EBNEO Commentary: Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia

August 16, 2022

Manuscript citation:

Watterberg KL, Walsh MC, Li L, Chawla S, D’Angio CT, Goldberg RN, et al.; Eunice Kennedy Shriver NICHD Neonatal Research Network. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med. 2022 Mar 24;386(12):1121-1131. doi: 10.1056/NEJMoa2114897. PMID: 35320643; PMCID: PMC9107291.

Reviewed by:

Jessica Jakubowicz, MD
Assistant Professor
Department of Pediatrics, Division of Neonatology
University of Arkansas for Medical Sciences/Arkansas Children’s Hospital
jmjakubowicz@uams.edu

Type of Investigation:

Treatment

Question:

In (P) preterm infants of gestational age less than 30 weeks who are intubated for at least 7 days at 14 to 28 days of life, does (I/C) hydrocortisone improve survival (O) without bronchopulmonary dysplasia at (T) 36 weeks postmenstrual age and without adverse neurodevelopmental effects at 22 to 26 months of corrected age?

Methods:

  • Design: double-masked, placebo-controlled, randomized trial
  • Allocation: Randomization was performed individually in a 1:1 ratio by the NRN Data Coordinating Center at RTI International with the use of permuted block randomization (in blocks of two and four), with stratification performed within center according to gestational age (<27 weeks vs. 27 to <30 weeks).
  • Blinding: Pharmacy personnel prepared masked hydrocortisone or placebo; all the other personnel remained unaware of the trial-group assignments.
  • Follow-up period:
    • Primary outcome: improvement in survival without physiologically defined moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age
    • Secondary outcome: survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age
  • Setting: 19 U.S. NICHD NRN academic centers (including 50 neonatal intensive care units)
  • Patients:
    • Inclusion criteria:
      • 14 to 28 postnatal days + gestational age at birth of less than 30 weeks
      • Born at or admitted to an NRN site at no more than 72 hours of postnatal age
      • Received mechanical ventilation through an endotracheal tube for at least 7 days
      • Receiving mechanical ventilation through an endotracheal tube at trial entry
    • Exclusion criteria:
      • Major congenital anomalies
      • Decision to limit intensive life support
      • Indomethacin or ibuprofen treatment within 48 hours before trial entry
      • Previous systemic glucocorticoid treatment for bronchopulmonary dysplasia
      • Hydrocortisone or other systemic glucocorticoids for at least 14 cumulative days or within 7 days before trial entry
    • Intervention:
      • Infants received saline placebo or hydrocortisone sodium succinate administered intravenously or orally (if no intravenous line was available) and tapered over a period of 10 days.
        • 4 mg per kilogram per day for 2 days
        • 2 mg per kilogram per day for 3 days
        • 1 mg per kilogram per day for 3 days
        • 5 mg per kilogram per day for 2 days
      • Mandatory extubation thresholds were specified.
        • Extubation could be elected at the discretion of the attending physician however an extubation attempt was required within 72 hours after starting hydrocortisone or placebo and within 24 hours after the following criteria had been met:
          • Fraction of inspired oxygen (Fio2) of less than 0.40 to maintain a saturation of at least 88%
          • Mean airway pressure of less than 8 cm of water
          • Hemodynamically stable condition in the opinion of the clinical team
        • Successful extubation was defined as remaining extubated for at least 1 week, including at least 3 days after the last dose of hydrocortisone or placebo.
      • Outcomes:
        • Primary outcome:
          • Efficacy outcome – Improvement in survival without physiologically defined moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, defined as:
            • Use of supplemental oxygen
            • Positive pressure ventilation
            • Both to maintain an oxygen saturation of more than 90%.
          • An ambient-air challenge was performed for infants estimated to be receiving an Fio2 of less than 0.30 by nasal cannula.
        • Safety outcome – Survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age, determined by an in-person trial visit and defined as any of the following:
          • Bayley Scales of Infant and Toddler Development–III (Bayley-III)
            • Cognitive composite score of less than 85
            • Motor composite score of less than
          • Gross Motor Function Classification System (GMFCS) level of at least II (on a scale from level 0 to V, with 0 indicating normal gross motor function and higher levels indicating greater impairment)
          • Severe vision impairment in both eyes (consistent with a visual acuity of <20/200)
          • Bilateral hearing impairment with or without amplification (on the basis of observation during the trial visit; report by the parent, guardian,or primary caregiver; or chart review).
        • Secondary outcomes:
          • Standard complications and growth measures after extremely preterm birth at 36 weeks of postmenstrual age and at 22 to 26 months of corrected age
          • Successful extubation during the intervention period
            • Defined as remaining extubated for at least 1 week, including at least 3 days after the last dose of hydrocortisone or placebo
          • Use of open label dexamethasone
            • According to the protocol, dexamethasone was restricted to infants remaining on mechanical ventilation.
          • Respiratory status at 40 weeks of postmenstrual age, according to the same measures used at 36 weeks.
          • Specific adverse events of interest included:
            • Spontaneous gastrointestinal perforation
            • Culture-proven sepsis
            • Hyperglycemia resulting in insulin treatment
            • Hypertension treated with antihypertensive agents
          • Analysis and Sample Size:
            • A sample size of 800 infants was chosen for 80% power to detect an increase in survival without moderate or severe bronchopulmonary dysplasia of 10 percentage points from a baseline survival of 35% or less (estimated from NRN data)
            • Two-sided type I error of 0.05 was used.
            • Eight protocol-specified interim analyses were conducted after every 100 infants reached status (death, discharge, transfer, or 120 postnatal days) to compare the incidence of serious adverse events between the two trial groups.
              • Nosocomial sepsis
              • Intestinal perforation
              • Respiratory deterioration or pneumonia
              • Death
            • All analyses were conducted according to the intention-to-treat principle.
            • P value was reported only for the primary outcome (with a two-sided P value of <0.05 considered to indicate statistical significance); all other analyses were reported as point estimates and 95% confidence intervals and are considered to be exploratory.
          • Patient follow-up:
            • 800 patients were enrolled and underwent randomization
              • 402 were assigned to the placebo group
              • 398 were assigned to the hydrocortisone group
            • 728 patients died or had data available on neurodevelopmental impairement (91.0% of enrolled infants who underwent randomization)

