the care of infants of
less than 26 weeks' gestation has spurred new approaches of surfactant administration.[5]
Animal-derived surfactants differ in their concentration of phospholipids and surfactant
proteins, which may affect efficacy. There is evidence of the superiority of porcine
(poractant alfa) versus bovine (beractant, bovactant) surfactants with respect to
clinical outcomes, including mortality, the need for redosing, oxygen requirements,
duration of oxygen treatment, and duration of mechanical ventilation.[6]
[7]
[8]
[9]
[10] A survival advantage for the high dose (200 mg/kg) of poractant alfa to treat RDS
as compared with the low dose (100 mg/kg) and the 100 mg/kg/dose of beractant and
50 mg/kg/dose of bovactant has been reported.[10] Also, the 100 mg/kg/dose has been shown to be an independent predictor of surfactant
redosing.[11] In this sense, the 2016 update of the European Consensus Guidelines on the Management
of RDS[12] recommends the administration of poractant alfa in an initial dose of 200 mg/kg.
Early surfactant administration reduces failure of continuous positive airway pressure
(CPAP).[4] In a population-based study, failure of CPAP for initial respiratory management
in preterm infants occurred in 43% of those at <29 weeks' gestation and was associated
with adverse outcomes including death and other major morbidities.[13] Moreover, CPAP failure usually occurs because of unremitting RDS and is predicted
by the need of a FiO2 ≥ 0.3 in the first hours of life.[14]
Despite clinical and pharmacokinetic data supporting the dose of poractant alfa of
200 mg/kg,[11]
[12]
[15] real-world studies have brought attention to the fact that the correct dose is not
often given as clinicians may be tempted to administrate a rounded dose to the vial
content.[16]
[17]
[18] To further explore everyday clinical practices in neonatal intensive care units
(NICUs) regarding the optimal dosing of surfactant, in an effort to ensure high standards
of newborn care, a retrospective cohort study was designed. The objective of the study
was to evaluate the initial dose of surfactant used in preterm infants with RDS.
Materials and Methods
Study Design and Participants
A multicenter, retrospective cohort study was performed in four level III NICUs in
Spain. The primary objective of the study was to evaluate the mean initial dose of
surfactant administered to preterm infants diagnosed with RDS. Secondary objectives
were (1) to assess the total number of doses of surfactant, (2) to determine the percentage
of patients treated with the initial dose of poractant alfa of 200 mg/kg ± 10%, and
(3) to describe adverse events and short-term respiratory outcomes.
Between January 1, 2013, and December 31, 2015, all preterm babies (gestational age < 37
weeks) with clinical symptoms of RDS receiving surfactant were eligible for the study.
By protocol, in all four participating hospitals, the initial surfactant dose prescribed
was 200 mg/kg in accordance with the recommendations of the 2013 European Consensus
Guidelines on the Management of RDS.[19] The availability of a minimal dataset in clinical records, including gestational
age, birth weight, FiO2 before surfactant administration, and total actual dose of surfactant received in
mg or mL as the initial treatment, was required for inclusion in the study. The study
protocol complied with all the relevant national regulations and institutional policies,
adhered to the tenets of the Declaration of Helsinki, and was approved by the Ethics
Committee of Hospital Universitari Vall d'Hebron of Barcelona, Spain.
Definition of Study Variables
RDS was defined as clinical respiratory distress (tachypnea, nasal flaring, chest
retractions, or grunting) that required invasive or noninvasive ventilatory support.
The need for surfactant administration required FiO2 ≥ 0.3 to achieve O2 saturation between 90 and 95%. Surfactant administration methods included intubation–surfactant–extubation
(INSURE), less invasive surfactant administration (LISA), and endotracheal tube (ETT).
Statistical Analysis
According to the primary objective of the study and considering a theoretical standard
deviation (SD) of 52.75 in the study population, a sample size of 167 infants was
required to estimate, with a confidence interval (CI) of 95%, the mean dose of surfactant
with a level of precision of 8 mg/kg. The required sample size of 167 was increased
to 196, assuming a percentage of 15% loss due to lack of minimal data required.
