Early versus delayed initiation of nasal continuous positive
airway pressure for treatment of respiratory distress
syndrome in premature newborns: A randomized clinical
trial
Zohreh Badiee, Fatemeh Naseri, and Alireza Sadeghnia
Department of Pediatrics, Division of Neonatology, Isfahan University of Medical Sciences, Isfahan, Iran
Address for correspondence:Dr. Zohreh Badiee, Division of Neonatology, Department of Pediatrics, Isfahan
University of Medical Sciences, Isfahan, Iran. E-mail: badiei@med.mui.ac.ir
Author information ►Article notes ►Copyright and License information ►
Received January 22, 2012; Accepted May 22, 2012.
Copyright: © 2013 Badiee.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.
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Abstract
Background:
This prospective study was performed to identify whether the early use of
nasal continuous positive airway pressure (n CPAP) would reduce the rate of
endotracheal intubation, mechanical ventilation and surfactant
administration.
Materials and Methods:
This study was conducted from June 2009 to September 2010 in the Shahid
Beheshti University Hospital, Isfahan-Iran. A total of 72 preterm infants with
25-30 weeks gestation who needed respiratory support at 5 min after birth
entered the study. Infants were randomly assigned to the very early CPAP
(initiated 5 min after birth) or to the late CPAP (initiated 30 min after birth)
treatment groups. The primary outcomes were need for intubation and
mechanical ventilation during the first 48 h after birth and secondary
outcomes were death, pneumothorax, intraventricular hemorrhage, duration
of mechanical ventilation and bronchopulmonary dysplasia.
Results:
There were no significant differences between the two groups with regard to
mortality rate, bronchopulmonary dysplasia and patent ductus arteriosus. The
need for surfactant administration was significantly reduced in the early CPAP
group (P = 0.04). Infants in the early CPAP group less frequently required
intubation and mechanical ventilation.
Conclusions:
Early n CPAP is more effective than late n CPAP for the treatment of
respiratory distress syndrome. In addition, the early use of n CPAP would
reduce the need for some invasive procedures such as intubation and
mechanical ventilation.
Keywords:Continuous positive airway pressure, premature infant,
respiratory distress syndrome
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INTRODUCTION
Neonatal respiratory distress syndrome (RDS) is an important cause of
morbidity and mortality in premature infants. The primary cause of neonatal
RDS is surfactant deficiency, which leads to decrease in lung compliance and
thereby hypoventilation and ventilation perfusion mismatch.[1,2]
In the previous decades, mechanical ventilation was the standard
management of RDS in very premature infants. However, intubation and
mechanical ventilation may be hazardous for the baby. For example,
intubation could be traumatic and may increase the risk of airway colonization
and infection. Moreover, artificial ventilation might predispose the premature
lung to bronchopulmonary dysplasia, which could be prevented by gentle
respiratory support during the early hours of life.[3,4]
Continuous positive airway pressure (CPAP) is a positive pressure applied to
the airways of spontaneously breathing infants throughout the respiratory
cycle and maintains functional residual capacity (FRC) and prevents alveolar
collapse at the end of expiration. It has been shown that the application of
nasal CPAP (n CPAP) is effective in the post-extubation care of pre-term
infants. In addition, n CPAP could decrease the work of breathing and reduce
atelectasis by increasing FRC during expiration.[5] On the other hand, some
studies have suggested that use of n CPAP during resuscitation of very low
birth weigth (VLBW) infants may be beneficial in reducing endotracheal
intubation.[6]
In a systematic review, Ho and colleagues assessed the beneficial effects of
early n CPAP (the need for FIO2 > 0.4 to maintain oxygen saturation [SPO2] of
more than 85% in the right hand) in the management of RDS. They concluded
that n CPAP could be effective in reducing subsequent need for intermittent
positive-pressure ventilation (IPPV). But, the majority of their trials were
performed before the 1980s, when antenatal steroid use and surfactant
administration were not a common practice. Therefore, they suggested
re-evaluation of the methods of early CPAP application for management of
RDS use in addition to antenatal steroid and surfactant.[2]
The primary objective of this study was to establish whether the very early use
of n CPAP has any advantageous over later use in the treatment of RDS in
addition to antenatal steroid and surfactant.
