Controversial therapies in
Neonatal Care
Julia Trintis, D.O.
Objectives
Discuss respiratory failure in premature
newborns.
Discuss current indications for inhaled
nitric oxide therapy in newborns.
Discuss chronic lung disease in newborns.
Discuss the benefits and hazards of
postnatal steroids.
Respiratory Failure: Risk Factors
Prematurity
Pulmonary Disease
Respiratory infections
Congenital Anomalies
Congenital heart
disease
Surfactant protein
deficiencies
Bronchopulmonary Dysplasia
Described by Northway in 1967
Severe chronic lung injury in premature infants
who survived hyaline membrane disease
Four distinct stages
– Respiratory distress syndrome
– Alveolar interstitial edema
– Extensive bronchial and bronchioalar metaplasia and
hyperplasia, Cystic emphysema and overinflation
– Massive fibrosis, destruction of alveoli and airways,
and consolidation
Evolution of “Bronchopulmonary
Dysplasia”
Classic BPD
–
–
–
–
Extensive, diffuse fibroproliferation
Alternating atelectasis with hyperinflation
Severe airway epithelial lesions
Marked airway smooth muscle hyperplasia
New BPD
Rare fibrosis
Less heterogeneity
Mild airway epithelial lesions
Milder airway changes
Definition of BPD and Diagnostic
Criteria
Epidemiology
BPD relatively rare in infants born beyond 32
weeks
NICHD (501-1500 grams): 22%
– Less than 1000 grams: 40%
“Although there has been a marked decrease in
BPD in larger infants, recent data from Vermont
Oxford database and NICHD network indicate
that in the years since 1996, there has been no
further decrease in the incidence of BPD.”
(Taeusch)
Pathogenesis of BPD
CP Spear 2006
Strategies for preventing BPD
Antenatal steroids
Surfactant
Permissive hypercapnia
Ventilator strategies
Reduce “excessive” O2
use
Good nutrition
Postnatal steroids
Inhaled Nitric Oxide???
Current indications for inhaled
nitric oxide therapy in newborns
Selective pulmonary
vasodilator
Improves oxygenation
and reduces need for
ECMO in term infants
with PPHN
Inhaled NO Therapy in Premature
Newborns
Initial reports showed iNO
improved oxygenation in
preterm infants with
severe respiratory failure
and with developing or
established BPD
Kinsella 1999, Banks 1999, Clark 2002
Animal Models
Reduces lung inflammation
Improves surfactant function
Attenuates hyperoxic lung injury
Promotes lung growth
Kang 2002, Ballard 2006, Cotton 2006
Potential Therapeutic Targets
Surfactant function/ production
Improve gas exchange
Reduce FiO2
Lower pulmonary artery pressure
Anti-inflammatory effects
Preserve or stimulate angiogenesis and
alveolarization in the developing lung
Inhaled NO in Premature Newborns:
Randomized Placebo-Controlled Trials
Author
Year
Patient #
Design
Schreiber
2003
207
Early, single center
Van Meurs
2005
420
Early, Brief, sick
Kinsella
2006
793
Early mild disease
Ballard
2006
582
Evolving BPD
EUNO
2008
800
Early, mild disease
Abman
Schreiber, 2003
Single center study
Randomized, double-blind, placebo controlled trial
207 patients
Showed reduction in the combined outcome of death
and BPD in preterm infants treated with inhaled Nitric
Oxide
Van Meurs, 2005
Large, Multicenter study
Randomized, double-blind, placebo controlled trial
420 neonates
Showed no significant reduction in rates of death or BPD
with inhaled nitric oxide in preterm infants with a birth
weight of less than 1500 grams
Kinsella, 2006
Large, Multicenter study
Randomized, double-blind, placebo controlled trial
793 neonates
Low dose inhaled NO (5 ppm) did not reduce the overall incidence
of BPD, except among infants with a birth weight of at least 1000 g,
but it did reduce the overall risk of brain injury.
Ballard, 2006
Large, Multicenter study
Randomized, double-blind, placebo controlled trial
582 neonates
Enrolled infants who were ventilator dependent at 7 to 21
days of age.
Randomly assigned to 24 day course of nitrogen placebo
or inhaled NO at initial dose of 20 ppm
NO treatment improved survival at 36 weeks PMA
without BPD ( 43.9% vs 36.8%) and reduced the
duration of oxygen therapy and hospitalization.