Data extracted from patients' records were entered into an electronic database for
analysis. All data were anonymized. Categorical variables are expressed as frequencies
and percentages, and quantitative variables as mean and 95% CI, mean and SD, or median
and interquartile range (IQR) (25th–75th percentile) as appropriate. Continuous data
were compared using Student's t-test and the analysis of variance or the Mann–Whitney U test and the Kruskal–Wallis test, and categorical data with the chi-square (χ
2) test or Fisher's exact test according to the distribution and size of the variables.
Analyses were performed for the overall study population and for the groups categorized
by gestational age between 23 and 28 weeks, between 29 and 32 weeks, and >32 weeks.
All tests of significance were two-sided and set at p < 0.05. The Statistical Analysis Systems software version 9.4 (SAS Institute, Cary,
NC) was used for statistical analysis.
Results
A total of 219 infants was eligible during the study period, but 13 (5.9%) were excluded
because inclusion criteria were not met (n = 5) or because of lack of minimal data required (n = 8). Therefore, the study population included 206 infants, 116 males and 90 females,
with a mean (SD) gestational age of 28.8 (3.1) weeks, mean birth weight of 1,227.3
(582.6) g, and median Apgar scores at 1 minute and 5 minutes of 6 (IQR 4–7) and 8
(IQR 7–9), respectively. According to gestational age, there were 120 infants in the
23- to 28- week group, 56 in the 29- to 32-week group, and 30 in the >32-week group.
Clinical findings before the administration of surfactant are shown in [Table 1]. Antenatal corticosteroid treatment was recorded in 84% of infants. In relation
to the use of ventilatory support immediately after birth in the delivery room, noninvasive
ventilation was used in 49% of neonates and invasive ventilation in 41.3%, and the
remaining 9.7% did not require any type of ventilatory support. All patients required
some type of ventilatory support during their stay in the NICU (invasive: 51.9%; noninvasive:
48.1%). Ventilatory failure requiring an increase in respiratory support was recorded
in 42 (20.4%) infants, with mechanical ventilation used in 27 (64.3%) of them, mostly
in infants initially treated with CPAP.
Table 1
Characteristics of the study population (n = 206) before the administration of surfactant
|
Variables
|
No. of patients (%)
|
|
Gender
|
|
|
Male
|
116 (56.3)
|
|
Female
|
90 (43.7)
|
|
Antenatal corticosteroids
|
173 (84)
|
|
Gestational age, mean (SD)
|
28.8 (3.1)
|
|
23–28 wk
|
120 (58.3)
|
|
29–32 wk
|
56 (27.2)
|
|
>32 wk
|
30 (14.6)
|
|
Delivery-related data
|
|
|
Cesarean section
|
152 (73.8)
|
|
Singleton
|
125 (60.7)
|
|
Multiple (twins, triplets)
|
81 (39.3)
|
|
Premature rupture of membranes
|
54 (26.2)
|
|
Chorioamnionitis
|
25 (12.1)
|
|
Cord prolapse
|
5 (2.4)
|
|
Fetal distress
|
27 (13.1)
|
|
Presence of meconium
|
5 (2.4)
|
|
Preeclampsia
|
30 (14.6)
|
|
Apgar score, mean (SD)
|
|
|
1 min
|
6 (2)
|
|
5 min
|
8 (2)
|
|
Birth weight, g, mean (SD)
|
1,227.3 (582.6)
|
|
Length, cm, mean (SD)
|
37.3 (5.8)
|
|
Immediate ventilatory support (delivery room)
|
|
|
Invasive
|
85 (41.3)
|
|
Mechanical ventilation
|
85 (41.3)
|
|
Noninvasive
|
|
|
IPPV prongs/nasal mask
|
58 (28.1)
|
|
SNIPPV
|
2 (1)
|
|
CPAP
|
40 (19.4)
|
|
Other
|
1 (0.5)
|
|
None
|
20 (9.7)
|
|
Ventilatory support in the NICU
|
206 (100)
|
|
Invasive
|
107 (51.9)
|
|
Mechanical ventilation
|
107 (51.9)
|
|
Noninvasive
|
99 (48.1)
|
|
IPPV
|
16 (7.8)
|
|
CPAP
|
78 (37.9)
|
|
BIPAP
|
5 (2.4)
|
|
O2 saturation, %, mean (SD)
|
89.7 (5.7)
|
Abbreviations: BIPAP, bilevel positive airway pressure; CPAP, continuous positive
airway pressure; IPPV, intermittent positive pressure ventilation; NICU, neonatal
intensive care unit; SD, standard deviation; SNIPPV, synchronized nasal intermittent
positive pressure ventilation.
