Comparison of Intratracheal Administration of Surfactant With or Without Budesonide to Prevent Bronchopulmonary Dysplasia: A Parallel Randomized Pilot Study

Abstract

Background

While advancements in premature neonatal care have led to a reduction in mortality and respiratory distress syndrome (RDS), the incidence of bronchopulmonary dysplasia (BPD) has remained unchanged over the past few decades. Few small, randomized trials have shown intratracheal budesonide in a surfactant vehicle as a promising treatment to reduce the incidence of BPD.

Objective

To investigate whether intratracheal administration of surfactant combined with budesonide results in decreased incidence of BPD, death, and other morbidities in preterm infants who were born <28 weeks and <1 kg.

Study Design

Prospective two-arm pilot randomized controlled trial with concurrent parallel design.

Participants and Methods

This study included extreme preterm (<28 weeks) and extreme low birth weight newborns with severe RDS. Neonates were randomly allocated to one of two groups (60 intervention and 61 control). The intervention group received intratracheal surfactant and budesonide, while the control group received only surfactant.

Results

The study population had a mean gestational age of 26.1 ± 0.2 weeks and birth weight of 766.1 ± 29.1 g. Death (RR 0.61 (0.1-3.62); P = 1.00) and combined BPD or death (RR 0.86 (0.55-1.33); P = .88) exhibited a nonsignificant decreasing trend. However, any intraventricular hemorrhage (IVH), severe brain injury (≥III IVH or periventricular leukomalacia), oxygen requirement at 24 h of life, and ventilation days were significantly lower in the intervention group.

Conclusion

Intratracheal budesonide and surfactant did not reduce BPD or death. As a pilot study, this study speaks about the trend and was not powered to comment on the significance of the result. Oxygen, ventilation needs, and preterm brain injury are considerably lesser with when budesonide is combined with surfactant among extreme preterm newborns.

Keywords

Bronchopulmonary dysplasia budesonide exogenous surfactant extreme preterm

Introduction

Bronchopulmonary dysplasia (BPD) is a complex respiratory condition resulting from mechanical ventilation in premature infants. Modern intensive care has resulted in approximately 85% survival rates for infants born extremely preterm; however, at least 50% of these infants subsequently develop BPD.¹ Nearly all infants born extremely preterm experience respiratory distress syndrome (RDS), with approximately 90% receiving exogenous surfactant therapy within the first 24 h post-birth.¹ Despite the introduction of surfactant therapy and significant advancements in neonatal care, the rates of BPD remain unchanged.² Early administration of continuous positive airway pressure (CPAP), vitamin A, and caffeine reduces the incidence of BPD.³ In neonates requiring intubation or ventilation, no intervention can entirely avert BPD.

Lung inflammation and host immune responses may cause BPD.⁴ Anti-inflammatory systemic glucocorticoids like dexamethasone are used to treat and prevent BPD, but have neurological side effects.⁵ Bench study showed budesonide given locally to airway and lung tissue has faster action, longer anti-inflammatory effect, and fewer systemic side effects.^{6, 7} Early inhaled budesonide therapy lowers BPD in preterm newborns owing to its significant topical effects.⁸ Prior to the inflammatory and oxidative damage cascade, intratracheal budesonide administration along with surfactant may help in reduction of BPD.

A study by Yeh et al. on very low birth weight (VLBW <1,500 g) infants indicates the feasibility, safety, and benefits of administering intratracheal corticosteroids during the acute phase of neonatal RDS.⁹ The objective of this study was to examine the impact of intratracheal budesonide combined with surfactant on BPD incidence in a high-risk cohort of extreme low birth weight (ELBW <1,000 g) and extreme preterm (<28 weeks) infants.

Materials and Methods

Study Population

This open-label randomized pilot trial with concurrent parallel design was done in a level 3 neonatal intensive care unit (NICU) in India, from March 2020 to March 2022. Institutional Ethics Committee permission was obtained, and this study was registered in the Clinical Trial Registry – India (CTRI). This study included inborn neonates with gestational age of (24-27⁺⁶) weeks and birth weight <1,000 g with severe RDS who received mechanical ventilation and exogenous surfactant for RDS within 6 h of life. Neonates with major congenital anomalies or lethal cardiopulmonary disorders were excluded. These babies were at risk of BPD. Informed written parental/guardian consent was obtained prior to randomization by the clinician using a specially designed information and consent form.

