Efficacy of budesonide in the prevention and treatment of bronchopulmonary dysplasia in premature infants and its effect on pulmonary function

Abstract

Objective: This study was designed to explore the efficacy of budesonide (BUD) in preventing and treating bronchopulmonary dysplasia (BPD) in premature infants and its effect on pulmonary function. Methods: A total of 94 premature infants with BPD who were born in our hospital were selected as the research subjects and divided into the control group (47 cases) for routine treatment and the research group (47 cases) for BUD therapy on the basis of routine treatment according to the random number table method. The incidence of BPD and the time of oxygen inhalation, ventilator ventilation, extubation and hospitalization were recorded in the two groups. In addition, arterial blood gas indexes (arterial oxygen saturation (SaO₂), arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂)), inflammatory response indicators (interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-α)), pulmonary function indexes (the ratio of time taken to reach peak expiratory flow to total expiratory time (TPTEF/TE), the ratio of peak expiratory volume to total expiratory volume (VPEF/VE), tidal expiratory flow at 25%/50%/75% remaining tidal volume (TEF25, TEF50, TEF75), and the incidence of complications were observed and compared. Results: After treatment, SaO₂ and PaO₂ increased in both groups, and their values in the research group were higher than those in the control group; PaCO₂ decreased in both groups, and the PaCO₂ in the research group was lower than that in the control group (P<0.05). The post-treatment TNF-α, IL-6 and IL-8 levels decreased in both groups, and their levels in the research group were lower than those in the control group (all P<0.001). TPTEE/TE, VPEF/VE, TEF25, TEF50 and TEF75 increased in both groups after treatment, and their values in the research group were higher than those in the control group (all P<0.01). The research group required shorter oxygen inhalation time, ventilator ventilation time, time to extubation and hospitalization time than the control group (all P<0.001). The incidence of BPD and other complications in the research group were lower than that in the control group (8.51%, 6.38% vs. 23.40%, 21.28%; P=0.049, 0.036). Conclusion: BUD is effective in the prevention and treatment of BPD in premature infants, which can effectively reduce the incidence of BPD and other complications, improve blood gas indexes, reduce inflammatory reactions and promotes good pulmonary function in children.

Introduction

Bronchopulmonary dysplasia, or bronchopulmonary dysplasia (BPD), is a type of lung injury caused by oxygen inhalation or mechanical ventilation, with the main clinical presentations of pulmonary edema, airway injury and inflammatory reactions [1]. It has a high incidence among premature infants, affecting approximately 25%-42% of very low birth weight infants [2]. The pathogenesis of BPD has not been clarified yet, but it is generally believed to be related to intrauterine infection, chorioamnionitis, pulmonary infection or lung injury caused by high inspiratory peak pressure and inhalation of high oxygen concentrations. After respiratory support, children with mild symptoms can gradually deoxygenate when the condition improves [3]. However, the course of disease in severely ill children can be prolonged to months or even years, with recurrent secondary respiratory tract infections and residual pulmonary dysfunction [4]. Therefore, early prevention and treatment of this disease is paramount.

At present, there is no standardized or reliable clinical treatment for BPD in premature infants, but the most widely used schemes such as prenatal hormone application, protective lung ventilation strategy, nutritional support, intubation-surfactant-exyubation (INSURE) technology, and drug treatment have proven to exert certain curative effects [5,6]. Of these, budesonide (BUD), as a glucocorticoid, has been shown to be able to inhibit respiratory inflammation, reduce respiratory hyperresponsiveness, relieve bronchospasms, improve ventilation function, and help premature infants be removed from oxygen inhalation and mechanical ventilation as soon as possible [7]. However, reports about the effect of BUD on pulmonary function in premature infants with BPD remains scant. In view of this, BUD was used to prevent and treat BPD in premature infants in this study, and its effects on pulmonary function and other indicators in premature infants were analyzed, specifically as follows.

Materials and methods

General data

Ninety-four premature infants born in the Qinghai Red Cross Hospital from December 2017 to December 2019 were selected as the research subjects, and they were divided into control group and research group according to a random number table, with 47 infants in each group. There was no significant difference in general data between the two groups (P>0.05), indicating group comparability (Table 1). This study was approved by the Medical Ethics Committee of Qinghai Red Cross Hospital.

Table 1.

