Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia

Design

Randomized, multinational trial

N= 863

Objective

Study Groups

Budesonide (n= 437)

Placebo (n= 426)

Inclusion Criteria

Exclusion Criteria

Expected to receive only palliative care, had dysmorphic features or congenital abnormalities affecting life expectancy, had known or suspected cyanotic heart disease, were not the second-born in a multiple-birth pregnancy unless the second-born was non-viable

Methods

Infants received either inhaled budesonide (2 puffs, 200 mcg per puff) or matching placebo administered Q12H in the first 14 days of life and one puff administered Q12H from day 15 until the last dose of the study drug has been administered.

Budesonide was administered through a metered-dose inhaler connected to a spacer within 12 hours of randomization; treatment was continued every 12 hours.

Duration

Enrollment period: April 1, 2010, to August 3, 2013

Treatment period: Up to 32 weeks postmenstrual age or until they no longer needed oxygen and positive-pressure support.

Follow-up: Until the infants reached a postmenstrual age of 36 weeks

Outcome Measures

Primary: Composite of death or bronchopulmonary dysplasia at a postmenstrual age of 36 weeks

Secondary: Necessity for surgical closure of a patent ductus arteriosus, reintubation rates, and other neonatal illnesses

Baseline Characteristics

Budesonide (n= 437)

Placebo (n= 426)

Infant characteristics

Birth weight, g

Gestational age at birth, wk

Male sex

Born at study hospital

Singleton birth

Apgar score at 5 min

Age at randomization

Intubated at randomization

Supplemental oxygen at randomization

798

26.1

50.8%

96.8%

81.7%

7

6.7

68.9%

48.5%

803

26.1

50.8%

97.9%

77.6%

7

6.6

68.5%

46.1%

Results

Endpoint

Budesonide (n= 437)

Placebo (n= 426)

The incidence of the primary composite outcome (death or BPD) was 40.0% in the budesonide group compared to 46.3% in the placebo group. The risk ratio for death or BPD was 0.86 (95% confidence interval [CI], 0.75 to 1.00; p= 0.05). While the incidence of BPD was significantly lower in the budesonide group (27.8% vs. 38.0%, p= 0.004), the adjusted odds ratio for death was 1.24 (95% CI, 0.91 to 1.69; p= 0.17).

Adverse Events

While adverse events including oral candidiasis, hyperglycemia, and hypertension were similar between groups, the budesonide group had a lower incidence of the need for surgical closure of a patent ductus arteriosus and reintubation.

Study Author Conclusions

Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality

InpharmD Researcher Critique

While the study demonstrates a significant reduction in BPD with early budesonide treatment, the potential increase in mortality raises concerns. Adrenal suppression was not mentioned within the study.

A follow-up study was conducted to assess the long-term outcome in neonates (see Table 2)

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

Design

Large, international, randomized, placebo-controlled trial

N= 863

Objective

To evaluate the long-term effects of early administration of inhaled budesonide on neurodevelopmental disability among extremely preterm infants, specifically for the prevention of bronchopulmonary dysplasia

Study Groups

Budesonide (n= 437)

Placebo (n= 419)

Inclusion Criteria

Infants with a gestational age between 23 weeks 0 days and 27 weeks 6 days who required positive-pressure respiratory support within 12 hours of birth

Exclusion Criteria

Methods

Infants were randomly assigned to receive inhaled budesonide or placebo within 24 hours of birth. The dose of budesonide administered was two puffs (200 mcg/puff) q12h in the first 14 days of life, then one puff q12h from day 15 onward until supplemental oxygen and positive-pressure support are no longer needed, or the infant reaches a postmenstrual age of 32 weeks, regardless of ventilatory status.

Duration

Outcome Measures

Primary outcome: Bronchopulmonary dysplasia or death at 36 weeks of postmenstrual age

Secondary long-term outcome: Composite outcome of neurodevelopmental disability, defined as cerebral palsy, cognitive delay, deafness, or blindness at a corrected age of 18 to 22 months

Baseline Characteristics

Budesonide (n= 308)*

Placebo (n= 321)*

Age at randomization, hours

827

822

26.2

26.2

51.0%

51.7%

90.3%

91.9%

Singletone birth

Receipt of caffeine or other methylxanthines

Corrected age at follow-up, months

* Number of infants with data

Results

Endpoint

Budesonide (n= 437)

Placebo (n= 419)

