Keywords
glucocorticoid - bronchopulmonary dysplasia - premature infants - low dose - prevention
and treatment effect
Introduction
In recent years, with the establishment of neonatal intensive care units (NICU) and
the continuous development and improvement of medical technology, more and more
premature infants can survive, especially among infants with low birth weight and
extremely low birth weight, but the incidence rate of bronchopulmonary dysplasia is
also rising [1]
[2]. Bronchopulmonary dysplasia can lead to
neurodevelopmental disorders in preterm infants, prolong their hospital stay,
increase the risk of readmitted treatment, and is also an important cause of death
in preterm infants [3]. Therefore, it is
particularly important to take active and effective preventive measures to reduce
the incidence of bronchopulmonary dysplasia in preterm infants. At present, there
is
no specific method to prevent and control bronchopulmonary dysplasia, and
nutritional support, oxygen therapy, and mechanical ventilation management are the
main measures [4].
It has been shown that inflammatory response processes within the immature lung
occupy a pivotal position in the pathogenesis of bronchopulmonary dysplasia in
premature infants [5]. Glucocorticoids are
a class of steroid hormones secreted by the adrenal cortex and can also be
chemically synthesized. They have anti-inflammatory, antitoxic, and anti-infective
effects, and are therefore widely used in clinical practice [6]. Budesonide, as a representative
glucocorticoid, can improve the success rate of extubation and reduce the adverse
consequences caused by long-term mechanical ventilation through multiple pathways
and mechanisms, including anti-inflammatory [7]. Currently, budesonide has been confirmed to have a certain prevention
and treatment effect on bronchopulmonary dysplasia, but there is still a great
controversy in clinical application because of their toxic and side effects [8]
[9]. Therefore, lowering the dose may be a breakthrough for the clinical
application of budesonide. However, at this stage, reports about the application of
low-dose budesonide on bronchopulmonary dysplasia in preterm infants are scarce.
Therefore, this study focuses on discussing the prevention and treatment effect of
low-dose budesonide on bronchopulmonary dysplasia in preterm infants.
Patients and Methods
Ethical approval of the research protocol
The study has obtained ethical approval from the Institutional Review Committee
of Lianyungang City First People’s Hospital. All guardians of participants have
written informed consent.
Patients
The study subjects are selected 144 premature infants who were admitted to the
NICU of Lianyungang City First People’s Hospital from March 2018 to March 2024.
Inclusion criteria: gestational age<32 weeks; birth weight<2500 g;
accumulated oxygen intake for more than 28 days after birth. Exclusion criteria:
premature infants who are allergic to glucocorticoids; premature infants who
received early glucocorticoid therapy due to hypotension and hypoglycemia;
premature infants whose parents refused treatment. A total of 396 preterm
infants were admitted to our NICU during the study period, of which 144 were
included in the study and 52 were excluded.
Calculation of sample size
The sample size is calculated by the formula: control sample size
(n)=
,P1=0.8, P2=0.5, P=(P1+P2)/2=0.65,
α=0.05, β=0.10, Zα/2=1.96, Zβ=1.282, c (distribution
ratio)=1, control group sample size (n)=experimental group sample size (n)=65,
considering 10% error, the final sample size is 144.
Random allocation and blinding
One hundred and forty-four cases were randomly allocated into a control group and
an experimental group using a simple random sampling method, with 72 cases in
each group. Additionally, all nursing staff and study participants involved in
this trial were blinded to the allocation of the groups. All patients in both
groups received a complete cycle of preventive therapy, and no patients dropped
out midway.
Prevention and treatment method
Control group received routine clinical prevention and cure: including oxygen
therapy, mechanical ventilation management, avoid the use of excessive oxygen
concentration and excessive mechanical ventilation pressure, as soon as possible
to adjust the ventilator parameters to the lowest level that the baby can
tolerate. At the same time, premature infants received nutritional support,
including protein, vitamins and minerals. On this basis, the experimental group
was given low dose glucocorticoid prophylaxis within 7 days of birth: 0.5 mg of
budesonide was added to 2 ml of saline in a nebulizer and nebulized under oxygen
for 10 minutes each time. After nebulization, facial skin and mucous membranes
were cleaned and residual liquid was removed. The treatment was carried out
twice a day. Both groups were treated for 10 days.
