Postnatal steroids for improving pulmonary outcome: Quest to find the right formulation and right regimen

 

Background

 

• Dexamethasone, the most commonly used postnatal steroid in premature neonates is associated with decrease in incidence of death or bronchopulmonay dysplasia.
• But its use in dosages comparable to those used in various clinical trials has been associated with increased risk of short term (hypertension, gastric perforation, and hyperglycemia) and long-term complications (cerebral palsy, decreased head size).
• American Academy of Pediatrics strongly discourages the use of postnatal steroids in premature neonates, outside the setting of large randomized controlled trials.
• With increasing awareness of worrisome side effects of postnatal steroids, there has been a gradual decline in their use as reported by various Western neonatal networks.
• Recent literature has highlighted the inverse relationship between use of postnatal steroids and incidence of bronchopulmonary dysplasia. This emphasizes the need to find the right formulation and right dose of postnatal steroids, which will maximize the benefits in pulmonary outcome with minimizing the long-term adverse neurosensory outcomes.

 

Recent literature

 

• We review four recently published studies on use of postnatal steroids for prevention/treatment of bronchopulmonary dysplasia.
• Bonsantea et al in a randomized controlled trial have tested the efficacy of early low-dose hydrocortisone in improving survival without oxygen dependence at 36 weeks of postconceptional age. Hydrocortisone prophylaxis improved O2-free survival and early cardio-circulatory function especially in neonates who have not received antenatal steroids. Neurodevelopmental outcome at 2 years of age are not reported .

• In a case-control study Rademaker et al looked at the effect of hydrocortisone on neurodevelopment outcome. After adjusting for gestational age, body weight, sex, mechanical ventilation, and small for gestational age, mean Intelligence Quotient, Visual Motor Integration test, memory test results, motor function and incidence of cerebral palsy were not different in the hydrocortisone-treated group and the non-steroid-treated group.

• Doyle et al report long-term outcome of a RCT, which investigated the use of low-dose dexamethasone in facilitating extubation. Rate of the combined outcome of death, or major disability at 2 years of age was not different in control and treatment arms.
• Parikh et al did volumetric MRI in a cohort of extremely low birth weight infants treated with relatively smaller doses of dexamethasone. When compared to controls, babies who have received dexamethasone had smaller total and regional cerebral tissue volumes.
• Read evidence based review in Indian Pediatrics July 2007.

 

Interpretation

 

Absence of evidence is not evidence of absence: These trials showing benefit/no harm of hydrocortisone and low-dose dexamethasone are small underpowered studies. Incidence of adverse outcomes in treatment and controls arms although not different; this does not translate into their being similar. In addition, we need to look into school-age outcomes like learning disabilities and behavioral disorders.

 

Even use of small doses of dexamethasone resulted in smaller total and regional cerebral tissue volumes. These volume-deficits may be antecedents of poor long term neurological outcomes.

 

In a neonate who has received a course of antenatal steroids, postnatal steroids may have no additional advantage.

 

These studies although encouraging should not lead to over-enthusiastic use of hydrocortisone for prevention and treatment of bronchopulmonary dysplasia.

 

Since clinicians would keep on using corticosteroids in premature babies, we need to understand how to use them safe & effectively. Hence, there is a need of large sufficiently powered clinical trials to find out the right formulation and the right dose regimen of postnatal steroids. These trials should measure standardized pulmonary and neurodevelopment outcomes at least till school age.

 

Early Low-Dose Hydrocortisone in Very Preterm Infants: A Randomized, Placebo-Controlled Trial

Neonatology 2007;91:217-221

F. Bonsantea, G. Latorreb, S. Iacobellib, V. Forziatib, N. Laforgiaa, L. Espositob, A. Mautonea

 

Background: Several reports indicate a decreased cortisol response to adrenocorticotropic hormone in preterm infants developing chronic lung disease and in preterm infants with refractory hypotension. Low-dose hydrocortisone (HC) may allow for beneficial effects.

 

Objective: Our aim was to assess whether HC is able to increase survival without chronic lung disease.

 

Methods: We performed a double-blind, randomized, placebo-controlled trial. Fifty mechanically ventilated infants (birth weight: 500-1,249 g) were randomized to receive treatment (HC 0.5 mg/kg/12 h for 9 days, then HC 0.5 mg/kg/24 h for 3 days) or placebo. Major outcome was survival without oxygen dependence at 36 weeks of postconceptional age (O2-free survival). 

 

Results: The basic characteristics were similar between the two groups. O2-free survival was higher in the HC group (64 vs. 32%). The advantage was particularly evident among infants without antenatal steroids. The mortality rate was 16% in the HC group versus 40% in the control group (difference not significant). Hypotension after recruitment was reduced by HC (0 vs. 30%). The incidence of gastrointestinal perforation and other adverse effects was similar between the two groups. 

 

Conclusions: HC prophylaxis improved O2-free survival and early cardiocirculatory function in our population, without important short-term effects. The neurodevelopmental outcome will be assessed at 2 years

 

Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children

J Pediatr. 2007;150:351-7

Rademaker KJ, Uiterwaal CS, Groenendaal F, Venema MM, van Bel F, Beek FJ, van Haastert IC, Grobbee E, de Vries LS.