Outcome at 36 weeks of postmenstrual age

Bronchopulmonary dysplasia

Brain injury

Cystic periventricular leukomalacia

87 (28.2%)

57 (18.5%)

12 (3.9%)

120 (37.4%)

45 (14.0%)

11 (3.4%)

0.01

Not significant

Not significant

Secondary long-term outcome*

Cerebral palsy

Blindness

Hearing loss

Cognitive delay**

24/330 (7.3%)

3/331 (0.9%)

1/330 (0.3%)

139/303 (45.9%)

21/340 (6.2%)

6/337 (1.8%)

4/337 (1.2%)

152/315 (48.3%)

1.18 (0.67 to 2.07)

0.51 (0.13 to 2.02)

0.26 (0.03 to 2.28)

0.95 (0.80 to 1.12)

0.57

0.33

0.19

0.56

* Data for these outcomes exclude infants who died before the scheduled tests and those who were alive but were not tested.

** Cognitive delay was defined as a Mental Development Index score of less than 85, assessed relative to a standardized mean of 100, on the Bayley Scales of Infant Development, Second Edition, on which the minimum score is 50 and the maximum score is 150, with higher scores indicating better performance.

In total, 43 infants (5%) were lost to follow-up, and 140 infants died before the follow-up assessment.

Adverse Events

Adverse events related to mortality were higher in the budesonide group, though the specific causes of death did not differ significantly between the treatments.

Study Author Conclusions

Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide.

InpharmD Researcher Critique

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

Design

Prospective, randomized, controlled, double-blind trial

N= 120

Objective

To evaluate the value of inhaled budesonide administration in neonatal respiratory distress syndrome (RDS) cases for near-term neonates

Study Groups

Budesonide (n= 60)

Placebo (n= 60)

Inclusion Criteria

Neonates diagnosed with RDS

Exclusion Criteria

Neonatal infection, respiratory diseases other than RDS, heart and neurological lesions, neonates who received exogenous surfactant

Methods

Neonates were randomly assigned to receive inhaled budesonide (2 mL, 0.25-mg/mL suspension) in addition to 2 mL of 0.9% saline or placebo (2 mL, humidified distilled sterile water). 

Budesonide was administered via nebulization through a face mask connected to an oxygen flowmeter (5 L/min) twice daily for 5 days immediately after diagnosis and admission (≤ 6 hours of birth in both groups). In neonates who required invasive mechanical ventilation, an accessory ventilator was used to deliver budesonide.

Duration

Enrollment: July 2016 to March 2018

Intervention: 5 days

Follow-up: Monitored on the first and fifth days of admission

Outcome Measures

Differences in mean RDS grades, Downes scores and serum interleukin-8 (IL-8) levels between first and fifth day of admission

Baseline Characteristics

Budesonide (n= 60)

Placebo (n= 60)

Weight, kg

Gestational age, wk

Age on admission, hr

Male sex

RDS grades on admission

Mode of delivery

Normal vaginal delivery

Cesarean section

18 (30%)

42 (70%)

17 (28%)

43 (72%)

0.841

Duration of hospitalization, days

Mortality

Results

Endpoint

Budesonide (n= 60)

Placebo (n= 60)

P-value

RDS grades

On first day of admission*

On fifth day of admission

2.24 ± 0.45

0.9 ± 0.35

2.23 ± 0.46

1.89 ± 0.61

0.904

0.001

Downes scores

On first day of admission*

On fifth day of admission

5.96 ± 0.12

3.651 ± 0.9

5.95 ± 0.13

5.59 ± 1.52

0.662

0.001

Serum IL-8 levels, pg/mL

On first day of admission*

On fifth day of admission

519 ± 59.1

161.1 ± 68.7

518 ± 60.2

489 ± 99.4

0.927

0.001

Adverse Events

None

Study Author Conclusions

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.

InpharmD Researcher Critique

While this study demonstrated a significant reduction in RDS grades, Downes scores, and IL-8 serum levels in neonates treated with budesonide, its small sample size and single-center design limit its overall generalizability. Additionally, although the study found no evident adverse events associated with budesonide use in neonates, adrenal suppression was not mentioned or evaluated.