Outcome measures
Peripheral venous blood of 3 ml was collected from two groups of preterm infants
before prophylactic medication and 10 days after medication, and the supernatant
was collected after centrifugation. IL-8, IL-10, and TGF-β1 levels were
determined by enzyme-related immunosorbent assay, and all operations were
carried out in strict accordance with the reagent and instrument instructions.
The occurrence and severity of bronchopulmonary dysplasia were observed in the
two groups. The diagnosis and grading of bronchopulmonary dysplasia is based on
the criteria published by the National Institute of Child Health and Human
Development (NICHD) in 2001 [10].
Based on corrected gestational age at 36 weeks, bronchopulmonary dysplasia is
defined as mild, moderate, or severe according to the following criteria: no
oxygen supplementation, inhaled oxygen concentration<0.30, and inhaled oxygen
concentration≥0.30 or the need for mechanical ventilation. The duration of
mechanical ventilation, oxygen inhalation and hospital stay in two groups were
recorded, and the body mass, head circumference and body length at 30 days after
birth were assessed in both groups. The safety of the two groups was
evaluated.
Statistical methods
The data analysis was conducted utilizing SPSS 24.0 software. Continuous
variables with a normal distribution were represented as the mean±standard
deviation, and comparisons between groups were made using the independent
samples t-test. Categorical data were expressed as frequencies and
percentages, with the rank sum test and Chi-square tests employed for
comparisons between the groups. p<0.05 was considered significant.
Results
Clinical features
There have no obvious differences in sex, birth weight, gestational age, cesarean
section and auxiliary ventilation mode between two groups (p>0.05), see from
[Table 1].
Table 1 Clinical characteristics of the two
groups.
|
Variable
|
Experimental group (n=72)
|
Control group (n=72)
|
t/χ
2
-value
|
p-Value
|
|
Sex (male/female)
|
42/30
|
45/27
|
0.261
|
0.609
|
|
Gestational age (weeks)
|
30.46±1.27
|
30.25±1.64
|
0.859
|
0.392
|
|
Birth weight (kg)
|
1.78±0.37
|
1.75±0.35
|
0.500
|
0.618
|
|
Cesarean section
|
|
|
0.291
|
0.590
|
|
Yes
|
51 (70.83)
|
48 (66.67)
|
|
|
|
No
|
21 (29.17)
|
24 (33.33)
|
|
|
|
Auxiliary ventilation mode
|
|
|
0.879
|
0.348
|
|
Mechanical ventilation
|
17 (23.61)
|
22 (30.56)
|
|
|
|
Continuous positive airway pressure
|
55 (76.39)
|
50 (69.44)
|
|
|
Serum indexes
After treatment, the serum IL-10 level in experimental group was increased, and
IL-8 and TGF-β1 levels were decreased compared with control group (p<0.05)
([Table 2]).
Table 2 Comparison of serum IL-8, IL-10, and TGF-β1
levels between two groups.
|
Groups
|
IL-8 (pg/ml)
|
IL-10 (μg/ml)
|
TGF-β1 (ng/ml)
|
|
Before treatment
|
After treatment
|
Before treatment
|
After treatment
|
Before treatment
|
After treatment
|
|
Experimental group (n=72)
|
0.38±0.09
|
0.25±0.06a
|
1.44±0.37
|
1.84±0.24a
|
8.87±2.17
|
6.49±1.36a
|
|
Control group (n=72)
|
0.40±0.12
|
0.34±0.07a
|
1.35±0.34
|
1.49±0.26a
|
9.09±2.68
|
8.18±2.13a
|
|
t-values
|
1.131
|
8.283
|
1.520
|
8.393
|
0.541
|
5.674
|
|
p-values
|
0.260
|
<0.001
|
0.131
|
<0.001
|
0.589
|
<0.001
|
a p<0.05 versus before treatment.
The occurrence and severity of bronchopulmonary dysplasia
The incidence rate of bronchopulmonary dysplasia in experimental group was
decreased, and the severity was significantly reduced compared to control group
(p<0.05) as shown in [Table
3].