Comparison of general data of the two groups of preterm infants (x̅ ± sd; n, %)

Groups	Control group (n=47)	Research group (n=47)	t/χ2	P
Gender (male/female)	28/19	26/21	χ2=0.174	0.677
Gestational age (weeks)	30.5±1.6	30.7±1.7	t=0.558	0.578
Weight (g)	1350.48±205.96	1325.63±200.74	t=0.592	0.555
Head circumference (cm)	27.77±1.16	28.14±1.44	t=1.372	0.173
Complications
Diabetes	7	9	χ2=0.301	0.583
Hypothyroidism	5	4	χ2=0.000	1.000
Apgar score immediately after birth	7.85±1.34	7.79±1.39	t=0.213	0.832

Inclusion and exclusion criteria

Inclusion criteria: The included premature infants were those with: (1) gestational ages <32 weeks; (2) birth weight <1500 g; (3) preterm delivery time ≥28 weeks; (4) mechanical ventilation; (5) no hereditary diseases from the parturients; (6) written informed consent from a guardian. Exclusion criteria: The excluded premature infants were those with: (1) hormone therapy within 28 days after birth; (2) congenital heart disease; (3) severe infectious diseases at admission; (4) liver and kidney failure; (5) pneumothorax or pulmonary infection.

Methods

Control group

The control group was given routine treatment. After admission, the premature infants were given symptomatic treatment such as oxygen inhalation, ventilator ventilation, nutritional support and pulmonary surfactant to promote alveolar maturation. In the meantime time, any disorder of calcium and phosphorus metabolism was corrected, balance of water, electrolytes, acids and bases were maintained, and antibiotics were used to prevent infection. Also, 0.9% normal saline was given as inhalation liquid for atomization treatment.

Research group

The research group was treated with BUD suspension (specification: 2 mL: 1 mg, AstraZeneca Pty Co., Ltd., Australia, registered number of approval: LOT325384) in addition to routine treatment. BUD (0.5 mL) was put into the container of ultrasonic atomizer (Jiangsu Yuyue Medical Equipment and Supply Co., Ltd., China, Su Food and Drug Administration Equipment (quasi) 2013 No.2230698), and the atomization tube was connected to the power supply for atomization inhalation twice a day. The premature infants in both groups were treated continuously for 2 weeks.

Outcome measures

Primary outcome measures

(1) Blood gas indexes: Arterial blood (4 mL) was drawn from premature infants before and 4 weeks after treatment for the determination of arterial oxygen saturation (SaO₂), arterial partial pressure of oxygen (PaO₂) and arterial partial pressure of carbon dioxide (PaCO₂) by the GEM premier 3000 Blood Gas Analyzer (Instrumentation Laboratory, United States).

(2) Inflammation indicators: Before and 4 weeks after treatment, the levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in premature infants were detected by radioimmunoassay with the GC-2010 Radioimmunoassay Counter provided by Anhui USTC Zonkia Scientific Instruments Co., Ltd., Hefei, China, and the levels of tumor necrosis factor (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA) with the aid of Beckman IAMMGE (Beckman Coulter Inc., United States). The kits were all purchased from Kerunda Bioengineering Co., Ltd., Shenzhen, China.

(3) Pulmonary function: Before and 4 weeks after treatment, the peak time ratio (TPTEE/TE), peak volume ratio (VPEF/VE) and expiratory flow rate (TEF25, TEF50, TEF75) at 25%, 50%, 75% of tidal volume (TEF25, TEF50, TEF75) were measured by the Pulmonary Function Test System CHEST AC-8800 (Chest M.I., Inc., Japan). Briefly, under the conditions of a stable heart rate and normal breathing, the premature infant was placed in a supine position after falling asleep. Then, the head and neck of the infant were kept neutral, and the mask was closely fastened to the mouth and nose of the infant to ensure smooth breathing and no air leakage. Finally, the flow velocity signals were transmitted to the computer through the flow velocity sensor for the detection of pulmonary function indexes.

(4) After treatment, the incidence of BPD was recorded according to Practical Neonatology (4th Edition) [5].

Secondary outcome measures

The time of oxygen inhalation, ventilator ventilation, extubation and hospitalization of premature infants were recorded.

The incidence of complications such as BPD, respiratory infection, patent ductus arteriosus, leukomalacia and septicemia during the treatment of premature infants was recorded, and various examinations were carried out.

Statistical methods

SPSS 23.0 software was used for data analysis. The measurement data were expressed as mean ± standard deviation (x̅ ± sd), and the inter-group comparison and the intra-group comparison before and after treatment were conducted by independent t test and paired t test respectively. The counting data were recorded as percentage and analyzed by chi-square test. P-value <0.05 was considered significant for all tests.

Results

General data

The general data such as gender, gestational age, weight, and head circumference showed no statistically significant difference between the two groups (P>0.05), indicating that the general characteristics of infants in both groups were comparable (Table 1).