European NO (EUNO) trial
Large, Multicenter study (35 centers)
Randomized, double-blind, placebo controlled trial
800 neonates
Preemies 24-29 weeks GA
Mild to moderate respiratory failure
Randomized to receive iNO 5ppm or placebo for 7-21
days
Results pending
– primary endpoint of chronic oxygen dependency reduction at 36
weeks' postconceptional age
– long-term lung and brain will be followed-up until 7 years of age.
Conclusion: Does inhaled NO have a role in the treatment
of preterm infants with respiratory failure?
Offering the critically ill, very preterm infant early,
sustained low dose prophylactic treatment with
NO does not appear to improve survival or BPD.
Data on effective dose, duration, time of
initiation, and selection of infants most likely to
benefit remain unclear.
Additional studies need to be performed before
the precise role of iNO in preventing BPD can be
defined.
Long term follow up is essential!
Postnatal Steroids and Chronic Lung Disease:
The Good, the Bad, and the Ugly
Chronic lung disease
defined as oxygen dependence at 36
weeks postconceptual age or oxygen
requirement for >28 days.
Associated with:
– poor nutrition and growth
– poor feeding skills
– prolonged hospitalization and episodes of
nosocomial infection
Story of steroids: “hastened
weaning from ventilator”
1980’s: initial reports suggested short term benefits of
steroids in vent dependent children
Mammel 1983
–
–
–
–
–
Dexamethasone used with severe BPD
N=6
Gestational age ranged from 27 to 33 weeks
birth weight from 800 to 1730 g.
Patients received Dexamethasone (0.5 mg/kg/day) or normal
saline for the first 3 days, then treatment was crossed over for
the next 3 days.
– all six patients had improved during dexamethasone therapy
Mammel et al. Lancet 1983.
Faster weaning from ventilator and
oxygen
Cummings, et al 1989
– Double blinded study on 36 preterm infants who were
dependent on O2 and mechanical ventilation at 2
weeks
– Dexamethasone given for 42 days improved
pulmonary and neurodevelopmental outcome at 6
and 15 months of age
O’Shea, et al 1993
– Longitudinal follow up on 61 preterm infants
– Infants had been treated with 42 day course of dex
starting at 2 weeks
– Dex associated with fewer days of assisted ventilation
but not with improved outcome at age 1
Dexamethasone became widely
used to prevent and/or treat CLD
– Retrospective study examining the outcome
of neonates between 500 g and 749 g
showed that 43% of infants born between
1990-1992 received dexamethasone vs 84%
between 1993-1995.
–
Hack M, Fanaroff AA. Early Hum Dev 1999
The pendulum swings…
Dex is good,
the more the
better
All steroids
are bad, no
babies
should get
them
1998: Increase in
neurodevelopmental dysfunction
Yeh, et al
large multicenter follow-up study
Outcomes at 2 year corrected age of infants who
participated in a double blinded controlled trial of
early dexamethasone for the prevention of CLD
133 children
marked increase in neurodevelopmental
dysfunction in neonates treated with
dexamethasone compared with controls
Yeh, et al. Pediatrics 1998.
1999: Dexamethasone has
some more side effects
Shinwell, et al
Long term neurodevelopmental outcome of children who
participated in early postnatal dexamethasone treatment
for prevention of chronic lung disease
Dexamethasone treated group associated with:
– Hypertension
– Hyperglycemia
– Gastrointestinal hemorrhage
– no reduction in either the incidence or severity of
chronic lung disease or mortality
.
Shinwell Es, et al. Arch Dis Child Fetal Neonatal Ed 2000
More alarming publications on the long term
negative effects of dexamethasone appeared
Higher incidence of cerebral palsy
Reduced brain volumes
MRI study at term equivalent age showed
reduced brain volumes in infants treated
with a moderately low dose of
dexamethasone after 28 days of life
Parikh, et al. Pediatrics, 2007.
2002
American Academy of Pediatrics stated outside clinical
trials, postnatal steroid use should be reserved only for
“exceptional clinical circumstances”.
“routine use of systemic dexamethasone for the
prevention or treatment of CLD in infants with VLBW is
not recommended.”
“the use of corticosteroids should be limited to
exceptions clinical circumstances…parents should be
fully informed about the known short-and long-term risks
and agree to treatment.”
AAP, Committee on Fetus and Newborn. Pediatrics, 2002.