Surfactant and Budesonide Regimens, Dosages, and Randomized Procedures

Block randomization with computer-generated permuted blocks of six was used, with half of the infants assigned to the intervention group and half to the control group. Allocation concealment was done by using sequentially numbered, opaque, sealed envelopes. Infants from multiple births were randomized individually. The intervention group received surfactant and budesonide. The surfactant used in our investigation was CUROSURF 200 mg/kg (2.5 mL/kg of an 80 mg/mL solution), manufactured by Chiesi Farmaceutici in Parma, Italy. As an intratracheal steroid (intervention group), we used 0.25 mg/kg budesonide (0.5 mg/2mL solution), Cipla, India, along with surfactant. An in vitro investigation of surfactometer and high-performance liquid chromatography showed that surfactant and budesonide mixture did not affect the biophysical and chemical properties of the surfactant.¹⁰ The surfactant and budesonide mixture looks similar to a surfactant and does not discolor or crystallize. The syringe was gently vortexed before intratracheal instillation, and the surfactant or surfactant with budesonide mixture was delivered as usual. Repeat doses of surfactant (100 mg/kg) with budesonide for infants in the intervention group and surfactant only for infants in the control group were given every 6-12 h if fraction of inspired oxygen (FiO₂) requirement was >30% after optimal lung recruitment.

Neonatal Intensive Care

After delivery, for neonates with respiratory distress, nasal continuous positive airway pressure (NCPAP) was initiated. Infants intubated with >30% FiO₂ with adequate NCPAP, poor respiratory efforts, or apnea were randomized to surfactant only or surfactant plus budesonide. During the NICU stay, patient triggered (assist control or synchronized intermittent mandatory ventilation) with volume guarantee mode was initiated. Neonates were extubated to NCPAP when the baby stabilized and required positive inspiratory pressure of 14-16 cm and FiO₂ <30%-40%. Intravenous fluid, parenteral nutrition, and feed were planned as per intensive care unit (ICU) protocol. Infants with hemodynamically significant patent ductus arteriosus (HsPDA) were administered intravenous paracetamol. Postnatal systemic dexamethasone was reserved for newborns on positive pressure ventilation with a FiO₂ >40%, even after 14 days of life. After parental consent, low-dose dexamethasone (DART regimen) was initiated if needed.¹¹

Outcome Measurements

Primary Outcomes

The primary outcomes looked at were death, BPD, and combined death plus BPD. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH, Bethesda, MD) definition of BPD, which is severity-based, was used in our study.¹²

Definition of BPD

Treatment with oxygen >21% for at least 28 days plus breathing room air at 36 weeks postmenstrual age (PMA) or discharge (mild BPD); need for <30% oxygen at 36 weeks PMA or discharge (moderate BPD); need for ≥30% oxygen and/or positive pressure at 36 weeks PMA or discharge (severe BPD).

Secondary Outcomes

Prematurity or steroid-related morbidities were studied as secondary outcomes. Intraventricular hemorrhage (IVH) as defined by Papile,¹³ cystic periventricular leukomalacia (PVL), retinopathy of prematurity (ROP) as defined by the International Classification of Retinopathy of Prematurity,¹⁴ patent ductus arteriosus (PDA) requiring treatment, necrotizing enterocolitis (NEC) with modified Bell’s criteria stage 2 or greater,¹⁵ spontaneous intestinal perforation (SIP), late-onset sepsis after 72 h of age were monitored. Hypertension and hyperglycemia requiring treatment and other outcomes such as inotrope use, repeat dose of surfactant, pneumothorax, pulmonary hemorrhage, days of respiratory support (invasive and noninvasive), and length of hospital stay were also noted.

Statistical Analysis

According to our past experience, approximately 80% of infants who met the inclusion criteria developed BPD or died. Power analysis was performed, assuming a reduction of BPD or death from 80% in the control group to 70% in the intervention group. A total of 778 patients were considered adequate for the study, with a 5% probability of type I error and a 10% chance of type II error.¹⁶ Being a pilot study, we needed 10% of the total required population,¹⁷ with 40 in each group as the sample size for this study.