Inhaled corticosteroids in transient tachypnea of the newborn: A randomized, placebo-controlled study

Design

Randomized, double-blind, placebo-controlled, multicenter study

N= 49

Objective

To determine if early inhaled corticosteroids could alleviate the respiratory distress and morbidity in late preterm and term neonates with transient tachypnea of the newborn (TTN)

Study Groups

Budesonide (n= 24)

Placebo (n= 25)

Inclusion Criteria

Post-menstrual age (PMA) ≥34 weeks, onset of tachypnea (respiratory rate [RR] ≥60 breaths/minute) within 6 hours of birth, tachypnea persisting ≥4 hours, chest radiograph with evidence of lung edema

Exclusion Criteria

Methods

Patients were randomized to receive 2 mL of either inhaled budesonide (1,000 mcg) or placebo (0.9% normal saline solution) via nebulization through a face mask at a flow rate of 5 L/minute. The first dose was administered within the first 6 hours of birth, and a second dose was given 12 hours after the first administration.

Clinical assessment before the first dose included RR, heart rate (HR), the fraction of inspired O₂ (FiO₂) to keep O₂ saturation within desired range, and respiratory support level; labs at baseline included complete blood count, venous blood gas, and immature to total neutrophil count, and blood glucose levels. Clinical assessments with RR, HR, and FiO₂ were conducted every 2 hours during the first 48 hours following drug administration or until respiratory distress resolved. TTN clinical score was assessed after 12 hours before second dose, as well as at 24 and 48 hours following study entry. Target oxygen saturation by pulse oximetry (SpO₂) levels for patients >37 weeks PMA was >95%, and >92% in patients 34 to 36 weeks PMA.

Duration

Enrollment: March 2012 to June 2016

Intervention: 12 hours 

Follow-up: Monitored 12, 24, and 48 hours following first dose

Outcome Measures

Assessment of respiratory distress by TTN clinical score, RR, HR, and FiO₂ to target SpO₂ compared to placebo at 12, 24, and 48 hours following first dose of inhaled study medication

Baseline Characteristics

Budesonide (n= 24)

Placebo (n= 25)

Gestational age, weeks

Age at enrollment, hours

Male

Baseline clinical assessment

RR, breath/minute

HR, beats/minute

SpO₂, %

FiO₂

TTN clinical score

73.6 ± 27.3

140 ± 19.1

95.7 ± 3.7

0.30 ± 0.10

4.3 ± 1.6

77.5 ± 24.8

135.2 ± 20.2

96.9 ± 3.5

0.29 ± 0.10

4.1 ± 2.1

O₂ or respiratory support

Results

Endpoint

Budesonide (n= 24)

Placebo (n= 25)

p-value

TTN clinical score

at 12 hours

at 24 hours

at 48 hours

1.9 ± 1.8

1.2 ± 1.5

0.5 ± 0.9

1.5 ± 1.7

1.3 ± 1.6

0.6 ± 1

0.4

0.8

0.63 

RR, breath/minute

at 12 hours

at 24 hours

at 48 hours

62.3 ± 21.4

58.4 ± 18.1

56.3 ± 22 

62.6 ± 20.6

58.5 ± 22.4

56.1 ± 22.5 

0.94

0.98

0.99 

HR, beats/minute

at 12 hours

at 24 hours

at 48 hours

139.1 ± 13.4

146.5 ± 15.2

138 ± 13.7

144.8 ± 14

143 ± 16.2

139.7 ± 15.7 

0.15

0.45

0.71 

SpO₂, %

at 12 hours

at 24 hours

at 48 hours

97.1 ± 2.8

96.1 ± 3.1

95.4 ± 8.2 

97.3 ± 3.23

97.6 ± 2

97.8 ± 2.2 

0.86

0.07

0.19 

FiO₂

at 12 hours

at 24 hours

at 48 hours

0.27 ± 0.1

0.3 ± 0.1

0.3 ± 0.2 

0.3 ± 0.1

0.3 ± 0.1

0.3 ± 0.1

0.85

0.33

0.71 

O₂ or respiratory support at 48 h

9 (37%)

11 (44%)

1

Adverse Events

No short-term adverse events were reported.

Study Author Conclusions

We conclude that our pilot study was unable to detect a significant effect of inhaled budesonide on the respiratory course of TTN in late preterm and term infants. We detected no short-term adverse outcomes.

InpharmD Researcher Critique

This study was conducted in both late pre-term and at-term neonates, and as such the adverse effects of inhaled budesonide on pre-term neonate populations have not been fully investigated. No adverse events with the use of inhaled budesonide were seen within this study. However, the small sample size did not allow for the identification of any uncommon adverse events. Adrenal suppression was not evaluated or mentioned by investigators.