Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis.

BACKGROUND: A combination of budesonide and surfactant decreases the rates of BPD in infants and lung injury in preterm sheep. Whether this combination will show benefit in the setting of chorioamnionitis and antenatal steroids is not known. METHODS: Ewes at 123 ± 1 day gestational age received intra-amniotic (IA) injections of 10 mg LPS before being randomized to receive either 0.25 mg/kg maternal betamethasone phosphate and acetate or saline by intramuscular (IM) injection at 48 and 24 h prior to delivery at 125 ± 1 day. Lambs (N = 6-9/group) underwent intentionally injurious ventilation for 15 min, then lambs received surfactant mixed with either: (1) saline; or (2) Budesonide 0.25 mg/kg and were ventilated for 4 h. RESULTS: Compared with LPS-exposed animals that received no IM steroid treatment, betamethasone exposed fetuses had improved hemodynamic stability, lung compliance, and ventilation efficiency. The addition of budesonide to surfactant further improved markers of injury and pro-inflammatory cytokine mRNA in both betamethasone IM or no IM lambs exposed to LPS IA. Antenatal betamethasone and IA LPS exposures decreased budesonide levels in the fetal lung and plasma. CONCLUSION: Antenatal betamethasone stabilizes physiologic parameters in LPS treated lambs. Budesonide mixed with surfactant further decreases injury and improves respiratory physiology in betamethasone treated animals. IMPACT: Antenatal betamethasone improved lung and systemic physiology in the setting of intra-amniotic LPS. The addition of budesonide to the surfactant further improved lung function. Budesonide levels in the plasma and lung were lower in lambs exposed to either LPS or LPS and Betamethasone animals, and these findings were not explained by increased esterification in the lungs. The combination of antenatal steroids and budesonide with surfactant had the lowest markers of pro-inflammatory cytokines in the lung of LPS exposed animals.

Preterm ovine respiratory epithelial cell responses to mechanical ventilation, lipopolysaccharide, and interleukin-13.

Mechanical ventilation causes airway injury, respiratory epithelial cell proliferation, and lung inflammation in preterm sheep. Whether preterm epithelial cells respond similarly to adult epithelial cells or are altered by mechanical ventilation is unknown. We test the hypothesis that mechanical ventilation alters the responses of preterm airway epithelium to stimulation in culture. Respiratory epithelial cells from the trachea, left mainstem bronchi (LMSB), and distal bronchioles were harvested from unventilated preterm lambs, ventilated preterm lambs, and adult ewes. Epithelial cells were grown in culture or on air-liquid interface (ALI) and challenged with combinations of either media only, lipopolysaccharide (LPS; 10 ng/mL), bronchoalveolar fluid (BALF), or interleukin-13 (IL-13). Cell lysates were evaluated for mRNA changes in cytokine, cell type markers, Notch pathway, and acute phase markers. Mechanical ventilation altered preterm respiratory epithelium cell types. Preterm respiratory epithelial cells responded to LPS in culture with larger IL-8 induction than adults, and mechanical ventilation further increased cytokines IL-1ß and IL-8 mRNA induction at 2 h. IL-8 protein is detected in cell media after LPS stimulation. The addition of BALF from ventilated preterm animals increased IL-1ß mRNA to LPS (fivefold) in both preterm and adult cells and suppressed IL-8 mRNA (twofold) in adults. Preterm respiratory epithelial cells, when grown on ALI, responded to IL-13 with an increase in goblet cell mRNA. Preterm respiratory epithelial cells responded to LPS and IL-13 with responses similar to adults. Mechanical ventilation or exposure to BALF from mechanically ventilated animals alters the responses to LPS.NEW & NOTEWORTHY Preterm lamb respiratory epithelial cells can be extracted from the trachea and bronchi and frozen, and the preterm cells can respond in culture to stimulation with LPS or IL-13. Brief mechanical ventilation changes the distribution and cell type of preterm respiratory cells toward an adult phenotype, and mechanical ventilation alters the response to LPS in culture. Bronchoalveolar lavage fluid from preterm lambs receiving mechanical ventilation also alters unventilated preterm and adult responses to LPS.

Psychosis spectrum features, neurocognition and functioning in a longitudinal study of youth with 22q11.2 deletion syndrome.