The data were collected using a standardized study proforma and transferred to MS Excel for further analysis. The continuous variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR). The categorical variables were expressed as % of frequency distribution. The two groups were compared by using either Student’s t-test, median test, or Fisher’s exact test, depending on the type of variables. To account for multiple outcomes, Bonferroni-corrected P values were presented for all the outcomes. All P values are two-sided, and an association was considered significant if P < .05. We reported relative risk (RR) with 95% confidence interval. Statistical Package for the Social Sciences (SPSS, version 27th) was used for all statistical analyses.¹⁸

Results

Patient Population

A total of 206 newborns were screened for study eligibility. In the first 6 h after birth, 145 neonates needed ventilation and surfactant for severe RDS. Of the 145 patients, 24 were excluded for various reasons: left hospital before the final outcome was assessed (9), did not consent (11), had multiple congenital defects (3), and death after extensive resuscitation in the delivery room (1). In this study, 121 neonates were randomized and analyzed: 60 in the intervention group (budesonide + surfactant) and 61 in the control group (surfactant). The mean gestational age of the study group was 26.1 ± 0.2 weeks, and the mean birth weight was 766.1 ± 29.1 g. The baseline characteristics were comparable between the groups (Table 1).

Table 1.

Comparison of Baseline Characteristics Among Study Groups.

Variables	Intervention (n = 60)	Control (n = 61)	P Value
Birth weight (mean)	775.1 ± 43.1	756.9 ± 39.8	.529
Gestation age	26.3 ± 0.4	26.0 ± 0.4	.260
Male	32/60 (53.3%)	28/61 (45.9%)	.469
SGA	6/60 (10%)	4/61 (6.5%)	.529
Antenatal betamethasone (two doses)	44/60 (73.3%)	45/61 (73.7%)	1.00
Chorioamnionitis	3/60 (5%)	5/61 (8.1%)	.717
Cesarean section	40/60 (66.6%)	37/61 (60.6%)	.571
DR—CPAP	10/60 (16.6%)	12/61 (19.6%)	.814
DR—intubation	50/60 (83.3%)	49/61 (80.3%)	.814
APGAR at 1 min, median (range)	5 (1–8)	5 (1–9)	.264
APGAR at 5 min, median (range)	7 (3–9)	7 (2–9)	.959
Modified CRIB II, median (range)	9 (7–14)	10 (6–13)	.266

Note: CPAP, continuous positive airway pressure; CRIB, clinical risk index for babies; DR, delivery room; SGA, small for gestation age.

Primary Outcomes

Primary outcomes examined in this study were incidence of death, BPD, and combined death or BPD. Death (intervention group: 9/60 [15%]; control group: 15/61 [24.5%]; P = 1.00) and combined BPD or death (intervention group: 44/60 [73.3%]; control group: 52/61 [85.2%]; P = .88) both showed decreasing trends in intervention group, which was not statistically significant. Incidence of BPD (intervention group: 35/60 [58.3%]; control group: 37/61 [60.6%]; P = 1.0) and the combined outcomes of death or severe BPD (intervention group: 14/60 [23.3%]; control group: 27/61 [44.2%]; P = .15) were similar in both groups (Table 2). In the intervention group, out of the 9 deaths, 2, 1, and 6 occurred on the third, before the seventh, and after the seventh days of life, respectively, compared to 5, 3, and 7 in the control group.

Table 2.

Primary Outcomes in Study Groups.

Variables		Intervention (n = 60)	Control (n = 61)	RR (95% CI)	Adjusted P Value
Death		9/60 (15%)	15/61 (24.5%)	0.61 (0.1–3.62)	1.000
BPD		35/60 (58.3%)	37/61 (60.6%)	0.96 (0.47–1.94)	1.000
BPD (severity)	Mild	22/60 (36.6%)	22/61 (36%)	1.01 (0.33–3.09)	1.000
	Moderate	8/60 (13.3%)	3/61 (4.9%)	2.71 (0.13–55.81)	1.000
	Severe	5/60 (8.3%)	12/61 (19.6%)	0.42 (0.04–4.43)	.912
BPD (all) or death		44/60 (73.3%)	52/61 (85.2%)	0.86 (0.55–1.33)	.880
BPD (severe or moderate) or death		22/60 (36.7%)	30/61 (49.2%)	0.75 (0.28–2)	1.000
BPD (severe) or death		14/60 (23.3%)	27/61 (44.2%)	0.52 (0.14–1.91)	.152

Note: BPD, bronchopulmonary dysplasia.

Secondary Outcomes

The adverse effects due to steroids like hyperglycemia, hypertension requiring treatment, clinical sepsis or bacteremia, and morbidities related to prematurity, like HsPDA, IVH, PVL, NEC, and severe ROP (>stage 2), were all evaluated as secondary outcomes in the current study (Table 3). The intervention group had no notable adverse effects, such as hyperglycemia or hypertension. Both groups required inotropes, had PDA that required treatment, and had an equal rate of intestinal perforation and culture-positive sepsis. The intervention group had a significantly lower incidence of any grade IVH (intervention group: 14/60 [23.3%]; control group: 27/61 [44.2%]; P = .020), as well as high-grade IVH (≥grade 3) or PVL (intervention group: 6/60 [10%]; control group: 16/61 [26.2%]; P = .032). Compared to the control, the intervention group required fewer inpatient days, which was not statistically significant (intervention 81.1 ± 9.1 days vs. control 86.3 ± 8.9 days).

