Inhaled Budesonide in Neonatal Respiratory Distress Syndrome of Near-Term Neonates: A Randomized, Placebo-Controlled Trial

Abstract

OBJECTIVE

This study evaluates the value of inhaled budesonide (BUD) administration in neonatal respiratory distress syndrome (RDS) cases especially for near-term neonates.

METHODS

A randomized controlled trial involving 120 neonates with respiratory distress, which was diagnosed as RDS, was conducted from July 2016 to March 2018. The neonates studied were divided into 2 groups: group 1 (the inhaled BUD group), consisting of 60 neonates who received BUD (2 mL, 0.25-mg/mL suspension) inhalation, twice daily for 5 days; and group 2 (the placebo group), consisting of 60 neonates with RDS who received humidified distilled sterile water inhalation (2 mL). Downes score, RDS grades, and interleukin 8 (IL-8) levels were monitored and measured on the first and fifth days of incubation.

RESULTS

Statistically significant differences (SSDs) in RDS grades, Downes score, and IL-8 levels on the fifth day of admission were observed between groups 1 and 2 (p = 0.001) and between the first and fifth days of incubation in group 1 (p = 0.001). The SSDs in the duration of hospitalization (p = 0.001) and the number of neonates receiving mechanical ventilation (p = 0.032) were found between both groups.

CONCLUSIONS

Budesonide inhalation is associated with improvements in clinical and laboratory parameters in neonates with RDS

Introduction

Respiratory distress syndrome (RDS) is a widespread serious chest disorder, especially in premature neonates. The main risk factors for the development of RDS include prematurity and asphyxia.^1,2 RDS is caused by defects in the secretion of surfactant due to immaturity of type II pneumocytes in the alveoli.^3,4 Surfactant deficiency, leading to alveolar collapse, causes respiratory distress due to defective gas exchange.^5,6 RDS could be prevented by several lines of treatment, including the administration of antenatal steroids to the mothers and exogenous surfactant to the premature neonates.^7–10

Neonatal RDS is considered an inflammatory process in the immature lung; according to the severity of inflammatory injury to the alveoli, subsequent leakage of serum proteins will cause surfactant inactivation.^11–15 Several studies have suggested that the inflammatory process is the main cause of pathogenesis in neonatal RDS.¹⁶ Inflammatory cytokines, such as interleukin 8 (IL-8), play an important role in lung damage among preterm infants with RDS and chronic lung disease.¹⁷ The apoptotic process occurring in the epithelial cells of the neonatal lung, induced by the inflammatory process, causes inflammatory lung damage in neonatal RDS.¹⁸

Anti-inflammatory agents like corticosteroids have a beneficial role in the management of neonatal RDS by interfering with the inflammatory processes in the neonatal lungs^19–22; however, systemic corticosteroids can have multiple adverse effects, including intestinal bleeding and growth failure.^23,24 Local inhaled corticosteroids like budesonide (BUD) might reduce lung inflammation with subsequent improvement in the severity of neonatal RDS but with undetectable adverse effects, compared with systemic corticosteroids.^25–27

Thus, this study evaluates the value of inhaled BUD administration in neonatal RDS cases especially for near-term neonates.

Materials and Methods

A prospective double-blinded randomized controlled trial involving 120 neonates with respiratory distress and diagnosed with RDS was conducted at the NICU of Tanta University Hospital from July 2016 to March 2018 and registered to the Thai Clinical Trials Registry (identification No.: TCTR20201228003). The neonates included in this study were divided into 2 groups by using the lottery method for randomization: group 1 (the inhaled BUD group) consisted of 60 neonates who received BUD inhalation, and group 2 (the placebo group) consisted of 60 neonates who received placebo.