2006
Finer et al prospective evaluation of
postnatal steroid administration in
California, from April 2002 to March 2003.
19.3% of children less than or equal to
1500 grams were still receiving steroids.
Finer NN, et al. Pediatrics 2006.
Dexamethasone dosing
Most previous studies started with a dose
of 0.5 mg/kg/day
Lower doses (0.15 mg/kg/day) were not
associated with adverse
neurodevelopmental outcomes in 2
studies
– Stark, et al: Early treatment (n=123)
– Doyle, et al: Later extubation study (n=58)
Watterberg
Side effects seen with early
Dexamethasone therapy
Infection and sepsis
Hyperglycemia
Hypertension
Cardiac hypertrophy
Delay in weight gain
Worse neurodevelopmental outcomes
Not all steroids are the same
Hydrocortisone has lower potency
Shorter half-life
Mineralocorticoid vs glucocorticoid
In in vitro neuronal cells, dexamethasone
stimulates apoptosis while
mineralocorticoids, are protective against
apoptosis.
Dexamethasone Hydrocortisone
Half life
36-72 hours
8-12 hours
Steroid
Glucocorticoid
Mineralocorticoid
Preservative
Sodium
bisulphite
No sodium
bisulphite
Apoptosis
Stimulates
Protects
Hydrocortisone for chronic lung
disease
Six reports have been published on
postnatal hydrocortisone administration for
prevention (n=5) or treatment (n=1) of
CLD
1972
First randomized placebo controlled trial of
hydrocortisone treatment
evaluated the ability of postnatally administered
hydrocortisone to alter the course of outcome in
infants with hyaline membrane disease.
44 infants (mean gestational age 32.5 weeks)
were treated with hydrocortisone or a lactose
placebo within 24 h after birth.
no remarkable effect on PaO2, PaCO2, need for
assisted mechanical ventilation or survival.
Baden, et al. Pediatrics 1972.
27 years later…1999
Watterberg et al enrolled 40 preterm
infants into a randomised pilot study to test
whether hydrocortisone would increase
the likelihood of survival without CLD
started low-dose hydrocortisone within 48
hours after birth
Treated for 12 days
Watterberg, et al. Pediatrics 1999.
Results
Among those treated with hydrocortisone, 60%
survived without supplemental oxygen at 36
weeks’ PMA vs 35% in placebo group.
Treatment decreased number of days on:
– .40% oxygen
– .25% oxygen
– Days on ventilator
– Oxygen at discharge
Adverse short term complications were similar between
the two groups
–
Watterberg KL, Gerdes JS, Gifford KL, et al. Pediatrics 1999
2003
Retrospective matched-cohort study
compared 25 preterm infants w/ CLD who
were treated with a much higher dose of
hydrocortisone with 25 controls
From day 7, no significant differences in
amount of extra oxygen needed between 2
groups
Heide-Jalving, et al. Acta Paediatr 2003.
Watterberg 2004
Multicenter trial
Prophylaxis of early adrenal insufficiency
to prevent BPD
Enrolled mechanically ventilated infants
with a birth weight of 500-999 gram infants
between 12 h and 48 h of life
Results
Prophylactic treatment of early adrenal
insufficiency did not improve survival
without CLD or mortality at 36 weeks.
Enrollment stopped at 360 infants
because of an increase in spontaneous
gastrointestinal perforation in the
hydrocortisone treated group.
2005 Peltoniemi
effect of early hydrocortisone treatment on
survival without CLD in infants less than or
equal to 30 weeks
tendency towards lower CLD in the
hydrocortisone treated group
Study was discontinued early due to
higher incidence of GI perforation
Peltoniemi O, Kari MA, Heinonen K, et al. J Pediatr 2005.
2007 Bonasarte et al
Double blinded, randomised, placebo controlled
trial
50 mechanically ventilated infants
Birth weights 500-1249 grams
Oxygen free survival was higher in the
hydrocortisone treated group
No difference in GI perforation between the
groups
Bonsante F, Latorre G, Iacobelli S, et al. Neonatology 2007
Long term follow-up
Few follow-up reports based on the initial
1972 hydrocortisone trial
no differences in lung, liver, adrenal,
thymus, heart and spleen pathology
attributable to steroid treatment
Significant association between the
occurrence of intraventricular hemorrhage
and hydrocortisone treatment
Taeusch et al. Pediatrics1973.
