Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

Respiratory Research, Dec 2009

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 (V T) to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with V T 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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://respiratory-research.com/content/pdf/1465-9921-10-124.pdf

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. - 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)


This is a preview of a remote PDF: http://respiratory-research.com/content/pdf/1465-9921-10-124.pdf

Noah H Hillman, J Jane Pillow, Molly K Ball, Graeme R Polglase, Suhas G Kallapur, Alan H Jobe. Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep, Respiratory Research, 2009, pp. 124, 10, DOI: 10.1186/1465-9921-10-124