The mean FiO2 value before the administration of surfactant was 0.47 (0.18). There were no significant
differences in FiO2 values according to gestational age, although higher values in infants in the >32-week
group were found ([Table 2]). The median time between birth and the administration of surfactant was 210 minutes
(IQR: 60–497 minutes). The median time was significantly shorter for infants in the
23 to 28 gestational weeks as compared with those in the 29 to 32 and > 32 weeks (p < 0.0001) ([Table 2]).
Table 2
FiO2 values and time from birth until the administration of surfactant in the overall
study population and according to gestational age
|
All patients (n = 206)
|
Gestational age
|
p-Value
|
|
23–28 wk (n = 120)
|
29–32 wk (n = 56)
|
> 32 wk (n = 30)
|
|
FiO2, %
|
|
|
|
|
|
|
Mean (SD)
|
0.47 (0.18)
|
0.47 (0.18)
|
0.44 (0.18)
|
0.52 (0.21)
|
0.137
|
|
Median (IQR)
|
0.40 (0.34–0.50)
|
0.40 (0.35–0.50)
|
0.40 (0.31–0.50)
|
0.47 (0.39–0.60)
|
|
|
Time from birth to use of surfactant, minutes
|
|
|
|
|
|
|
Mean (SD)
|
416.1 (566.6)
|
219.1 (322.9)
|
566.1 (594.4)
|
924.3 (873.1)
|
<0.001
|
|
Median (IQR)
|
210 (60–497)
|
100 (30–272)
|
301.5 (196–837)
|
669 (285–144)
|
|
Abbreviations: IQR, interquartile range; SD, standard deviation.
A total of 202 (98.1%) infants were treated with poractant alfa and the remaining
4 (1.9%) with beractant. Regarding the administration methods, ETT was used in 94.7%
of the patients and LISA in only 5.3%. In the ETT group, the INSURE method (extubating
in <1 hour) was used in 36.4% of babies and the remaining 63.6% were extubated for
>1 hour after surfactant administration. Extubation > 1 hour was significantly more
frequent in the 23- to 28-week group (74.8%) as compared with the 29- to 32-week (47.1%)
and >32-week groups (48.3%) (p = 0.0005).
In relation to the primary objective of the study, the mean initial dose of poractant
alfa was 173.9 (37.3) mg/kg (median: 186.2; IQR: 149.1–200 mg/kg). As shown in [Fig. 1], there were differences in the doses of surfactant according to gestational age,
with lower doses among infants in the >32-week group (p < 0.001). A total of 47.5% of infants received an initial surfactant dose of 200
mg/kg ± 10% (180–220 mg/kg), 47% received doses < 180 mg/kg (–10%), and 5.4% received
doses > 220 mg/kg (+ 10%). Differences according to gestational age were also observed,
with a significantly higher percentage of infants in the >32-week group treated with
<180 mg/kg as compared with the 29- to 32-week and 23- to 28-week groups (p = 0.006) ([Table 3]). Mean doses of surfactant administered according to birth weight are shown in [Fig. 2].
Fig. 1 Initial doses of surfactant (mg/kg) according to the gestational age.
Fig. 2 Initial doses of surfactant (mg/kg) according to birth weight.