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MATERIALS AND METHODS
This study was conducted from June 2009 to September 2010 at the Shahid
Beheshti University Hospital, Isfahan-Iran. The study was approved by the
local research ethics committee and written informed consent was obtained
from the parents. Inborn neonates with gestational age between 25 and 30
weeks who received respiratory support because of RDS and an ability to
breath spontaneously at 5 min after birth were included. The diagnosis of RDS
was based on at least two of the following classic symptoms: need of
supplemental oxygen, tachypnea, intercostal retraction, grunting and
exclusion of other causes of respiratory distress.
We excluded infants from the study if they had major congenital
malformation, demonstrated gasping respiration or required endotracheal
intubation due to respiratory failure (a partial pressure of CO2 more than 60
mmHg and a pH less than 7.25) immediately after birth. Infants were
resuscitated according to the Neonatal Resuscitation Program guideline. A
T-piece resuscitator (Neopuff Infant Resuscitator; Fisher-Paykel, Auckland,
New Zealand) was used in the delivery room for administering CPAP and
positive-pressure ventilation.
All pre-term infants included in the study were sequentially numbered and
randomized at 1 min after birth to the early CPAP or late CPAP groups using
sequentially numbered sealed envelopes and a stratified randomization for
gestational age. In the early CPAP group, continuous distending pressure
(CDP), at a pressure of 6 cmH2O, using a nasopharyngeal tube was used in the
delivery room. After transporting infants to the NICU, the nasopharyngeal
tube was discarded and a binasal prong (equipped with Hudson-prong) was
used for delivering CPAP by bubble-CPAP. In the late CPAP group, oxygen
was administrated by an oxyhood until 30 min after birth. If the infants
required oxygen for more than 30 min, then n CPAP was administered at a
pressure of 6 cmH2O with a single nasopharyngeal tube. After NICU
admission, short binasal prongs connected to a bubble-CPAP at the same
pressure were used. We administered surfactant (beractant, 100 mg/ kg)
using the INSURE (Intubation, SURfactant administration, Extubation)
method for those newborns who had SPO2 less than 88% in spite of an FiO2
more than 0.6, and repeated every 6 h up to four doses if newborns needed
FiO2 more than 0.6 until 48 h after birth. Intubation criteria were arterial pH
<7.2, PaCO2 >65 mmHg or recurrent apnea unresponsive to methyl xanthine
therapy after initiation of n CPAP.
Brain sonography was done on the 3rd, 7th and 14th days after birth to identify
intraventricular hemorrhage (IVH), and newborns who had IVH underwent
biweekly skull sonography to detect the possible occurrence of
post-hemorrhagic hydrocephalus. The diagnosis of bronchopulmonary
dysplasia was based on the need for any supplemental oxygen after 28 days
from birth.[7] The diagnosis of sepsis neonatarum was based on the detection
of the attending neonatologist.
Primary and secondary outcomes
The primary outcomes were the need for intubation and mechanical
ventilation during the first 48 h after birth and the secondary outcomes were
death, pneumothorax, intraventricular hemorrhage, need for mechanical
ventilation and bronchopulmonary dysplasia.
Statistical analysis
We estimated that a sample size of 36 infants was needed in each group to
discover a difference of 33% regarding the need for intubation and mechanical
ventilation with 80% power and a significance of 0.05. Student's t test,
Chi-square test and Fisher's exact test were used for continuous and
categorical variables, appropriately. Analysis were performed with the SPSS
computer program (SPSS Inc., Chicago, IL, USA), with significance accepted
for P-values <0.05.
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RESULTS
A total of 76 infants were enrolled in the study. The study flowchart is shown
in Figure 1. The demographic and clinical characteristics of the patients are
shown in Table 1.
Figure 1
Study flow
Table 1
Baseline demographic and clinical characteristics of the study population
There were no significant differences between the two groups with regard to
birth weight, gestational age, sex, Apgar value at 5 min after birth and
frequency of cesarean section.
The overall mortality rate was 19.4%, with 16.7% in the early CPAP group and
22.2% in the late CPAP group (P value = 0.7). Sepsis neonatarum was the
most common cause of mortality.
Brochopulmonary dysplasia (BPD) occurred in 2.8% of early CPAP group and
5.6% of the late CPAP group (P value = 0.5), and these differences were not
significant. There was no case of pneumothorax in both groups.
The incidence of patent ductus arteriosus was 2.8% in both groups.
The mean duration of hospitalization was 32.3 days for the early CPAP group
and 35.9 days for the late CPAP group (P value = 0.4).