24 survivors examined at 1 year of age
Griffiths Developmental Scale showed a
normal developmental quotient in both
groups
substantial difference in the results for the
gross motor development with a lower
mean score for the hydrocortisone group
Van de Heide et al
25 preterm infants treated with high-dose
hydrocortisone
age of 5–7 years this group did not differ
from a non-treated control group with
regard to:
– neurological outcome
– psychomotor development
– school performance
Watterberg et al
294 survivors, 252 (86%) infants who
participated in prophylactic hydrocortisone
trial
evaluated at the age of 20.0 months
incidence of cerebral palsy was similar
significantly smaller percentage of infants
treated with hydrocortisone had a Mental
Developmental Index below 70
Lodygensky and Rademaker 2005
Follow up study
23 preterm-born children received
hydrocortisone treatment for chronic lung
disease
starting dose of 5 mg/kg/day, tapered over a
minimum of 3 weeks
35 children not treated
quantitative MRI and neurocognitive assessment
at 8 years of age
Both groups had similar volumes of grey matter,
white matter, cerebral fluid and hippocampus
Rademaker 2007
62 preterm-born children treated with
hydrocortisone for CLD were compared
with 164 children who did not receive
steroids during their admission to the
NICU
mean IQ, and visual-motor integration and
memory test results, were similar in the
hydrocortisone-treated and non-treated
groups
Karemaker et al
retrospective matched-cohort
long-term effects on behavior and motor
skills in school age (7–10 years) children
who received either dexamethasone or
hydrocortisone for CLD
dexamethasone group had more
neuromotor problems than children in the
control group
Puzzled yet?
Summary
In long-term follow-up studies at 5–8 years
of age preterm infants not treated with
hydrocortisone compared with those who
were treated for CLD, no differences have
been found:
– in neurocognitive or motor outcome
– incidence of brain abnormalities on MRI
Summary
2 prophylactic hydrocortisone studies,
stopped early due to increased incidence
of spontaneous GI perforation with
combined indomethacin tx
two publications reported an increased risk
of disseminated Candida infections in
infants treated with hydrocortisone
Summary
Moderately early steroid treatment can result in
reductions in:
– Failure to extubate
– CLD
– Neonatal mortality
Risks of short term and potentially long term
adverse effects
– Limited long term outcomes, especially in school age
children
Summary
modify the dosage
Limit the drug–drug interactions
Scrutinise patient selection in
corticosteroid trials on very high-risk
infants in early life
Treat beyond 2 weeks of postnatal age to
avoid the interactive effect of
hydrocortisone with indometacin
Questions?
References
Mammel MC, Green , Johnson, et al. Controlled trial of dexamethasone therapy in infants with bronchopulmonary
dysplasia. Lancet 1983; 1:1356-8.
Yeh, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N
Engl J Med 2004;350:1304-13.
Yeh, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 1998;101:E7.
Shinwell Es, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis
Child Fetal Neonatal Ed 2000.
AAP, Committee on Fetus and Newborn. Pediatrics, 2002.
Finer NN, et al. Pediatrics 2006.
Parikh, et al. Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants.
Pediatrics, 2007; 119:265-72.
Baden, et al. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics
1972, 50:526-34.
Heide-Jalving M, Kamphuis PJ, van der Laan MJ, et al. Short- and long-term
effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatr
2003;92:827–35.
Watterberg KL, Gerdes JS, Gifford KL, et al. Prophylaxis against early adrenal insufficiency to prevent chronic lung
disease in premature infants. Pediatrics1999;104:1258–63.
Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990s. Early
Hum Dev 1999;53:193–218.
References cont.
Watterberg KL, Gerdes JS, Gifford KL, et al. Prophylaxis against
early adrenal insufficiency to prevent chronic lung disease in
premature infants. Pediatrics 1999;104:1258–63.
Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal
insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.
Pediatrics 2004;114:1649–57.
Peltoniemi O, Kari MA, Heinonen K, et al. Pretreatment cortisol values may
predict responses to hydrocortisone administration for the prevention of
bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005;146:632–7.
Bonsante F, Latorre G, Iacobelli S, et al. Early low-dose
hydrocortisone in very preterm infants: a randomized, placebocontrolled trial. Neonatology 2007;91:217–21
Taeusch HW Jr, Wang NS, Baden N, et al. A controlled trial of
hydrocortisone therapy in infants with respiratory distress syndrome:
II. Pathology. Pediatrics 1973;52:850–4.