Table 3
Initial doses of surfactant in the overall study population and according to gestational
age
|
Surfactant doses
|
All patients (n = 202)
|
Gestational age
|
p-Value
|
|
23–28 wk (n = 118)
|
29–32 wk (n = 56)
|
>32 wk (n = 28)
|
|
Median dose, mg/kg
|
186.2
|
190.1
|
171.1
|
166.4
|
|
|
Target 200 ± 10%, mg/kg
|
|
|
|
|
0.026
|
|
>220
|
11 (5.4)
|
9 (7.6)
|
2 (3.6)
|
0
|
0.271
|
|
180–220
|
96 (47.5)
|
64 (54.2)
|
23 (41.1)
|
9 (32.1)
|
0.057
|
|
<180
|
95 (47)
|
45 (38.1)
|
31 (55.4)
|
19 (67.9
|
0.006
|
|
Mean (SD) dose, mg/kg
|
|
|
|
|
|
|
>220
|
239 (22.9)
|
|
|
|
<0.001
|
|
180–220
|
197.7 (8.1)
|
|
|
|
|
<180
|
142.2 (27.5)
|
|
|
|
Abbreviation: SD, standard deviation.
The need of increasing respiratory support after surfactant therapy occurred in 18.4%
of patients, with mechanical ventilation, intermittent positive pressure ventilation,
and synchronized nasal intermittent positive pressure ventilation being the most commonly
used rescue ventilation modes.
Redosing was needed in 57 patients (59 redosings) due to persistent high oxygen requirements
in 86.2% of the cases. The median time between the initial dose and the first redosing
was 16.3 hours (IQR: 10.5–27), and the total mean dose of surfactant retreatment was
121.2 (36.9) mg/kg. Need for intubation within the first 72 hours after surfactant
administration was recorded in 27 (13.1%) patients.
A total of 168 (81.6%) patients were treated with caffeine citrate, 134 (79.8%) of
them for the prophylaxis of apnea and 33 (19.6%) for the treatment of apnea.
Among all patients treated with at least one dose of surfactant, only one case of
transient bradycardia (93 beats/minute) and oxygen desaturation (82%) possibly related
to treatment was recorded.
Discussion
This study performed in routine daily practice provides evidence of administration
of surfactant doses below the recommendations for treating babies with RDS. The mean
first dose of poractant alfa was 173.9 (37.3) mg/kg, which is 13.5% lower than the
theoretically prescribed and recommended dose of 200 mg/kg. Interestingly, we found
statistically significant differences in the doses of surfactant administered to patients
among the three gestational age groups. In this respect, infants of lower gestational
age at birth received higher initial doses of surfactant than infants of a more advanced
gestational age, but in all cases, doses were below those prescribed. Extremely preterm
infants (< 28 weeks) received a mean dose of 181.6 mg/kg, which was 9.2% below the
recommended dose of 200 mg/kg. Infants of 29 to 32 weeks' gestational age and those
>32 weeks' gestational age were given mean doses of 168.2 and 151.3 mg/kg, respectively,
which were 15.9 and 24.3% inferior to the target dose. A further analysis according
to the distribution of initial surfactant doses by percentiles was consistent with
these findings.
Globally, 47.5% of infants received doses of surfactant < 180 mg/kg (below the ± 10%)
and were considered to be undertreated. Considering a median dose of 186.2 mg/kg,
38.1% of extremely preterm babies were undertreated (<180 mg/kg) as compared with
67.9% of moderate-late preterm babies. Also, overtreatment (>220 mg/kg) was more frequent
in extremely preterm than in late preterm infants (37.6% versus 0%). Therefore, surfactant
doses above or below the recommendations showed a clear relationship with gestational
age.
The problem of inappropriateness of surfactant dosing for preterm neonates with RDS
has been addressed in two previous studies only, both of which have drawn attention
to the urgent need of making clinicians aware of errors in surfactant administration.[16]
[17] In a retrospective population-based cohort study of 455 infants, 25.4% were undertreated
and 24.8% overtreated, with a tendency to overtreat extremely preterm and extremely
low birth weight neonates and a trend to undertreat neonates > 28 weeks' gestation,
which, in turn, were more often subjected to surfactant redosing.[16] In a retrospective study of 119 infants with a median gestational age of 30 weeks
and birth weight of 1,300 g, 51.2% received a dose lower than 150 mg/kg (mean dose
145.8 mg/kg), with rounding down as the most plausible explanation.[17] Also, in a retrospective analysis of 987 infants with a median gestational age of
29 weeks and birth weight of 1,190 g, the median first dose was 170 mg/kg, with 79.8%,
19.1, and 1.1% requiring one, two, and three doses, respectively.[18] In this study, 47.5% of infants received a dose of 200 mg/kg ± 10%, and the dose
was lower than 180 mg/kg in 47% of patients. Dose rounding due to vial optimization
to minimize costs has been suggested as a possible reason for inappropriate surfactant
dosing.[16]
[17] In a European survey of surfactant replacement therapy in 338 preterm infants with
a median gestational age of 27 weeks and birth weight of 860 g, the median first dose
of poractant alfa was 168 mg/kg.[20] Moreover, in a Polish survey of 987 infants from 53 NICUs, the median first dose
was 170 mg/kg,[18] also lower than the recommended 200 mg/kg dose.
