Post on 05-Jul-2018
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Role of postnatal steroids in
neonatology
Dr. Anirudha
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Use of steroids in BPD
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Introduction:
The incidence of hronic lung disease (BPD) is
approximately !"# in extremely lo$ birth $eight infants and
is associated $ith mortality and poor neurodevelopmental
outcomes%
The pathogenesis of &D is regarded as multifactorial'
including infectioninflammation' oxidative stress'
barotraumavolutrauma' genetic factors and the absence of
antenatal steroids %
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Introduction (cont.…)
Recently' etterberg et al% proposed that early adrenal
insufficiency $as the basis of &D' based on their finding that
infants $ho subse*uently developed &D had significantly
lo$er cortisol secretion in response to adrenocorticotrophic
hormones than those $ithout &D%
Based on these findings' glucocorticoids therapy has been
underta+en for prophylactic or therapeutic purposes for &D'
but its efficacy and safety have still not been fully clarified%
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Treatment protocol :
DART protocol:
(IV/PO) Deamet!asone"
"%",- mg+g per dose every ./ hourly for first 0 days'
"%"- mg+g per dose every ./ hourly for 0 days'
"%"/- mg+g per dose every ./ hourly for / days' "%". mg+g per dose every ./ hourly for / days'
Bet$een Day , and Day .! of life%
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Treatment protocol (Ctd….):
#$drocortisone1 started at - mg+gday for 0 days' $ith
$eaning over , to ." days% 2f no response by / to 0 days' stoptreatment%
3s per the recommendations of the /"." 3merican 3cademyof Pediatrics 1 4"%/ mg+gday) of Deamet!asone (in babies
$ho remain ventilator dependent after .5/ $ee+s of age)%
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Benefits:
2n early trials' treatment $ith glucocorticoids (usually
dexamethasone) in infants' $ho remained ventilator dependent for /
to 0 $ee+s' resulted in increased rs (Dynamic compliance) '
decreased Rrs ( Respiratory system Resistance)' diminished 6/ re*uirement and earlier extubation%
Ho$ever' treatment $ith glucocorticoids does not appear to have asubstantial impact on long7term pulmonary outcomes' such as
duration of supplemental 6/ re*uirement' length of hospital stay or
mortality%
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Benefits:
(Ctd…) 8ubse*uent trials of earlier treatment' recurrent pulses and
lo$er doses have yielded inconsistent results as either a
prophylactic or attenuating agent%
Randomi9ed trials of inhaled glucocorticoids also did not
demonstrate improved pulmonary outcome%
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%!ort term %ide e&&ects o& 'lucocorticoids :
Transient adrenal suppression
:astric ulceration' 2ntestinal perforation
:lucose 2ntolerance
8ystemic Hypertension
Transient catabolic state
2ncreased ris+ of sepsis
Hypertrophic ardiomyopathy
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on term dra*+ac,s:
2n addition to these short7term side effects' long7term follo$
up of infants treated $ith postnatal corticosteroids' primarily
dexamethasone' has raised concerns about impairedneurodevelopement and gro$th%
Because of this potential harm and lac+ of $ell7establishedlong7term benefit' routine use of corticosteroids is
discouraged and reserved only for infants $ith progressive
respiratory failure that is refractory to all other therapies%
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-idence
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Mec!anism o& action : Preterm infants $ho are given postnatal corticosteroids
demonstrate some decreased inflammatory mar+ers and
suppression of cyto+ine7mediated inflammatory reactions in their
tracheal aspirates ( :ronec+ et al' .;;0)%
Proposed T!eories 1 The potential for increased surfactant
synthesis' enhanced
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Mec!anism o& action (Ctd…..) :
These potential benefits are balanced against the +no$ledge that
dexamethasone results in persistent decrease in alveolar
numbers in animal models (Massaro and Massaro' /""")%
linical studies have demonstrated acute improvements in
dynamic compliance and pulmonary resistance after treatment
$ith postnatal corticosteroids' although small follo$7up studies
have demonstrated no differences in respiratory morbidity despite
fe$er children $ith abnormal pulmonary function at = - years of