Diagnosis of RDS. The clinical diagnosis of RDS was classified as grade 1 (tachypnea only), grade 2 (retraction with tachypnea), grade 3 (grade 2 with grunting), and grade 4 (grade 3 with cyanosis). With regard to chest x-ray findings, RDS was classified as grade 1 where fine granular densities are found, grade 2 where air bronchograms are observed, grade 3 where the characteristic ground-glass appearance is perceived, and grade 4 where white lungs are observed.²⁸

Neonates diagnosed with RDS were included in this study, whereas neonates with any type of infection, respiratory diseases other than RDS, heart lesions, neurological lesions, and those who received exogenous surfactant were excluded from the study. The sample size and power analysis were calculated by using Epi-Info software statistical package, version 2002 (Atlanta, GA).²⁹ The criteria used for sample size calculation were as follows: 95% confidence limit, 80% power of the study. The sample size was N = 60 for each study group.²⁹

Drug Administration. Group 1 received BUD inhalation (2 mL, 0.25-mg/mL suspension) (AstraZeneca, Södertälje, Sweden) in addition to 2 mL of 0.9% saline via nebulization through a face mask connected to an oxygen flowmeter (5 L/min), twice daily for 5 days; and in neonates who needed invasive mechanical ventilation (MV), we used accessory ventilator pieces to deliver BUD. Group 2 received humidified distilled sterile water (2 mL). These procedures were done by the nurses responsible for those neonates, and the physicians were blinded to these procedures (double-blinded). The study had started immediately after diagnosis and admission (in the first 6 hours of birth in both groups) as shown in Table 1.

Table 1.

Comparative Characteristics Between the Studied Groups

Demographics	Group 1: Inhaled BUD (n = 60)	Group 2: Placebo (n = 60)	Test	p value
Weight, mean ± SD, kg	2.27 ± 0.8	2.28 ± 0.79	t: 0.069	0.945
Gestational age, mean ± SD, wk	35.5 ± 1.2	35.6 ± 1.3	t: 0.442	0.662
Apgar score at 5 min, mean ± SD	6.15 ± 0.3	6.2 ± 0.25	t: 0.989	0.323
Age on admission, mean ± SD, hr	5.1 ± 0.9	5 ± 1	t: 0.583	0.657
Downes scores on admission, mean ± SD	5.96 ± 0.12	5.95 ± 0.13	t: 0.441	0.662
RDS grades on admission, mean ± SD	2.24 ± 0.45	2.23 ± 0.46	t: 0.123	0.904
Sex, n (%)
Male	45 (75)	46 (77)	χ2: 0.046	0.831
Female	15 (25)	14 (23)
Mode of delivery, n (%)
Normal vaginal delivery	18 (30)	17 (28)	χ2: 0.040	0.841
Caesarean section	42 (70)	43 (72)
Duration of hospitalization, mean ± SD, days	8.2 ± 1.6	11 ± 1.9	8.729	0.001
Mortality, n (%)	1 (1.7)	3(5)	1.029	0.309

BUD, budesonide; RDS, respiratory distress syndrome

Data Collection. History, chest examination, and radiography (x-ray) were performed for all neonates studied to diagnose RDS; RDS grades and Downes scores were obtained on the first and fifth day after admission (first and fifth day of life), and C-reactive protein test was done to exclude infection.

Specimen Collection and Measurement of IL-8 and Proinflammatory Cytokines. From each neonate, 1 ml of blood sample was obtained on the first and fifth day of admission (first and fifth day of life). Serum IL-8 levels were estimated. The samples were stored at temperatures ranging from −20°C to −70°C. Serum IL-8 levels were measured with enzyme-linked immunosorbent assay.³⁰

Statistical Analysis. All statistical analyses were performed with Statistical Package for the Social Sciences, version 21 (IBM Corp, Armonk, NY). Data were presented as mean ± standard deviation. The independent-samples t test was used to compare the 2 groups. Paired-samples t test was used for comparisons in the same group. For qualitative data, the χ² test was used. p values less than 0.05 were used to denote statistical significance.

Results

Initially, 161 near-term neonates were considered for inclusion; of these, 24 neonates were excluded because they did not meet the inclusion criteria. In addition, 15 neonates were excluded by exclusion criteria, and the parents of 2 neonates declined to participate because of transfer to another hospital. Finally, 120 neonates were included in this study, 60 neonates for inhaled budesonide group & 60 neonates for placebo group. Only 4 cases in inhaled budesonide group who had needed invasive ventilation while 12 cases in placebo group had needed invasive ventilation. Only 1 case was died in inhaled budesonide group while 3 cases were died in placebo group. (Figure).

Figure.

Consort or study flow chart of participating neonates in the study.