Table 3.

Other Respiratory and Secondary Outcomes in Study Groups.

Variables	Intervention (n = 60)	Control (n = 61)	P Value
Surfactant redosing	11/60 (18.3%)	19/61 (31.1%)	.140
Pulmonary hemorrhage	1/60 (1.6%)	4/61 (6.5%)	.364
Pneumothorax	1/60 (1.6%)	3/61 (4.9%)	.618
FiO₂ requirement at 24-HOL (in survivors)	23.3 ± 1.2	29.1 ± 2.3	.001
FiO₂ weaned to 21% at DOL (in survivors)	11.1 ± 1.5	13.2 ± 5.1	.002
Duration of invasive ventilation	6.5 ± 1.8	9.8 ± 2.2	.024
Duration of noninvasive ventilation	29.5 ± 5.7	29.6 ± 5.6	.467
DOL at which no respiratory support/O₂	52.9 ± 12.3	59.5 ± 10.2	.408
Use of systemic postnatal steroids	2/60 (3.3%)	5/61 (8.1%)	.439
Hyperglycemia requiring insulin	1/60 (1.6%)	1/61 (1.6%)	1.000
Hypertension requiring treatment	1/60 (1.6%)	3/61 (4.9%)	.618
Ionotropic requirement	20/60 (33.3%)	29/61 (47.5%)	.139
PDA requiring treatment	30/60 (50%)	37/61 (60.6%)	.274
Any IVH	14/60 (23.3%)	27/61 (44.2%)	.020
IVH ≥ grade 3 or PVL	6/60 (10%)	16/61 (26.2%)	.032
ROP > stage 2	7/60 (11.6%)	6/61 (9.8%)	.777
Intestinal perforation (NEC/SIP)	5/60 (8.3%)	6/61 (9.8%)	1.000
Culture-positive sepsis	16/60 (26.6%)	24/61 (39.3%)	.176
Duration of hospitalization (in survivors, mean)	81.1 ± 9.1	86.3 ± 8.9	.408
Gestational age at discharge (weeks)	37.4 ± 1.8	38.7 ± 1.1	.244

Note: DOL, days of life; FiO₂, fraction of inspired oxygen; HOL, hours of life; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; SIP, spontaneous intestinal perforation

Other Respiratory Outcomes

Respiratory outcomes between the intervention and control groups, including need for surfactant redosing, FiO₂ requirement, duration of invasive and noninvasive ventilation, duration of caffeine, use of postnatal systemic steroids for BPD, and complications like pulmonary hemorrhage and pneumothorax, were compared (Table 3). The intervention group compared to the control group had significantly lower FiO₂ requirement at 24 h of life (23.3 ± 1.2 vs. 29.1 ± 2.3, P value = .001), and was weaned to 21% FiO₂ early (11.1 ± 1.5 days vs. 13.2 ± 5.1 days, P = .002). The total duration of invasive respiratory support (6.5 ± 1.8 days vs. 9.8 ± 2.2 days) was significantly less in the intervention group compared to the control group. Two infants (3.3%) in the intervention group and five infants (8.1%) in the control group received systemic dexamethasone therapy.

Discussion

This study compared intratracheal surfactant and budesonide to surfactant alone for prevention of BPD in extreme preterm infants admitted to a tertiary-level neonatal ICU. This is the first prospective, randomized, controlled pilot trial conducted in an Indian population. There was no significant difference in the incidence of BPD, deaths, and combined death and BPD in ELBW (<1,000 g) preterm infants.

Surfactant is used as a carrier because of the “Marangoni effect.” A surface tension difference causes mass transfer along an interface between two fluids. When surfactant is injected into infants with RDS, convection flow may help atelectatic zones expand and medication be deposited even in collapsed lungs.¹⁹ In a rabbit model, Fajardo et al.²⁰ showed that surfactant delivered more corticosteroids than a nebulizer with less systemic side effects. Surfactant helps distribute budesonide efficiently.

