Role of postnatal steroids in

neonatology
Dr. Anirudha

Indications :

Prevention and treatment of Bronchopulmonary Dysplasia

(BPD) (Most Common)

Prior to extubation

Refractory neonatal hypotension

Meconium aspiration syndrome

Refractory Hypoglycemia

Use of steroids in BPD

Introduction:

The incidence of Chronic lung disease (BPD) is

approximately 40% in extremely low birth weight infants and
is associated with mortality and poor neurodevelopmental
outcomes.

The pathogenesis of CLD is regarded as multifactorial,

including infection/inflammation, oxidative stress,
barotrauma/volutrauma, genetic factors and the absence of
antenatal steroids .

Introduction (cont.)

Recently, Wetterberg et al. proposed that early adrenal

insufficiency was the basis of CLD, based on their finding that
infants who subsequently developed CLD had significantly
lower cortisol secretion in response to adrenocorticotrophic
hormones than those without CLD.

Based on these findings, glucocorticoids therapy has been

undertaken for prophylactic or therapeutic purposes for CLD,
but its efficacy and safety have still not been fully clarified.

Treatment protocol :

DART protocol:
(IV/PO) Dexamethasone@
0.075 mg/kg per dose every 12 hourly for first 3 days,
0.05 mg/kg per dose every 12 hourly for 3 days,
0.025 mg/kg per dose every 12 hourly for 2 days,
0.01 mg/kg per dose every 12 hourly for 2 days,
Between Day 7 and Day 14 of life.

Treatment protocol (Ctd.):

Hydrocortisone: started at 5 mg/kg/day for 3 days, with

weaning over 7 to 10 days. If no response by 2 to 3 days, stop
treatment.

As per the recommendations of the 2010 American Academy

of Pediatrics : <0.2 mg/kg/day) of Dexamethasone (in babies
who remain ventilator dependent after 12 weeks of age).

Benefits:

In early trials, treatment with glucocorticoids (usually

dexamethasone) in infants, who remained ventilator dependent for 2
to 3 weeks, resulted in increased Crs (Dynamic compliance) ,
decreased Rrs ( Respiratory system Resistance), diminished O 2
requirement and earlier extubation.

However, treatment with glucocorticoids does not appear to have a

substantial impact on long-term pulmonary outcomes, such as
duration of supplemental O2 requirement, length of hospital stay or
mortality.

Benefits:
(Ctd)

Subsequent trials of earlier treatment, recurrent pulses and

lower doses have yielded inconsistent results as either a
prophylactic or attenuating agent.

Randomized trials of inhaled glucocorticoids also did not

demonstrate improved pulmonary outcome.

Short term Side effects of Glucocorticoids :

Transient adrenal suppression

Gastric ulceration, Intestinal perforation
Glucose Intolerance
Systemic Hypertension
Transient catabolic state
Increased risk of sepsis
Hypertrophic Cardiomyopathy

Long term drawbacks:

In addition to these short-term side effects, long-term follow

up of infants treated with postnatal corticosteroids, primarily
dexamethasone, has raised concerns about impaired
neurodevelopement and growth.

Because of this potential harm and lack of well-established

long-term benefit, routine use of corticosteroids is
discouraged and reserved only for infants with progressive
respiratory failure that is refractory to all other therapies.

Evidence

Mechanism of action :

Preterm infants who are given postnatal corticosteroids

demonstrate some decreased inflammatory markers and
suppression of cytokine-mediated inflammatory reactions in their
tracheal aspirates ( Groneck et al, 1993).

Proposed Theories : The potential for increased surfactant

synthesis, enhanced -adrenergic activity, increased antioxidant
production, stabilization of cell and lysosomal membranes and
inhibition of prostaglandin and leukotriene synthesis (Watterberg
et al, 1999).

Mechanism of action (Ctd..) :

These potential benefits are balanced against the knowledge that

dexamethasone results in persistent decrease in alveolar
numbers in animal models (Massaro and Massaro, 2000).