BACKGROUND: Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome. METHODS: 157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS-). RESULTS: We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS- group. Neurocognitive performance was generally comparable in PS+ and PS- groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS- counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change. CONCLUSIONS: Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

Effects of Discontinuation of Weekly Surveillance Testing on Methicillin-Resistant Staphylococcus aureus in the NICU.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) infection is a major cause of serious morbidity and mortality in the neonatal intensive care unit (NICU). There is no clear consensus on infection control measures. Some approaches to MRSA colonization management may be burdensome with unclear benefits. The objective of this study was to determine if stopping weekly MRSA surveillance with active detection and contact isolation (ADI) was associated with a change in infection rate. STUDY DESIGN: This is a retrospective cohort study of infants admitted to two affiliated NICUs. The ADI cohort infants received weekly nasal MRSA cultures and were placed in contact isolation if MRSA colonized for the duration of their hospitalization. The No Surveillance cohort infants were only placed in isolation if there was active MRSA infection or if MRSA colonization was identified incidentally. The rates of infection were determined between the cohorts. RESULTS: There were 8,406 neonates representing 193,684 NICU days in the comparison period. In the ADI cohort, MRSA colonization occurred in 3.4% of infants and infection occurred in 29 infants (0.4%). There were no differences between cohorts in the percent of infants with a MRSA infection at any site (0.5 vs. 0.5%, p = 0.89), rate of MRSA infections per 1,000 patient-days (0.197 vs. 0.201, p = 0.92), rate of bloodstream infections (0.12 vs. 0.26%, p = 0.18), or in the overall mortality rate (3.7 vs. 3.0% p = 0.13). ADI represented an annual cost of $590,000. CONCLUSION: The rates of MRSA infection did not change when weekly ADI was discontinued and was associated with a decrease in cost and resource utilization. KEY POINTS: · Placing MRSA-colonized infants in contact isolation is a common practice.. · Data are limited with respect to efficacy in the NICU.. · This study provides evidence that active detection and contact isolation for MRSA colonization may not be beneficial..

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide.

BACKGROUND: Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS). METHODS: Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared. RESULTS: Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h. CONCLUSIONS: In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation. IMPACT: The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis.

Use of the RAM Cannula with Early Bubble Continuous Positive Airway Pressure Requires Higher Pressures: Clinical and In vitro Evaluations.

OBJECTIVE: Early bubble continuous positive airway pressure (bCPAP) in the delivery room (DR) reduces early intubation, mechanical ventilation, and bronchopulmonary dysplasia. The RAM cannula, adopted for ease of patient care, is a high resistance nasal interface that, when used with bCPAP, only transmits a portion of set pressures and attenuates the bubble effects. This study aimed to review early bCPAP pressures and bCPAP failure with the RAM cannula interface over a 6-year period. STUDY DESIGN: Retrospective, single-center study of infants delivered <1,250 g from 2013 to 2018 (n = 735) begun on bCPAP in the DR with the RAM cannula. In vitro testing of bCPAP pressure transmission was also performed for multiple nasal interfaces and nasal occlusion percentages. RESULTS: The percentage of infants intubated in the DR decreased over time (59 to 42%), while the average bCPAP pressure increased from 5.3 to 6.8 cmH2O. A total of 355 infants (48%) were admitted to the neonatal intensive care unit (NICU) from the DR on BCPAP. The failure rate for bCPAP in NICU within 72 hours decreased from 45 to 24% as the maximum CPAP increased from 5.8 to 7.6 cmH2O. Pneumothorax rates did not change. CPAP pressure transmission decreased with all sizes of the RAM cannula. CONCLUSION: When utilizing the RAM cannula for bCPAP, higher CPAP levels were associated with decreases in DR intubations and CPAP failure within the first 72 hours. If clinicians choose to use the RAM cannula for bCPAP, they will need higher set pressures to achieve lung inflation and the beneficial oscillatory effect will be diminished. KEY POINTS: · The transmission of the pressure oscillations from bubble CPAP is diminished with the RAM cannula.. · Increasing set CPAP pressures was associated with a decreased delivery room intubation rate and a decreased CPAP failure rate within 72 hours.. · Clinicians using the RAM cannula for bCPAP will need to increase pressures to obtain adequate lung inflation or change to a nasal interface designed for bCPAP..

Surfactant plus budesonide decreases lung and systemic responses to injurious ventilation in preterm sheep.