age (>ixon et al' /"",)%
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Timin o& e&&ect :
Based on t$o meta7analyses of treatment before and after , days of
age (Halliday et al' /"";a' /"";b)' postnatal dexamethasone has
similar beneficial effects on death or BPD at 0? $ee+s (RR "%,/ to "%,0@
;-# 2s $ithin "%?.' "%A- for both treatment intervals) and decreased
need for mechanical ventilation' $ith no significant impact on survival to
hospital discharge%
The aggregation of studies comparing hydrocortisone administered in
the .st $ee+ of life to placebo demonstrates no effects on mortality or
BPD%
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!ic! +a+ies0 Potential criteria for treatment $ould be i6/ ="%?"' mean air$ay pressure
=./ to .! cm H/6 and age = , days%
3t minimum' infants $ho might be candidates for dexamethasone therapy$ould be those $ith severe' persistent disease' treated under a protocol
$ith a short exposure (0 days)' $ith dosing initiated at 4 "%/- mg+gday
and after informing the family of the short and long7term effects%
2nterestingly' alsh et al (/""? b) reported decreasing postnatalcorticosteroids rates in three maCor >orth 3merican neonatal net$or+s
from /"". to /""0' follo$ing the societies statement' $ith no concurrent
change in the rate of BPD%
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-idence reardin %teroid Aderse e&&ects
MaCor concerns 1 Hypertension' Hyperglycemia' Hypertrophic
cardiomyopathy' 3drenal suppression and Decreased gro$th%
ith administration of postnatal corticosteroids in the .st $ee+ of
life' the ris+ of gastrointestinal perforation is significantly
increased' regardless of $hich steroid is administered (RR1 .%A.@;-# 21 .%00' /%!A)%This effect may be associated $ith concurrent
administration of indomethacin%
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%ide e&&ects :(Ctd……)
2ndividual studies have reported an increased ris+ of later cerebral
palsy (P) in children $ith dexamethasone in infancy (8hin$ell et
al' /"""@ Eeh et al' .;;A)%
The meta7analyses support this concern $ith dexamethasone
initiated in the .st $ee+ of life ($ith no effect seen $ith
Hydrocortisone)' although the relationship $as not statistically
significant $hen treatment is initiated after , days of age (Halliday
et al' /"";a'/"";b)%
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%ide e&&ects :(Ctd……)
The lac+ of substantial beneficial effects and the concern
regarding adverse effects led the 3merican 3cademy of Pediatrics
and anadian Pediatric 8ociety to recommend against any routine
use of postnatal dexamethasone in /""/ (ommittee on the fetus
and ne$born' /""/)
3 more recent assessment' $hile ac+no$ledging the uncertainty
around specific outcomes' does illustrate the overlap bet$een thenumber needed to treat ( prevent BPD) and the number needed to
harm (cause P) for early dexamethasone treatment (8chmidt et
al' /""A
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%ide e&&ects : (Ctd……)
This is further supported by an independent meta7analysis
(8hin$ell and Fventov7riedman'/"";)' demonstrating
significantly increased ris+ of neuro7developemental impairment
(>D2) and P $ith any dexamethasone exposure and a largecohort study demonstrating a dose7dependent increased ris+ of
death or >D2 at .A to // months corrected age' regardless of
postmenstrual age at the time of dexamethasone exposure
(ilson7ostello et al' /"";)%
Thus' the avoidance of postnatal dexamethasone is prudent'
given $hat is +no$n about the ris+s and benefits and there are
significant data to support the use of any other systemic steroid
at this point in time%
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In!aled steroids:
3lthough inhaled steroids initiated in the first / $ee+s of life have been
studied for prevention of BPD' there are no data suggesting either immediate
or later clinical improvement $ith this intervention' although there is a trend
to$ard decreased systemic steroid use in these infants (8hah et al' /"",)%
3 pilot study of budesonide $ith beractant (8urvanta' 3bbot' olumbus' 6hio)
compared to beractant alone for treatment of RD8 resulted in a significantly
lo$er rate of death or BPD at 0? $ee+s (0/# vs% ?.#)' $ithout evidence of
substantial adverse effects (Eeh et al' /""A)%
These findings are some$hat surprising' given that the maCority of infants
received only a single dose of study medication%
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Ot!er
Indications
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1se prior to etu+ation :