Clinical studies have demonstrated acute improvements in

dynamic compliance and pulmonary resistance after treatment
with postnatal corticosteroids, although small follow-up studies
have demonstrated no differences in respiratory morbidity despite
fewer children with abnormal pulmonary function at > 5 years of
age (Nixon et al, 2007).

Timing of effect :
Based on two meta-analyses of treatment before and after 7 days of
age (Halliday et al, 2009a, 2009b), postnatal dexamethasone has
similar beneficial effects on death or BPD at 36 weeks (RR 0.72 to 0.73;
95% CIs within 0.61, 0.85 for both treatment intervals) and decreased
need for mechanical ventilation, with no significant impact on survival to
hospital discharge.

The aggregation of studies comparing hydrocortisone administered in

the 1st week of life to placebo demonstrates no effects on mortality or
BPD.

Which babies?

Potential criteria for treatment would be FiO 2 >0.60, mean airway pressure
>12 to 14 cm H2O and age > 7 days.

At minimum, infants who might be candidates for dexamethasone therapy

would be those with severe, persistent disease, treated under a protocol
with a short exposure (3 days), with dosing initiated at < 0.25 mg/kg/day
and after informing the family of the short and long-term effects.

Interestingly, Walsh et al (2006 b) reported decreasing postnatal

corticosteroids rates in three major North American neonatal networks
from 2001 to 2003, following the societies statement, with no concurrent
change in the rate of BPD.

Evidence regarding Steroid Adverse effects

Major concerns : Hypertension, Hyperglycemia, Hypertrophic

cardiomyopathy, Adrenal suppression and Decreased growth.

With administration of postnatal corticosteroids in the 1st week of

life, the risk of gastrointestinal perforation is significantly
increased, regardless of which steroid is administered (RR: 1.81;
95% CI: 1.33, 2.48).This effect may be associated with concurrent
administration of indomethacin.

Side effects :(Ctd)

Individual studies have reported an increased risk of later cerebral

palsy (CP) in children with dexamethasone in infancy (Shinwell et
al, 2000; Yeh et al, 1998).

The meta-analyses support this concern with dexamethasone

initiated in the 1st week of life (with no effect seen with
Hydrocortisone), although the relationship was not statistically
significant when treatment is initiated after 7 days of age (Halliday
et al, 2009a,2009b).

Side effects :(Ctd)

The lack of substantial beneficial effects and the concern

regarding adverse effects led the American Academy of Pediatrics
and Canadian Pediatric Society to recommend against any routine
use of postnatal dexamethasone in 2002 (Committee on the fetus
and newborn, 2002)

A more recent assessment, while acknowledging the uncertainty

around specific outcomes, does illustrate the overlap between the
number needed to treat ( prevent BPD) and the number needed to
harm (cause CP) for early dexamethasone treatment (Schmidt et
al, 2008

Side effects : (Ctd)

This is further supported by an independent meta-analysis

(Shinwell and Eventov-Friedman,2009), demonstrating
significantly increased risk of neuro-developemental impairment
(NDI) and CP with any dexamethasone exposure and a large
cohort study demonstrating a dose-dependent increased risk of
death or NDI at 18 to 22 months corrected age, regardless of
postmenstrual age at the time of dexamethasone exposure
(Wilson-Costello et al, 2009).

Thus, the avoidance of postnatal dexamethasone is prudent,

given what is known about the risks and benefits and there are
significant data to support the use of any other systemic steroid
at this point in time.

Inhaled steroids:

Although inhaled steroids initiated in the first 2 weeks of life have been
studied for prevention of BPD, there are no data suggesting either immediate
or later clinical improvement with this intervention, although there is a trend
toward decreased systemic steroid use in these infants (Shah et al, 2007).

A pilot study of budesonide with beractant (Survanta, Abbot, Columbus, Ohio)

compared to beractant alone for treatment of RDS resulted in a significantly
lower rate of death or BPD at 36 weeks (32% vs. 61%), without evidence of
substantial adverse effects (Yeh et al, 2008).

These findings are somewhat surprising, given that the majority of infants
received only a single dose of study medication.

Other
Indications

Use prior to extubation :

Some babies with RDS who require intubation can develop lung
injury and inflammation and become dependent on ventilator.