Blood gas indexes

The blood gas indexes did not identify any significant difference between the two groups before treatment (P>0.05). After treatment, SaO₂ and PaO₂ increased in both groups, and their levels in the research group were higher than those in the control group; PaCO₂ decreased in the two groups, and the PaCO₂ concentration in the research group was lower than that in the control group (all P<0.01). The results indicate that BUD is beneficial to improve the ventilation function of premature infants (Table 2; Figure 1).

Table 2.

Comparison of blood gas indexes between the two groups of premature infants (x̅ ± sd)

Groups	Control group (n=47)	Research group (n=47)	t	P
SaO2 (%)
Before treatment	81.85±8.24	81.87±8.28	0.012	0.990
After treatment	96.86±5.47	99.57±4.18	2.699	0.008
t	10.404	13.083
P	<0.001	<0.001
PaO2 (mmHg)
Before treatment	45.28±5.35	45.16±5.25	0.110	0.913
After treatment	72.67±6.29	82.37±7.39	6.853	<0.001
t	22.740	28.141
P	<0.001	<0.001
PaCO2 (mmHg)
Before treatment	45.73±3.58	44.67±3.56	0.081	0.936
After treatment	40.30±3.58	38.25±3.37	2.858	<0.01
t	7.217	8.978
P	<0.001	<0.001

Note: SaO₂: arterial oxygen saturation; PaO₂: arterial partial pressure of oxygen; PaCO₂: arterial partial pressure of carbon dioxide.

Figure 1.

Comparison of blood gas indexes between the two groups of premature infants. A: SaO₂; B: PaO₂; C: PaCO₂. Compared with the same group before treatment, ***P<0.001; compared with control group, ##P<0.01, ###P<0.001. SaO₂: arterial oxygen saturation; PaO₂: arterial partial pressure of oxygen; PaCO₂: arterial partial pressure of carbon dioxide.

Inflammatory factors

Before treatment, there was no statistically significant difference in inflammatory response indicators between the two groups (P>0.05). After treatment, serum levels of TNF-α, IL-6 and IL-8 decreased in both groups, but the reductions were more significant in the research group (all P<0.001). This suggests that BUD contributes to the alleviation of inflammatory reactions in premature infants (Table 3; Figure 2).

Table 3.

Comparison of inflammatory factors between the two groups of preterm infants (x̅ ± sd)

Groups	Control group (n=47)	Research group (n=47)	t	P
TNF-α (μg/mL)
Before treatment	16.47±4.36	16.50±4.31	0.034	0.973
After treatment	11.98±3.74	8.36±3.04	5.149	<0.001
t	5.359	10.581
P	<0.001	<0.001
IL-6 (μg/mL)
Before treatment	14.71±3.46	14.93±3.52	0.306	0.760
After treatment	10.05±2.63	6.08±2.53	7.458	<0.001
t	7.351	13.996
P	<0.001	<0.001
IL-8 (pg/mL)
Before treatment	15.04±3.35	15.50±3.51	0.650	0.517
After treatment	10.18±2.44	6.58±2.63	6.880	<0.001
t	8.039	13.943
P	<0.001	<0.001

Note: IL-6: interleukin-6; IL-8: interleukin-8; TNF-α: tumor necrosis factor.

Figure 2.

Comparison of inflammatory factors between the two groups of preterm infants. A: TNF-α; B: IL-6; C: IL-8. Compared with the same group before treatment, ***P<0.001; compared with control group, ###P<0.001. IL-6: interleukin-6; IL-8: interleukin-8; TNF-α: tumor necrosis factor.

Pulmonary function

No significant difference was observed in pulmonary function between the two groups before treatment (P>0.05). After treatment, TPTEE/TE, VPEF/VE, TEF25, TEF50 and TEF75 all increased in both groups, and their values in the research group were higher than those in the control group (all P<0.01). These results demonstrate that BUD is favorable to improve the pulmonary function of premature infants (Table 4).

Table 4.

Comparison of pulmonary function between the two groups of premature infants (x̅ ± sd, %)

Groups	Control group (n=47)	Research group (n=47)	t	P
TPTEE/TE
Before treatment	19.71±2.06	19.93±2.32	0.486	0.628
After treatment	25.05±3.23	29.08±3.97	5.398	<0.001
t	9.556	13.642
P	<0.001	<0.001
VPEF/VE
Before treatment	20.47±2.36	21.10±2.51	1.254	0.213
After treatment	26.98±3.74	29.36±4.04	2.964	0.004
t	10.092	12.295
P	<0.001	<0.001
TEF25 (ms)
Before treatment	25.14±3.36	25.37±3.49	0.326	0.746
After treatment	29.25±3.63	32.63±4.15	4.203	<0.001
t	5.697	9.179
P	<0.001	<0.001
TEF50 (ms)
Before treatment	39.71±4.46	38.93±4.12	0.248	0.805
After treatment	45.05±5.63	49.08±5.93	3.379	0.001
t	5.097	9.637
P	<0.001	<0.001
TEF75 (ms)
Before treatment	43.47±5.26	44.50±5.51	0.927	0.356
After treatment	50.98±6.74	56.36±6.24	4.016	<0.001
t	6.022	9.767
P	<0.001	<0.001