Intratracheal budesonide treatment enhanced gas exchange, oxygenation index, lung edema, intrapulmonary shunts, and lung neutrophil count.^21–23 After administration, unbound budesonide esterifies fast. Within 20 min of inhalation or intratracheal injection, 80% of radiolabeled budesonide in rats’ trachea and large airways became esters.⁷ Esterified budesonide enters the airways gradually. Budesonide’s intratracheal action extends local tissue affinity and efficacy as well as airway action, which is why it was effective for days even though only one or two doses were given in our study. This technique may lessen systemic side effects since the systemic compartment generates fewer esters than the airways.²⁴

Porcine surfactant (CUROSURF) was used in this study because it is feasible, uses less volume than other surfactants, can be mixed easily (when combined with budesonide, the mixture has the same appearance as a surfactant alone, without crystallization or discoloration), and has not been previously studied.

Two meta-analyses,^25–27 which included 10 studies, on airway administration of budesonide and surfactant found reduced BPD, mechanical ventilation time, and hospitalization, 8 of which used intratracheal budesonide, and 2 used nebulized budesonide. In this study, BPD, mortality, and combined death or BPD incidence were not significantly different. A possible reason is that most meta-analyses included VLBW infants, unlike this study, where only ELBW infants with a mean gestation of 26 weeks were studied.

The current study’s total incidence of BPD, combined with death or BPD, was higher as compared to other studies because our study population was more premature and smaller (<28 weeks and ELBW) than previously studied (<32 weeks and VLBW) neonates.^{9, 27–29} Despite the high prevalence of BPD in the current study population, only two newborns in the control group were discharged with home oxygen, and the prevalence of ROP ≥stage 2 was minimal (10%).

As stated previously, esterified budesonide is released slowly and has a prolonged effect on the lungs, which is implied by the fact that the intervention group required less FiO₂ at 24 h of birth, weaned to 21% FiO₂ earlier, and spent less time on respiratory support (invasive and noninvasive). Our findings suggested that budesonide was effective early in therapy, which may have translated to less oxygen and respiratory support, resulting in slightly earlier hospital discharge in the intervention group.

Although statistically not significant, the intervention group had less inotrope requirement than the control group in this study. This can possibly be due to the effect of an increase in cardiac stroke volume while stabilizing blood pressure of budesonide.^{29, 30} This effect of budesonide on blood pressure stability may benefit newborns.

The intervention group had a lower incidence of any IVH (P = .02) and high-grade IVH (grades 3 and 4) and PVL than the control group (P = .03). A lower IVH may be due to fewer ventilation days, less ionotropic requirement, and less HsPDA, all contributing to a stable course during the stay. However, the present study was not powered to look for these outcomes, and other variables were not examined. Corticosteroids are known to induce hyperglycemia, hypertension, and an increased risk of infection, as well as long-term effects on physical development, neuromotor, and cognitive function.^{30, 31} In this study, we only examined the short-term side effects of steroids and observed no differences in serum glucose, blood pressure, or culture-positive sepsis between both groups.

Limitations of our study were that blinding was not done, due to which measurement bias could not be completely eliminated. Long-term effects on physical growth and neurodevelopment were not followed up. A larger study population is needed to evaluate these outcomes. Post hoc power analysis for the primary outcome had shown that the study with the current sample size is grossly underpowered (69.1%). This could be the reason for the lack of statistical significance of the differences in various primary outcomes among the two study groups.

Conclusion

Intratracheal instillation of budesonide and surfactant is feasible and safe. The research groups had similar rates of death, BPD, and combined BPD and death in extreme preterm newborns with RDS. The study, being a pilot study with 10% of the calculated sample size, can only comment on the trend and was not powered to comment on the significance of the result. Previous studies were mostly from the USA, China, and Taiwan. This is the first randomized study done in India, a population with diverse ethnicity, genetics, and higher perinatal infection rate. We intended to include only the ELBW babies who are a high-risk population among preterm for developing BPD.

Footnotes

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Author Nalinikanta Panigrahy is an Associate Editor of Journal of Neonatology and did not take part in the peer review or decision-making process for this submission. Author didn’t receive any financial benefits or fees for any scientific advice or for any other association or contribution.

Ethical Approval

After approval from the Institutional Ethics Committee after submitting the study protocol, consent form, and parent information leaflet, this study was registered in the Clinical Trial Registry of India (CTRI number: CTRI/2020/02/023310).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Informed Consent

Informed written parental/guardian consent was obtained prior to randomization by the clinician using a specially designed information and consent form.

ORCID iDs

Nalinikanta Panigrahy

Vijayanand Jamalpuri

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