Table 3 The occurrence and severity of bronchopulmonary
dysplasia between two groups.
|
Groups
|
Mild
|
Moderate
|
Severe
|
Total incidence rate
|
χ
2
-values
|
p-Values
|
|
Experimental group (n=72)
|
6 (8.33)
|
4 (5.56)
|
0 (0.00)
|
10 (13.89)
|
20.202
|
<0.001
|
|
Control group (n=72)
|
7 (9.72)
|
22 (30.56)
|
6 (8.33)
|
35 (48.61)
|
|
Z-values
|
2.518
|
|
|
|
|
p-values
|
0.012
|
|
|
|
The duration of mechanical ventilation, oxygen inhalation and hospital
stay
The duration of mechanical ventilation, oxygen inhalation and hospital stay in
experimental group were shorter than control group (p<0.05) as shown in [Table 4].
Table 4 Comparison of the duration of mechanical
ventilation, oxygen inhalation, and hospital stay between two
groups.
|
Groups
|
Mechanical ventilation time (d)
|
Oxygen intake time (d)
|
Hospitalization time (d)
|
|
Experimental group (n=72)
|
11.46±2.74
|
23.58±3.46
|
29.88±3.96
|
|
Control group (n=72)
|
17.55±3.26
|
29.28±4.31
|
35.74±4.86
|
|
t-values
|
12.134
|
8.751
|
7.932
|
|
p-values
|
<0.001
|
<0.001
|
<0.001
|
Physical indexes
The body mass, head circumference, and body length between two groups at 30 days
after birth have no notable difference (p>0.05) ([Table 5]).
Table 5 Comparison of physical indexes between two
groups.
|
Groups
|
Body mass (kg)
|
Head circumference (cm)
|
Body length (cm)
|
|
Experimental group (n=72)
|
1.85±0.37
|
34.49±2.78
|
32.09±3.66
|
|
Control group (n=72)
|
1.92±0.32
|
35.07±3.22
|
31.85±3.28
|
|
t-values
|
1.214
|
1.567
|
0.414
|
|
p-values
|
0.227
|
0.249
|
0.679
|
Safety
No related complications including infection, gastrointestinal bleeding,
electrolyte disturbance, pneumothorax, necrotizing enterocolitis, and
hyperglycemia had occurred in two groups.
Discussion
In recent years, with the birth and survival of more premature infants, the incidence
of bronchopulmonary dysplasia has gradually increased [11]. The pathogenesis of this disease is
still unclear, and it is believed that oxygen dependence, lung injury and fibrosis
repair are involved in the pathogenesis of this disease [12]. Bronchopulmonary dysplasia can cause
multi-system functional damage, among which the damage to the respiratory system and
nervous system will last until adulthood, seriously affecting the physical and
mental health of children, but also bring heavy economic pressure to the family and
society [13]. Therefore, prevention and
treatment of bronchopulmonary dysplasia of premature infants has become an urgent
problem. Currently, clinical measures to combat bronchopulmonary dysplasia include
protective ventilation, avoidance of oxygen toxicity, infection control and
nutritional support, but this has not reached international consensus [14]
[15]. Inflammation is a key link in the pathogenesis of bronchopulmonary
dysplasia [16]. Glucocorticoids are widely
used in the prevention and treatment of bronchopulmonary dysplasia by virtue of
their potent anti-inflammatory effects, but they may be accompanied by the emergence
of short-term adverse effects, such as upper gastrointestinal hemorrhage,
hyperglycemia, hypertension and intestinal perforation, which have led to concerns
about their safety [17]. Currently,
intravenous glucocorticoids are recommended only for children at high risk of
bronchopulmonary dysplasia 7 days after birth or later. Compared with intravenous
medication, aerosol inhalation of glucocorticoids has the advantage of acting on the
local area with less systemic exposure, which may ensure a certain effect while
avoiding the occurrence of adverse reactions [18]. Therefore, aerosol inhalation has become one of the potential ways
of hormone delivery. Meanwhile, the appropriate reduction of glucocorticoid dose can
also provide a new way to avoid adverse reactions. Inspired by the above views, this
study investigated the prevention and treatment effect of low dose budesonide
aerosol inhalation on bronchopulmonary dysplasia in premature infants.