Local antifungal prophylaxis was orally administered to the neonates in group 1; thus, no side effects were detected after BUD inhalation in this study. Nurses responsible for these neonates performed this procedure and the physicians were blinded to it (double-blinded).

A non–statistically significant difference (non-SSD) in the comparative characteristics was observed between both groups (Table 1). In addition, non-SSDs in RDS grades and Downes scores on admission were found between both groups (p = 0.904 and 0.662, respectively) and between the first and fifth day after admission in group 2 (p = 0.066 and 0.070, respectively), whereas SSDs in RDS grades and Downes scores on the fifth day after admission were observed between both groups (p = 0.001 and 0.001, respectively) and between the first and fifth day after admission in group 1 (p = 0.001 and 0.001, respectively) (Table 2).

Table 2.

Comparison Between RDS Grades, Downes Scores, and IL-8 Levels for Both Groups on the First and Fifth Days of Admission

	Group 1: Inhaled BUD (n = 60)	Group 2: Placebo (n = 60)	t test	p value
RDS grades, mean ± SD
On first day of admission,*	2.24 ± 0.45	2.23 ± 0.46	0.123	0.904
On fifth day of admission	0.9 ± 0.35	1.89 ± 0.61	11.629	0.001
p value	0.001	0.003
Downes scores, mean ± SD
On first day of admission*	5.96 ± 0.12	5.95 ± 0.13	0.441	0.662
On fifth day of admission	3.651 ± 0.9	5.59 ± 1.52	8.501	0.001
p value	0.001	0.070
Serum IL-8 levels, mean ± SD, pg/mL
On first day of admission*	519 ± 59.1	518 ± 60.2	0.089	0.927
On fifth day of admission	161.1 ± 68.7	489 ± 99.4	21.018	0.001
p value	0.001	0.056

BUD, budesonide; IL-8, interleukin 8; RDS, respiratory distress syndrome

* First day of life.

A non-SSD in serum IL-8 levels on admission was found between both groups (p = 0.927) and between the first and fifth day after admission in group 2 (p = 0.056), whereas an SSD in serum IL-8 levels was found on the fifth day after admission between both groups (p = 0.001) and between the first and fifth day after admission in group 1 (p = 0.001) (Table 2).

Binary logistic regression analysis of RDS grades, Downes scores, and serum IL-8 levels at the fifth day of admission showed that the p value of RDS grades, Downes scores, and serum IL-8 levels at the fifth day of admission were significant at 0.001, 0.004, and 0.001, respectively; this finding indicated that serum IL-8 levels were superior to RDS grades and Downes scores in the diagnosis of neonatal RDS (Table 3).

Table 3.

Binary Logistic Regression Analysis of RDS Grades, Downes Scores, and Serum IL-8 Levels at the Fifth Day of Admission

Fifth Day of Admission	Odds Ratio	95% Confidence Interval	p value
RDS grades	0.632	0.297–0.854	0.001
Downes scores	0.429	0.145–0.745	0.004
Serum IL-8, pg /mL	0.597	0.397–0.854	0.001

IL-8, interleukin 8; RDS, respiratory distress syndrome

Moreover, an SSD in the number of cases requiring only nasal cannula–delivered oxygen (2 L/min) and the number of cases that required invasive MV was observed between both groups (p = 0.003 and 0.032, respectively), whereas a non-SSD in the number of cases that required nasal continuous positive airway pressure was found between both groups (p = 0.426) (Table 4).

Table 4.

Number of Cases According to Their Requirement for Various Types of Respiratory Support

Cases Needing	Group 1: Inhaled BUD (n = 60)	Group 2: Placebo (n = 60)	χ2 Test	p value
Nasal cannula, 2 L/min, n (%)	16 (26.7)	4 (6.7)	8.637	0.003
Nasal continuous positive airway pressure, n (%)	40 (66.7)	44 (73.3)	0.631	0.426
Invasive mechanical ventilation, n (%)	4 (6.7)	12 (20)	4.607	0.032

BUD, budesonide

An SSD in the duration of neonatal hospitalization (days) was observed between both groups (p = 0.001). The mortality rate for the inhaled BUD group was 1.7% (n = 1) and was lower than that for the placebo group, which was 5% (n = 3) (Table 1). There were 2 cases (3.4%) of pneumothorax in the inhaled BUD group compared with 6 cases (10%) in the placebo group.