 

Main Results:
  • The outcome of survival without moderate or severe bronchopulmonary dysplasia was known for all enrolled infants, and the outcome of survival without moderate or severe neurodevelopmental impairment was known for 91.0%.
  • Baseline characteristics of the two groups did not differ except more boys were assigned to the placebo group.
Primary Outcome:

 

Primary Outcomes and Their Components
Outcome Hydrocortisone

(N=398)

Placebo

(N=402)

Rate Ratio

(95% CI)

Efficacy
Survival without moderate or severe BPD at 36 wk of postmenstrual age – no. (%) 66(16.6) 53 (13.2) 1.27 (0.93-1.74)
Death by 36 wk of postmenstrual age – no. (%) 19 (4.8) 28 (7.0) 0.66 (0.38-1.16)
Moderate or severe BPD at 36 wk of postmenstrual age – no./total no. (%) 313/379 (82.6) 321/374 (85.8) 0.96 (0.91-1.02)
Safety
Survival without moderate or severe NDI – no./total no. (%) 132/358 (36.9) 134/359 (37.3) 0.98 (0.81-1.18)
Survival without severe NDI – no./total no. (%) 230/358 (64.2) 231/359 (64.3) 1.01 (0.90-1.12)
Known to have died by follow-up – no. (%) 43 (10.8) 46 (11.4) 0.91 (0.62-1.34)
Moderate or severe NDI in survivors – no./total no. (%) 183/315 (58.1) 179/313 (57.2) 1.03 (0.90-1.17)

 

Secondary outcomes:
  • More infants in the hydrocortisone group were successfully extubated than in the placebo group (178 of 398 [44.7%] vs. 135 of 402 [33.6%]).
  • The rate ratio for extubation was 1.54 (95% CI, 1.23 to 1.93).
  • The hydrocortisone group had fewer days of mechanical ventilation than the placebo group before 36 weeks of postmenstrual age (median, 37 days vs. 40 days; median difference, −3 days; 95% CI, −5 to −1).
  • However, similar numbers in each group had been extubated by 36 weeks of postmenstrual age, and total duration of supplemental oxygen therapy and length of hospital stay did not differ substantially between the two groups.
  • Open-label dexamethasone was administered to 39.7% of the infants in the hydrocortisone group and 42.1% of those in the placebo group.