8ome babies $ith RD8 $ho re*uire intubation can develop lung
inCury and inflammation and become dependent on ventilator%
Dexamethasone is effective at facilitating extubation and
reducing BPD but is associated $ith significant long7term
adverse effects' including an increased ris+ of cerebral palsy
$hen used during the first $ee+ of life%
The greater the ris+ of BPD' then the more li+ely it is that
benefits of steroids $ill out$eigh the ris+s %
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Reime prior to etu+ation
: Three doses of Dexamethasone G "%/- mg+gdose every ./
hours starting A to ./ hours before the next extubation%
(or attenuation of postextubation air$ay edema' $ith stridorous
obstruction leading to respiratory failure)
There is also evidence from case series that much lo$er doses
of dexamethasone ("%"- mg+gday) might be effective infacilitating extubation%
3 rapid tapering course of 2 Dexamethasone' starting at "%/-
mg+gday and lasting for -7, days' $as advised%
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1se prior to etu+ation (Ctd….) :
3lthough this regimen has not been tested in clinical trials' a short
course and relatively lo$ 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%
2nhaled Betamethasone does not prevent BPD but does decrease
the need for systemic steroids and facilitate earlier extubation ofventilated infants $ith BPD%
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Rescue lucocorticosteroid t!erap$ &or
Re&ractor$ #$potension:
Refractory hypotension commonly occurs in premature ne$borns
and is associated $ith a high mortality rate' an increased
incidence of intraventricular hemorrhage and periventricularleu+omalacia and poor neurodevelopmental outcomes%
onsider lo$ dose hydrocortisone ( G 0 mg+gday) for /7- days in three
divided doses)
8tudies support the efficacy of Hydrocortisone in raising BP $ithin / hours of
administration' yet the long term neurologic effects of this treatment in &Bs
remain to be investigated%
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-idence:
There are several retrospective trials regarding rescue glucocorticosteroid
therapy to treat neonatal refractory hypotension% Ho$ever' there are
insufficient numbers of $ell7designed randomi9ed controlled trials (RTs)
regarding glucocorticosteroid therapy for refractory hypotension in
preterms%
3mong the four RTs included in a recent ochrane Revie$ ' :aissmaier
et al% used dexamethasone (DFI) and >g 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% Ho$ever' their study designs $ere not sufficient to
determine the safety of rescue use of glucocorticoid%
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-idence (Ctd…..) :
ith regard to studies using hydrocortisone as the primary
treatment of hypotension (not for hypotension unresponsive to
inotropes)' Bourchier et al% compared hydrocortisone versusdopamine in a randomi9ed controlled manner $ith a relatively
small sample si9e' and found no significant advantage of
hydrocortisone against dopamine use%
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In Meconium Aspiration %$ndrome :
The use of corticosteroids in M38 is generally not recommended
although this approach has been proposed to reduceinflammation induced by meconium and minimi9e prostaglandin7
mediated pulmonary vasoconstriction%
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In re&ractor$ !$pol$cemia :
Hydrocortisone (G- mg+gday) is generally indicated $hen
neonate cannot maintain its glucose levels $ithin normal range
despite receiving :DR of ./7.- mg+gmin%
2t reduces peripheral glucose utili9ation' increase
gluconeogenesis and increases the effects of glucagon%
Before administrating Hydrocortisone' it is important that a cortisol
level be dra$n and sent to the laboratory%
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Ta,e !ome messae :
Because of this potential harm and lac+ of $ell7established long7term
benefit' routine use of corticosteroids is discouraged and reserved only for
infants $ith progressive respiratory failure that is refractory to all othertherapies in BPD%
The steroids may be used routinely prior to extubation but only in
cases of refractory hypotension' refractory hypoglycemia (notresponding to multiple drugs) and generally not recommended in
meconium aspiration syndrome%
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Ta,e !ome messae : (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 , days of life to
minimi9e the potential adverse effects%
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