In our study, when total mean doses were compared in the different birth weight groups,
greater decreases were observed in the 1,251 to 1,500, 1,501 to 2,000, and >2,000 g
groups for which more than one vial content of poractant alfa (Curosurf) should be
used since the product is presented in 1.5- or 3-mL vials. However, the fact that
54.2% of neonates in the 23- to 28-week group received a dose of 200 mg/kg ± 10% as
compared with 41.1% in the 29- to 32-week group and 32.1% in the >32-week group may
also reflect greater concern for the clinical care of very premature infants. On the
other hand, the time elapsed from birth to the administration of surfactant was significantly
shorter in the 22- to 28-week group than in older infants. In a randomized, masked
comparison trial of preterm infants (n = 293) with RDS treated with an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of poractant alfa or 100 (n = 98) mg/kg of beractant, need of redosing was significantly lower in infants treated
with an initial dose of 200 mg/kg.[6] Other outcomes including mortality up to 36 weeks in neonates born at ≤32 weeks
were also significantly lower in the 200 mg/kg group as compared with 100 mg/kg of
poractant alfa or 100 mg/kg of beractant.[6] Moreover, in a systematic review and meta-analysis of five randomized controlled
trials involving 529 infants in which poractant alfa versus beractant for rescue treatment
was compared, infants treated with poractant alfa at 100 mg/kg (low dose) or 200 mg/kg
(high dose) exhibited statistically significant reductions in deaths, the need for
redosing, oxygen requirements, duration of oxygen treatment, and duration of mechanical
ventilation.[21] Further studies are needed to determine if treatment with surfactant doses below
the recommendations, as seen in our study, is associated with worse respiratory outcomes.
A relevant finding of this study was an actual FiO2 mean value of 0.47 before surfactant therapy, surprisingly higher than the recommended
FiO2 threshold level of 0.30 to 0.40 depending on gestational age.[12] Differences in FiO2 values according to gestational age were observed, with higher levels in the >32-week
group, although differences were not statistically significant. Also, CPAP was the
most frequent noninvasive ventilation method (78.8%). However, noninvasive ventilation
was associated with a higher percentage of ventilatory failure. In these cases, mechanical
ventilation was the rescue ventilatory support most frequently used when CPAP failed
and intubation within 72 hours of birth was required. In a study of CPAP failure in
Australian and New Zealand Neonatal Network data from 2007 to 2013 in a cohort of
11,684 babies initially managed on CPAP only, failure was recorded in 43% of infants
commencing on CPAP at 25 to 28 weeks' gestation and in 21% at 29 to 32 weeks.[13] CPAP failure was associated with a substantially higher rate of pneumothorax, and
a heightened risk of death, BPD, and other morbidities compared with those managed
successfully on CPAP.[13]
Results of this study should be interpreted taking into account some limitations,
including variability of clinical practice among the participating NICUs, the retrospective
design of the study based on data collected from medical records, and results obtained
for the use of poractant alfa. Poractant alfa is the most common surfactant in Europe
and was the main compound used and analyzed in this study.
In conclusion, underdosing of poractant alfa is an apparently inadvertent error in
surfactant administration at the bedside. Preterm babies diagnosed with RDS requiring
surfactant therapy may be at a risk of undertreatment. Specific actions to avoid unintentional
underdosage of surfactant are urgently needed.