 

OBJECTIVE: To investigate neurodevelopment at school age in preterm infants treated with hydrocortisone for bronchopulmonary dysplasia (BPD) in the neonatal period.

 

STUDY DESIGN: Preterm infants  (n = 226; gestational age  < or = 32 weeks and / or body weight < or = 1500 grams) performed subtests of the Wechsler Intelligence Scale for Children-Revised, the Visual Motor Integration test, a 15-Word Memory Test and the Movement Assessment Battery for Children at school age. Conventional MRI of the brain was obtained. Sixty-two children who received hydrocortisone for BPD (starting dose, 5 mg/kg/day; median duration, 27.5 days) were compared with 164 nontreated neonates.

 

RESULTS: Hydrocortisone-treated infants were younger, lighter, and sicker than their non-steroid-treated counterparts. Adjustments for gestational age, body weight, sex, mechanical ventilation, and small for gestational age were made. Adjusted mean Intelligence Quotient, Visual Motor Integration test, and memory test results were the same in the hydrocortisone-treated group and the non-steroid-treated group (99 versus 101, P = .62; 97 versus 99, P = .49, 7.9 versus 7.5, P = .42, respectively). Motor function and incidence of cerebral palsy in both groups was not different (11% versus 7%, P = .97). Occurrence of brain lesions on MRI was similar for the two groups.

 

CONCLUSIONS: Neonatal hydrocortisone treatment for BPD had no long-term effects on neurodevelopment.

 

Outcome at 2 years of age of infants from the DART study: a multicenter, international, randomized, controlled trial of low-dose dexamethasone

Pediatrics. 2007;119:716-21

Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB; DART Study Investigators

 

OBJECTIVE: Low-dose dexamethasone facilitates extubation in chronically ventilator-dependent infants with no obvious short-term complications. The objective of this study was to determine the long-term effects of low-dose dexamethasone.

 

METHODS: Very preterm (<28 weeks' gestation) or extremely low birth weight (birth weight <1000 g) infants who were ventilator dependent after the first week of life for whom clinicians considered corticosteroids were indicated were eligible. After informed consent, infants were randomly assigned to masked dexamethasone (0.89 mg/kg over 10 days) or saline placebo. Survivors were assessed at 2 years' corrected age by staff blinded to treatment group allocation to determine neurosensory outcome, growth, and health.

 

RESULTS: The trial was abandoned well short of its target sample size because of recruitment difficulties. Seventy infants were recruited from 11 centers, 35 in each group: 59 survived to 2 years of age, and 58 (98%) were assessed at follow-up, but data for cerebral palsy were available for only 56 survivors. There was little evidence for a difference in the major end point, the rate of the combined outcome of death, or major disability at 2 years of age (dexamethasone group: 46%; controls: 43%). Rates of mortality before follow-up (11% vs 20%), major disability (41% vs 31%), cerebral palsy (14% vs 22%), or of the combined outcomes of death or cerebral palsy (23% vs 37%) were not substantially different between the groups. There were no obvious effects of low-dose dexamethasone on growth or readmissions to hospital after discharge.

 

CONCLUSIONS: Although this trial was not able to provide definitive evidence on the long-term effects of low-dose dexamethasone after the first week of life in chronically ventilator-dependent infants, our data indicate no strong association with long-term morbidity.

 

Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants

Pediatrics. 2007;119:265-72

Parikh NA, Lasky RE, Kennedy KA, Moya FR, Hochhauser L, Romo S, Tyson JE

 

OBJECTIVE: Our goal was to relate postnatal dexamethasone therapy in extremely low birth weight infants (birth weight of < or = 1000 g) to their total and regional brain volumes, as measured by volumetric MRI performed at term-equivalent age.

 

METHODS: Among 53 extremely low birth weight infants discharged between June 1 and December 31, 2003, 41 had high-quality MRI studies; 30 of those infants had not received postnatal steroid treatment and 11 had received dexamethasone, all after postnatal age of 28 days, for a mean duration of 6.8 days and a mean cumulative dose of 2.8 mg/kg. Anatomic brain MRI scans obtained at 39.5 weeks (mean) postmenstrual age were segmented by using semiautomated and manual, pretested, scoring algorithms to generate three-dimensional cerebral component volumes. Volumes were adjusted according to postmenstrual age at MRI.

 

RESULTS: After controlling for postmenstrual age at MRI, we observed a 10.2% smaller total cerebral tissue volume in the dexamethasone-treated group, compared with the untreated group. Cortical tissue volume was 8.7% smaller in the treated infants, compared with untreated infants. Regional volume analysis revealed a 20.6% smaller cerebellum and a 19.9% reduction in subcortical gray matter in the dexamethasone-treated infants, compared with untreated infants. In a series of regression analyses, the reductions in total cerebral tissue, subcortical gray matter, and cerebellar volumes associated with dexamethasone administration remained significant after controlling not only for postmenstrual age but also for bronchopulmonary dysplasia and birth weight. 

 

CONCLUSIONS: We identified smaller total and regional cerebral tissue volumes in extremely low birth weight infants treated with relatively conservative regimens of dexamethasone. These volume deficits may be the structural antecedents of neuromotor and cognitive abnormalities reported after postnatal dexamethasone treatment.