Adverse events:

  • Hypertension was more common in the hydrocortisone group; 4.3% requiring antihypertensive medication compared with 1.0% in the placebo group (adjusted rate ratio, 4.27; 95% CI, 1.45 to 12.55).

 

Conclusion:

The authors conclude that hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups.

 

Commentary:

Bronchopulmonary dysplasia (BPD) remains a serious complication of prematurity, affecting almost half of infants born at less than 28 weeks gestation. Infants with BPD have an increased risk of death and neurodevelopmental impairment (NDI) (1). The causes of BPD are multifactorial with prematurity, mechanical ventilation and pulmonary inflammation potentially playing  significant roles (2).

 

Glucocorticoid use in the prevention and/or treatment of BPD has been studied previously, particularly the use of dexamethasone and more recently hydrocortisone. Glucocorticoids are thought to have potential in treating and/or preventing BPD due to their inhibition of proinflammatory signals and promotion of anti-inflammatory signals. Glucocorticoids are known to have risks, particularly an increased risk of neurodevelopmental impairment. Most established risks have been seen with dexamethasone as it is the most used and studied up to this point as it pertains to BPD. With a known need for well-designed large RCT’s to establish the optimal type of corticosteroid, dosage, and timing of initiation, more trials have been established (3).

 

With a focus on hydrocortisone and its efficacy and safety when used for the treatment and/or prevention of BPD, there have been trials evaluating timing of initiation classified as “early” and “late” initiation. “Early” defined typically as < 7 days after birth and “late” as  > or = 7 days of birth.

 

Per a recent Cochrane review (4), early hydrocortisone was shown to reduce mortality but had little to no effect on BPD at 36 weeks’ postmenstrual age (PMA). There was however a reduction of the combined outcome of mortality or BPD at 36 weeks’ PMA. Hydrocortisone along with dexamethasone was also seen to increase the risk of gastrointestinal perforation. Hydrocortisone was not shown to increase cerebral palsy or the combined outcome of mortality or cerebral palsy.

 

Hydrocortisone initiated from 7 to 14 days after birth in very preterm infants receiving mechanical ventilation and continued for 22 days did not result in improved survival free of BPD at 36 weeks PMA. More infants were successfully extubated from mechanical ventilation in the hydrocortisone group. Hyperglycemia was a major side effect. (1).

 

Late hydrocortisone (started 14 days after birth) was not shown to decrease mortality, BPD at 36 weeks’ PMA or the combined outcome of mortality or BPD (2).  Watterberg et al, demonstrate that hydrocortisone shows promise in the area of safety but the data is still lacking to demonstrate improved survival when using a later initiation for timing.

 

As BPD continues to be a major source of morbidity and mortality in our NICUs, it is vital that an appropriate prevention/treatment or set of treatments (5) is found. Postnatal corticosteroids show promise but there is a continued need to establish the type, dosage, and timing that is best for this population. As the edge of viability continues to move towards younger gestational ages, this likely will persist as an area of neonatology that only grows in urgency.

References:

  1. Onland W, Cools F, Kroon A, Rademaker K, Merkus MP, Dijk PH, et al.; STOP-BPD Study Group. Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2019 Jan 29;321(4):354-363. doi: 10.1001/jama.2018.21443. PMID: 30694322; PMCID: PMC6439762.

  2. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021 Nov 11;11(11):CD001145. doi: 10.1002/14651858.CD001145.pub5. PMID: 34758507; PMCID: PMC8580679.

  3. Onland W, De Jaegere AP, Offringa M, van Kaam A. Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2017 Jan 31;1(1):CD010941. doi: 10.1002/14651858.CD010941.pub2. PMID: 28141913; PMCID: PMC6464844.

  4. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021 Oct 21;10(10):CD001146. doi: 10.1002/14651858.CD001146.pub6. PMID: 34674229; PMCID: PMC8530019.

  5. Greenough A. Hydrocortisone to Prevent Bronchopulmonary Dysplasia – Not a Silver Bullet. N Engl J Med. 2022 Mar 24;386(12):1181-1183. doi: 10.1056/NEJMe2200247. PMID: 35320649.

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