Dexamethasone is effective at facilitating extubation and

reducing BPD but is associated with significant long-term
adverse effects, including an increased risk of cerebral palsy
when used during the first week of life.

The greater the risk of BPD, then the more likely it is that
benefits of steroids will outweigh the risks .

Regime prior to extubation :

Three doses of Dexamethasone @ 0.25 mg/kg/dose every 12

hours starting 8 to 12 hours before the next extubation.
(For attenuation of postextubation airway edema, with stridorous
obstruction leading to respiratory failure)

There is also evidence from case series that much lower doses
of dexamethasone (0.05 mg/kg/day) might be effective in
facilitating extubation.

A rapid tapering course of IV Dexamethasone, starting at 0.25

mg/kg/day and lasting for 5-7 days, was advised.

Use prior to extubation (Ctd.) :

Although this regimen has not been tested in clinical trials, a short
course and relatively low dose of hydrocortisone has been used
successfully to potentially reduce ventilator settings and facilitate
extubation as it is claimed to have less potential for adverse
effects.

Inhaled Betamethasone does not prevent BPD but does decrease

the need for systemic steroids and facilitate earlier extubation of
ventilated infants with BPD.

Rescue glucocorticosteroid therapy for

Refractory Hypotension:
Refractory hypotension commonly occurs in premature newborns
and is associated with a high mortality rate, an increased
incidence of intraventricular hemorrhage and periventricular
leukomalacia and poor neurodevelopmental outcomes.

Consider low dose hydrocortisone ( @ 3 mg/kg/day) for 2-5 days in three

divided doses)

Studies support the efficacy of Hydrocortisone in raising BP within 2 hours of

administration, yet the long term neurologic effects of this treatment in VLBWs
remain to be investigated.

Evidence:

There are several retrospective trials regarding rescue glucocorticosteroid

therapy to treat neonatal refractory hypotension. However, there are
insufficient numbers of well-designed randomized controlled trials (RCTs)
regarding glucocorticosteroid therapy for refractory hypotension in
preterms.

Among the four RCTs included in a recent Cochrane Review , Gaissmaier

et al. used dexamethasone (DEX) and Ng et al. used hydrocortisone, are
intended to treat early neonatal refractory hypotension by glucocorticoid
therapy. The authors in both of the trials concluded that glucocorticoid
therapy significantly reduced the use of inotropes in the management of
refractory hypotension. However, their study designs were not sufficient to
determine the safety of rescue use of glucocorticoid.

Evidence (Ctd..) :

With regard to studies using hydrocortisone as the primary

treatment of hypotension (not for hypotension unresponsive to
inotropes), Bourchier et al. compared hydrocortisone versus
dopamine in a randomized controlled manner with a relatively
small sample size, and found no significant advantage of
hydrocortisone against dopamine use.

In Meconium Aspiration Syndrome :

The use of corticosteroids in MAS is generally not recommended

although this approach has been proposed to reduce
inflammation induced by meconium and minimize prostaglandinmediated pulmonary vasoconstriction.

In refractory hypoglycemia :

Hydrocortisone (@5 mg/kg/day) is generally indicated when

neonate cannot maintain its glucose levels within normal range
despite receiving GDR of 12-15 mg/kg/min.

It reduces peripheral glucose utilization, increase

gluconeogenesis and increases the effects of glucagon.

Before administrating Hydrocortisone, it is important that a cortisol

level be drawn and sent to the laboratory.

Take home message :

Because of this potential harm and lack of well-established long-term
benefit, routine use of corticosteroids is discouraged and reserved only for
infants with progressive respiratory failure that is refractory to all other
therapies in BPD.

The steroids may be used routinely prior to extubation but only in

cases of refractory hypotension, refractory hypoglycemia (not
responding to multiple drugs) and generally not recommended in
meconium aspiration syndrome.

Take home message : (Ctd)

There are significant data to support the use of systemic

steroids at this point in time hence, these should be preferred
over inhaled steroids.

The steroid treatment should be given after 7 days of life to

minimize the potential adverse effects.