Note: TPTEF/TE: the ratio of time taken to reach peak expiratory flow to total expiratory time; VPEF/VE: the ratio of peak expiratory volume to total expiratory volume.

Treatment-related indicators

The oxygen inhalation time, ventilator ventilation time, extubation time and hospitalization time in the research group were all less than those in the control group (all P<0.001), indicating that BUD is conducive to shortening the duration of oxygen inhalation and ventilator usage in premature infants (Table 5; Figure 3).

Table 5.

Comparison of treatment-related indicators of preterm infants between the two groups (x̅ ± sd, d)

Groups	Oxygen inhalation time	Ventilator ventilation time	Extubation time	Hospitalization time
Control group (n=47)	15.4±1.5	5.4±0.4	5.8±1.0	38.4±2.7
Research group (n=47)	13.9±1.1	4.2±0.3	4.3±1.1	33.7±2.0
t	5.478	16.618	6.678	9.657
P	<0.001	<0.001	<0.001	<0.001

Figure 3.

Comparison of treatment-related indicators between the two groups of preterm infants. A: Oxygen inhalation time; B: Ventilator ventilation time; C: Extubation time; D: Hospitalization time. Compared with control group, ###P<0.001.

Incidence of BPD and other complications

The incidence of BPD and other complications in the research group was lower than that in the control group (P<0.05), suggesting that BUD is beneficial to reduce the incidence of complications in premature infants (Table 6).

Table 6.

Comparison of the incidence of bronchopulmonary dysplasia and other complications between the two groups of premature infants (n, %)

Groups	Control group (n=47)	Research group (n=47)	χ2	P
Incidence of bronchopulmonary dysplasia	11 (23.40)	4 (8.51)	3.887	0.049
Respiratory tract infection	5 (10.64)	2 (4.26)	0.617	0.432
Pulmonary hypertension	2 (4.26)	0 (0.00)	0.511	0.475
Patent ductus arteriosus	1 (2.13)	0 (0.00)	0.000	1.000
White matter softening	0 (0.00)	1 (2.13)	0.000	1.000
Septicemia	2 (4.26)	0 (0.00)	0.511	0.475
Total incidence	10 (21.28)	3 (6.38)	4.374	0.036

Discussion

BPD reduces the oxygen-carrying function of the blood, leading to respiratory distress syndromes in children [6]. The early stages of the disease will lead to inflammatory reactions and exudation in the lungs, while in the later stages, it can cause lung scarring and alveolar wall rupture, resulting in serious lung injury [7]. Oxygen with mechanical ventilation support is the mainstay to prevent and treat BPD in premature infants, but on the other hand, it also increases the risk of respiratory infection and brain tissue injury, especially virus infection. If the infection invades the lungs, it may lead to rapid decompensation of pulmonary function in premature infants within one year, aggravating lung injury [8].

BUD was used for atomization inhalation treatment in the present study. It was found that after treatment, the improvement of blood gas indexes in the research group was better than that in the control group, suggesting that BUD can effectively improve blood gas indexes and pulmonary function of premature infants. Similar to our results, the research of Cheng also revealed that the blood gas indexes of premature infants with BPD were notably improved after treatment with BUD [9]. PaO₂ is the pressure value produced by the dissolution of oxygen molecules in arterial blood, which can be used to judge the severity of hypoxia in the body. The normal value of PaO₂ in premature infants is 50-70 mmHg, and a lower value indicates that the body is in a hypoxic state [10]. While PaCO₂ is commonly used to measure alveolar ventilation, with a normal range of 35-45 mmHg in newborns. Increased PaCO₂ indicates respiratory acidosis, and can also lead to cerebral microvascular dilatation, and hyperemia, inducing brain edema. PaCO₂>50 mmHg is suggestive of respiratory failure, while PaCO₂ reduction is commonly seen in mechanical hyperventilation [11]. SaO₂ can indirectly reflect the value of PaO₂, and the normal reference value of SaO₂ is between 85% and 95%. SaO₂<85% implies that premature infants are in respiratory failure, while SaO₂<80% is equivalent to PaO₂<50 mmHg, indicating that the premature infants are in a state of severe hypoxia [12]. As for TPTEF/TE, it is the main index reflecting airway obstruction. The lower the ratio of TPTEF/TE, the more serious the airway obstruction in premature infants. VPEF/VE changes are roughly the same as TPTEF/TE, which is another indicator reflecting airway obstruction [13]. According to Fudan University, TPTEF/TE and VPEF/VE values can be classified into mild (23%-28%), moderate (15-22%) and severe obstruction (<15%) [14]. The results of this study showed that after treatment, TPTEE/TE, VPEF/VE, TEF25, TEF50 and TEF75 all increased in both groups, and the values in the research group were higher than those in the control group. Li et al. used BUD to treat premature infants with BPD, and found that after 2 weeks of treatment, pulmonary function indicators such as tidal volume, VPEF/VE and TPTEE/TE were significantly improved, which were consistent with the results of this study [15]. It suggests that BUD can effectively improve the pulmonary function of premature infants with BPD.

