Effect of Low Dose Glucocorticoid Inhalation on Bronchopulmonary Dysplasia in Premature Infants

Abstract

The aim of the study was to explore the effect of low dose glucocorticoid on bronchopulmonary dysplasia in premature infants, to provide new ideas for clinical prevention and cure of bronchopulmonary dysplasia in premature infants. The 144 cases of premature infants were divided into 72 each: control group and experimental group. Control group received routine clinical prevention and cure, while experimental group was received low dose glucocorticoid on the basis of control group. The serum interleukin-10 (IL-10) , interleukin-8 (IL-8), and transforming growth factor-1 (TGF-β1) before and after treatment were compared between two groups. The incidence and severity of bronchopulmonary dysplasia was compared between two groups. The mechanical ventilation time, oxygen inhalation time and hospitalization time in two groups were recorded, and the body mass, head circumference and body length at 30 days after birth were assessed in both groups. After treatment, the serum IL-10 level in experimental group was increased and IL-8, TGF-β1 levels were decreased compared with control group (p <0.05). The incidence rate of bronchopulmonary dysplasia in experimental group was 13.89% and the disease severity in experimental group was significantly reduced (p<0.05). Both groups exhibited no notable adverse reactions (p>0.05). Low-dose glucocorticoids have a significant preventive and therapeutic effect on bronchopulmonary dysplasia in preterm infants, and have a high safety, showing high clinical application value for bronchopulmonary dysplasia in preterm infants.

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, Z_α/2=1.96, Z_β=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.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 08 July 2024

Accepted after revision: 05 September 2024

Article published online:
30 September 2024