Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep
Noah H Hillman
2
J Jane Pillow
1
Molly K Ball
0
Graeme R Polglase
1
Suhas G Kallapur
2
Alan H Jobe
2
0
Northwestern University, Department of Neonatology
,
Chicago, IL 60614
,
USA
1
School of Women's and Infants' Health, The University of Western Australia
,
Perth, WA 6009
,
Australia
2
Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology
,
Cincinnati, OH 45236
,
USA
Background: Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia. Objective: To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury. Methods: 129 d gestational age lambs (n = 5-8/gp; term = 150 d) were operatively delivered and ventilated after exposure to either 1) no medication, 2) antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3) 0.5 mg/kg Dexamethasone IV at delivery or 4) Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (VT) to 15 mL/ kg for 15 min and then given surfactant. The lambs were ventilated with VT 8 mL/kg and PEEP 5 cmH20 for 2 h 45 min. Results: High VT ventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids. Conclusions: Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury.
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Introduction
The majority of very low birth weight infants are
intubated and receive mechanical ventilation at birth [1]. A
few large tidal volume breaths can inactivate surfactant
[2], and initiation of ventilation with large tidal volumes
activates an inflammatory cascade in the medium and
small airways [3]. In surfactant deficient animals, normal
tidal volume ventilation from birth initiates an
inflammatory cascade characterized by inflammatory cell influx
into the lungs, increased alveolar protein, inflammatory
cytokine mRNA induction, and systemic acute phase
inflammatory responses [4]. Mechanical ventilation is
associated with an increased risk of bronchopulmonary
dysplasia (BPD), and alternatives to delivery room
intubation and ventilation tend to decrease BPD [5,6]. Lung
inflammation is a major contributor to the
pathophysiology of BPD [7].
Antenatal corticosteroids have pleotrophic effects that
include induced lung maturation and decreased neonatal
mortality, respiratory distress syndrome (RDS),
intraventricular hemorrhage, and necrotizing enterocolitis, but no
decrease in BPD [8]. Antenatal corticosteroids also
increase the antioxidant defenses of very low birth weight
infants and preterm sheep [9,10]. Antenatal
corticosteroids are currently recommended for women 24 to 34
weeks gestation at risk for preterm delivery [11]. Postnatal
corticosteroids, primarily dexamethasone, are used to
wean infants from ventilatory support and to decrease
BPD [12]. Although some infants exposed to postnatal
corticosteroids have impaired neurodevelopment, infants
with high risk for BPD benefit from weaning from the
ventilator and a decrease in BPD [13]. Hydrocortisone, used
to treat relative adrenal insufficiency in premature infants,
decreased the incidence of BPD in infants exposed to
chorioamnionitis [14]. The presumed beneficial effects of
corticosteroids in BPD are to decrease lung inflammation
and microvascular permeability [15].
The initiation of ventilation at birth with large tidal
volumes for 15 minutes causes an acute stretch induced lung
injury and a systemic inflammatory response [16].
Ventilation of preterm lambs activates Early growth protein 1
(Egr-1) and other pro-inflammatory signaling pathways
[17] that are inhibited by corticosteroids [18].
Corticosteroids decrease stretch induced lung injury in adult animals
[19]. Corticosteroids given prior to cardiopulmonary
bypass also decrease systemic inflammation and acute
phase responses [20]. Since different corticosteroids have
different potencies and glucocorticoid effects [21], we
have tested the common corticosteroids used clinically in
preterm infants. We hypothesized that antenatal
betamethasone or postnatal dexamethasone or cortisol will
decrease lung and systemic injury caused from initiating
ventilation with high VT in preterm sheep.
Materials (...truncated)