It has been clinically found that inflammatory reactions are also a key to this disease. Premature infants have immature immune systems that lack defense mechanisms against inflammatory mediators, leading to elevated levels of IL-6, IL-8 and TNF-α. With intricate biological activity, TNF-α acts on vascular endothelial cells and plays a role in immune regulation, infection and inflammatory response [16]. It can enhance the bactericidal effect by activating neutrophils, and promote inflammatory reactions via inhibiting or enhancing the secretion of inflammatory factors. IL-6, a pleiotropic cytokine and a key component of inflammatory mediator networks, can regulate the secretion of various cells and is capable of modulating immune responses and hematopoietic function. A variety of infectious diseases can lead to a significant increase in IL-6. When infection occurs in the body, the activity of inflammatory factors will be activated, and IL-6 will be generated first to induce TNF-α secretion, thus playing an important role in the body’s anti-infection response [17]. The main biological activity of IL-8 is to activate neutrophils to release a series of active products, thereby inducing collective inflammatory reactions that lead to cell damage [18]. In this study, the levels of serum TNF-α, IL-6 and IL-8 in the research group were all lower than those in the control group after treatment, suggesting that BUD can effectively reduce inflammatory reactions in premature infants with BPD.

BUD is mostly used in the treatment of diseases such as chronic obstructive pulmonary disease and bronchial asthma. It has a potent anti-inflammatory effect, which is conducive to lowering airway inflammation and hypersensitivity, contracting respiratory blood vessels, decreasing mucus secretions and promoting the improvement of airway symptoms, as well as reducing respiratory resistance [19,20]. In addition, BUD is water-soluble to a certain extent, which can maintain the effective blood concentration in the mucosal layer while binding to the mucosal tissues, so that the drug action time can be prolonged, increasing the ability of anti-inflammation. For premature infants, small doses and atomization inhalation are used, which help to deposit most of the drug in the lungs to directly act on the lung cells. With high concentration of drugs in target organs, the drug is more effective, and the side effects of systemic medication can be avoided [21,22]. The results of this study revealed that after treatment, oxygen inhalation time, ventilator ventilation time and hospitalization time in the research group were effectively shortened compared with those in the control group, and the incidence of BPD was lower. Which further confirms that BUD is effective in the prevention and treatment of BPD in premature infants, which can help premature infants come off of a ventilator and extubation as soon as possible, reducing the incidence of BPD and be discharged earlier. Pulmonary hypertension is also one of the common complications in premature infants, which may be associated with increased pulmonary arterial pressure and elevated vascular resistance caused by pulmonary vascular immaturity or endothelial cell fibrosis [23]. The increase of pulmonary artery pressure will enormously impair the exchange of qi and blood, thus increasing the duration of oxygen inhalation and mechanical ventilation, and even aggravate the development of BPD [24]. Although BUD cannot facilitate the maturity of pulmonary vessels and alveoli in premature infants, it can reduce the severity and incidence of complications such as pulmonary hypertension by alleviating inflammatory reactions [25]. Our results also revealed that the complication rate was lower in the research group, indicating that BUD has a considerable effect in reducing complications.

However, due to the small sample size of this study and the lack of a multicenter, prospective and randomized large sample control study, the results of this study need to be further tested for evidence in the future.

To sum up, given that BUD is beneficial to lower the incidence of BPD and other complications, improving blood gas indexes and pulmonary function of premature infants, reducing inflammatory reactions, and helps infants no longer need oxygen inhalation and mechanical ventilation as soon as possible, its efficacy in the prevention and treatment of BPD in premature infants deserves recognition.

Disclosure of conflict of interest

None.