Overall, more infants in the late CPAP group received surfactant than in the
early CPAP group (P value = 0.04). In the early CPAP group, 38.9% of the
neonates received one dose, 8.3% received two doses and 2.8% received three
doses of surfactant. The figures for the late CPAP group were 63%, 8.3% and
5.6%, respectively.
Incidence of IVH was higher in the late CPAP group (83%) than in the early
CPAP group (58.3%), and these differences were significant (P value = 0.037).
Sepsis occurred about two-times more in the late CPAP group (66.7%) than in
the early CPAP group (30.6%), with P value = 0.004. Infants in the early
CPAP group less frequently required intubation and mechanical ventilation,
although it was not statistically significant (P value = 0.06).
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DISCUSSION
In the present study, we found that the Introduction of early n CPAP for
management of RDS can reduces the need for endotracheal intubation and
surfactant administration in pre-term infants. Moreover, early use of n CPAP
have been associated with a lower incidence of sepsis and IVH.
Application of CPAP could increase tidal volume and FRC. At histological
examination, surfactant-deficient lungs have areas of atelectasis and
overinflation, which could be effectively prevented by application of n CPAP
shortly after birth.[8,9,10] Therefore, early application of n CPAP may be
effective in the management of RDS. Previous descriptions have been
described in trials in which “early” CPAP was started at a variable period of
time extending several hours after birth. However, the best time for starting n
CPAP has never been determined for premature infants by randomized
controlled trials.[2,11,12,13,14]
Krouskop and coworkers compared two methods of n CPAP application in
pre-term infants: early CPAP (FiO2 requirement more than 0.4) and late
CPAP (FiO2 requirement more than 0.7) for treatment of RDS. They did not
find any differences in survival or complications between the groups. However,
the mean birth weight of their study groups was more than 1700 g, which is
more than our patients’ weight.[11]
Han and colleagues randomly allocated 82 pre-term infants to the early CPAP
group (n CPAP at birth) or the late CPAP group (when FiO2 reached more
than 0.5). They found no differences in outcome with regard to death or
intubation and mechanical ventilation.[8] Surfactant was not administered in
this study and one explanation for the lack of early CPAP efficacy is that
patients may not be given great benefit from CPAP use without surfactant
therapy.
Sandri and colleagues evaluated the benefits of prophylactic n CPAP in infants
of 28–31 weeks gestation. They randomly allocated 230 infants to
prophylactic (started within 30 min of birth, irrespective of oxygen
requirement) or rescue (when FiO2 requirement more than 0.4) n CPAP. They
concluded that prophylactic n CPAP could not reduce the need for mechanical
ventilation or surfactant administration.[12] In contrary to our study, they
started n CPAP within 30 min after birth and not in the delivery room.
Therefore, the surfactant-deficient lungs of their patients might be atelectatic
before n CPAP use.
In a retrospective study, Gittermann and coworkers found that the early use of
n CPAP (applied very soon after initiation of respiratory distress) could
significantly reduce the need for intubation and mechanical ventilation
without decreasing the incidence of bronchopulmonary dysplasia,[13] which is
comparable to our results.
Miksch et al. performed a retrospective study to assess the beneficial effects of
early n CPAP for treatment of RDS in very low birth weight infants. They
found that in infants with birth weight less than 1000 g, the use of early n
CPAP significantly reduced intubation rate, duration of ventilation and
incidence of bronchopulmonary dysplasia.[10]
Morley and colleagues randomized 610 infants with a gestational age of
25–28 weeks to CPAP or intubation an ventilation at 5 min after birth, they
found no significant differences in bronchopulmonary dysplasia and death
between the groups.[4]
De Klerk and colleagues showed that early application of n CPAP (usually
during 10 min of admission) could decrease endotracheal intubation,
surfactant administration and duration of mechanical ventilation, which is
corresponding to our results.[14]
In our study, surfactant administration was reduced in the early CPAP group.
Therefore, we found that the early use of n CPAP could be cost-effective in the
treatment of RDS, which is comparable to the study of Miksch et al.[10]
This study has some limitations, including the small number of study groups
and absence of long-term outcomes. Also, it was not blinded. However, it has
a unique concept because of very early use of n CPAP in the delivery room.
In conclusion, our study demonstrated that early use of n CPAP is an effective
and safe method for the treatment of RDS in pre-term newborns. Moreover,
early CPAP could reduce the need for some invasive procedures such as
intubation and mechanical ventilation.
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Footnotes
Source of Support: Nil
Conflict of Interest: None declared
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Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
Footnotes
REFERENCES