As a chemokine, IL-8 can not only induce preterm birth, but also cause lung injury
in
postpartum preterm infants. IL-10 as an anti-inflammatory factor, can inhibit the
production of IL-8. TGF-β1, as a transforming growth factor, can reduce the host
defense of bronchial epithelial cells and aggravate airway injury by affecting the
expression of vitamin D-mediated host defense peptide. The above serum indicators
are closely related to the occurrence of bronchopulmonary dysplasia in preterm
infants [19]
[20]. In this study, the serum levels of
IL-8, IL-10, and TGF-β1 were measured in two groups, and the results showed that
compared with the control group, the levels of IL-10 in experimental group were
increased, while the levels of IL-8 and TGF-β1 were decreased after treatment. In
this study, the incidence rate of bronchopulmonary dysplasia in experimental group
was decreased, and the disease severity was relieved compared to control group,
suggesting low dose budesonide aerosol inhalation can effectively prevent
bronchopulmonary dysplasia. It may be because on the one hand, budesonide has a
strong anti-inflammatory effect, which can reduce the infiltration of inflammatory
cells and the release of inflammatory mediators, such as IL-8 and TGF-β1, thus
alleviating airway inflammation and reducing the occurrence of bronchopulmonary
dysplasia. On the other hand, budesonide can promote the secretion of alveolar
surfactant, reduce the surface tension of alveolar, prevent alveolar collapse, and
help maintain normal lung function. At the same time, budesonide can reduce
oxidative stress response and protect lung tissue from oxidative damage, thereby
preventing bronchopulmonary dysplasia. The points have been confirmed in the study
of Yao et al. [21]. The findings exhibited
that, in comparison to the control group, the experimental group experienced a
shorter duration of mechanical ventilation, oxygen inhalation, and hospital stay.
This reveals that low-dose budesonide aerosol inhalation therapy can effectively
reduce the mechanical ventilation time, oxygen inhalation time and hospital stay of
preterm infants, which may be attributed to the anti-inflammatory effect of
budesonide, which can reduce lung injury and promote lung repair in preterm infants,
so that they can leave mechanical ventilation and oxygen inhalation earlier, and
shorten the hospital stay. In Liu’s study [22], the budesonide was combined with pulmonary surfactant applied in the
bronchopulmonary dysplasia, the results showed that budesonide combined with
pulmonary surfactant (PS) can shorten the duration of respiratory support, reduce
the incidence and severity of bronchopulmonary dysplasia, without increasing the
glucocorticoid-related complications.
This study further investigated the changes of physical indicators of preterm
infants, and the results showed that there were no apparent differences in body
mass, head circumference and body length between two groups at 30 days after birth.
This may be because the main effect of budesonide is anti-inflammatory and promote
lung maturation, rather than directly promote the physical development of premature
infants, so the effect on physical fitness is not obvious. Secondly, the physical
development of preterm infants is affected by many factors, including genetics,
nutrition, diseases, etc. Therefore, although budesonide aerosol inhalation can
prevent bronchopulmonary dysplasia, it does not significantly affect physical
development. In addition, individual differences and sample size are also important
factors affecting the difference. Therefore, it remains imperative to enlarge the
sample size and conduct a large number of multi-center and prospective studies. In
this study, no significant adverse reactions were observed during the treatment of
low-dose budesonide aerosol inhalation, suggesting that low-dose glucocorticoids
have high safety in premature infants.
Conclusions
Low dose budesonide aerosol inhalation has a remarkable prevention and treatment
effect on bronchopulmonary dysplasia in premature infants, which can effectively
reduce the incidence of bronchopulmonary dysplasia, alleviate the severity of the
disease, shorten the duration of mechanical ventilation, oxygen inhalation and
hospital stay, and has a high safety. Nonetheless, this study still has some
shortcomings. First of all, due to limited time, some parents did not have a strong
awareness of follow-up, so dynamic follow-up data of multiple age stages of the
study subjects were not obtained. Second, the sample size of this study is small,
so
it cannot be completely sure that there is no bias in the research results, and a
multi-center double-blind randomized experiment is needed to further verify the
research results. Finally, this study was conducted based on a single drug, and
subsequent studies can be conducted based on the study of different drugs, ways of
administration, and dosages to effectively evaluate the effect of glucocorticoids
on
the prevention and treatment of bronchopulmonary dysplasia.