Discussion

This study investigated the therapeutic effect of BUD inhalation on neonatal RDS. The results of this study will contribute to the literature by highlighting the possibility of using inhaled BUD as a safe, cheap, and effective adjuvant therapy for neonatal RDS. Several studies have suggested that the process of inflammation is the main cause of pathogenesis in RDS in neonates,¹⁶ so we use IL-8 in addition to RDS grades and Downes score for follow-up in our cases.

This study showed an SSD in RDS grades, Downes scores, and serum IL-8 levels on the fifth day of incubation between both groups (p = 0.001) and between the first and fifth day after admission in group 1 (p = 0.001). In addition, SSDs in the duration of hospitalization and the number of cases requiring MV were found between groups 1 and 2 (p = 0.001 and 0.032, respectively). This study revealed that the mortality rate (1.7%) for the inhaled BUD group was lower than that (5%) for the placebo group, but the difference was insignificant (p = 0.309).

Moreover, this study revealed that the Downes scores of neonates who received BUD inhalation in group 1 improved when compared with those of neonates with RDS who did not receive BUD inhalation; this finding conforms to other studies showing that premature neonates with RDS who receive steroid inhalation have reduction in complications with no evident adverse effects.³¹

In addition, this study revealed that neonates with RDS who received BUD inhalation (group 1) had decreased RDS grades when compared with those in group 2 (the placebo group); this finding conforms to the findings of other studies in which early administration of inhaled BUD/formoterol in neonates with RDS leads to improved oxygenation.³²

In this study, increased serum IL-8 levels were observed in neonates with RDS who did not receive BUD inhalation, and the same result was observed by some researchers who have reported that neonates with RDS have elevated levels of proinflammatory cytokines, especially IL-8, and serum IL-8 levels are correlated with the severity of RDS.³³

Moreover, in this study, inhaled BUD–treated neonates with RDS had a shorter hospitalization duration than the neonates in the placebo group; this finding is in agreement with other studies reporting that BUD inhalation in neonates with RDS is associated with a decreased incidence of complications, which are caused by a long stay in an incubator with oxygen as in neonates with bronchopulmonary dysplasia (BPD).³⁴

This study showed that no obvious side effect had occurred in the inhaled BUD group, and this result conforms to the results of other studies that have reported that BUD inhalation seems an obvious logical alternative to systemic steroids, with minimal or nearly absent obvious side effects with the same beneficial effect on RDS.^35–39

In this study, the inhaled BUD group had both fewer neonates requiring MV and a lesser mortality rate than the placebo group, and this conforms to other studies stating that early steroid inhalation therapy may be beneficial to ventilated premature neonates with RDS⁴⁰ and also conforms to studies that have concluded that steroid inhalation with surfactant is an effective and safe option for neonates with RDS for preventing BPD and reducing mortality.⁴¹

Some studies have shown that using a mixture of BUD and surfactant decreases the risk of BPD in premature neonates with RDS, which partially conforms to the results of this study.⁴² However, another study has concluded that inflammatory conditions and the number of complicated cases of BPD in neonates with RDS did not improve after BUD inhalation.⁴³ The results of this study contradict the results of a study showing that steroid inhalation in neonates with RDS did not decrease the cytokine response or improve neonatal respiratory functions.⁴⁴

The outcomes of several studies have suggested that BUD inhalation improves neonatal pulmonary functions with negligible adverse effects. In addition, evidence exists for the clinical efficacy and safety of BUD inhalation as a well-established anti-inflammatory drug for preventing and treating several pulmonary diseases.^45,46

Conclusion

This study concluded that BUD inhalation improves the clinical and laboratory parameters in neonates with RDS; moreover, this study recommends BUD inhalation for neonates with RDS, and further studies should be conducted on the same topic, using a large number of neonates.

Glossary

ABBREVIATIONS

BPD

bronchopulmonary dysplasia

BUD

budesonide

IL-8

interleukin 8

MV

mechanical ventilation

NICU

neonatal intensive care unit

non-SSD

non–statistically significant difference

RDS

respiratory distress syndrome

SSD

statistically significant difference