Mechanical ventilation from birth with normal tidal volumes (VT) causes lung injury and systemic responses in preterm sheep. The addition of budesonide to surfactant therapy decreases these injury markers. Budesonide and surfactant will decrease the injury from injurious VT ventilation in preterm sheep. Lambs at 126 ± 1 day gestational age were ventilated from birth with either: 1) Normal VT [surfactant 200 mg/kg before ventilation, positive end expiratory pressure (PEEP) 5 cmH2O, VT 8 mL/kg] or 2) Injury VT (high pressure, 100% oxygen, no PEEP) for 15 min, then further randomized to surfactant + saline or surfactant + 0.25 mg/kg budesonide with Normal VT for 6 h. Lung function and lung, liver, and brain tissues were evaluated for indicators of injury. Injury VT + saline caused significant injury and systemic responses, and Injury VT + budesonide improved lung physiology. Budesonide decreased lung inflammation and decreased pro-inflammatory cytokine mRNA in the lung, liver, and brain to levels similar to Normal VT + saline. Budesonide was present in plasma within 15 min of treatment in both ventilation groups, and less than 5% of the budesonide remained in the lung at 6 h. mRNA sequencing of liver and periventricular white matter demonstrated multiple pathways altered by both Injury VT and budesonide and the combination exposure. In lambs receiving Injury VT, the addition of budesonide to surfactant improved lung physiology and decreased pro-inflammatory cytokine responses in the lung, liver, and brain to levels similar to lambs receiving Normal VT.

Surfactant and budesonide for respiratory distress syndrome: an observational study.

BACKGROUND: In preterm infants on moderately high ventilator support, the addition of budesonide to surfactant lowered bronchopulmonary dysplasia (BPD) rates by 20% without increased morbidity or mortality. The aim of this cohort comparison was to determine the safety and efficacy of the combination in infants with milder respiratory distress syndrome (RDS). METHODS: In August 2016 we began administering budesonide (0.25 mg/kg) mixed with surfactant (Survanta 4 mL/kg) to all infants ≤ 1250 g who failed CPAP and required intubation. Infants were compared to a historical cohort (2013-2016) who received surfactant alone. RESULTS: BPD or death did not change between the historical surfactant cohort (71%, n = 294) and the budesonide cohort (69%, n = 173). Budesonide was associated with a decrease in the need for continued mechanical ventilation, severe BPD type II or death (19-12%), grade III BPD or death (31-21%), and the median gestational age at discharge was 1 week earlier. Histologic chorioamnionitis was associated with decreased budesonide effects. Secondary morbidities (NEC, IVH, ROP, Sepsis) were similar. CONCLUSION: Overall BPD rates remained unchanged with the addition of budesonide. Budesonide was associated with decreased severity of BPD, decreased mechanical ventilation use, earlier discharge, and similar short-term outcomes.

Dose of budesonide with surfactant affects lung and systemic inflammation after normal and injurious ventilation in preterm lambs.

BACKGROUND: The addition of budesonide (Bud) 0.25 mg/kg to surfactant decreased the lung and systemic responses to mechanical ventilation in preterm sheep and the rates and severity of bronchopulmonary dysplasia (BPD) in preterm infants. We hypothesized that lower budesonide concentrations in surfactant will decrease injury while decreasing systemic corticosteroid exposure. METHODS: Preterm lambs received either (1) protective tidal volume (VT) ventilation with surfactant from birth or (2) injurious VT ventilation for 15 min and then surfactant treatment. Lambs were further assigned to surfactant mixed with (i) Saline, (ii) Bud 0.25 mg/kg, (iii) Bud 0.1 mg/kg, or (iv) Bud 0.04 mg/kg. All lambs were then ventilated with protective VT for 6 h. RESULTS: Plasma Bud levels were proportional to the dose received and decreased throughout ventilation. In both protective and injurious VT ventilation, <4% of Bud remained in the lung at 6 h. Some of the improvements in physiology and markers of injury with Bud 0.25 mg/kg were also found with 0.1 mg/kg, whereas 0.04 mg/kg had only minimal effects. CONCLUSIONS: Lower doses of Bud were less effective at decreasing lung and systemic inflammation from mechanical ventilation. The plasma Bud levels were proportional to dose given and the majority left the lung.

Interhospital Transport of Infants on Bubble Continuous Positive Airway Pressure via Ground and Air.

OBJECTIVE: The purpose of this study was to evaluate the use of a respiratory protocol for the interhospital transport of infants with respiratory distress on bubble continuous positive airway pressure (bCPAP) and provide information on the safety of bCPAP during transport via ground and helicopter. METHODS: We evaluated a retrospective cohort study of neonates (gestational age 22-41 weeks) transported to our level 4 neonatal intensive care unit (NICU) before (n = 529) and after implementing (n = 540) protocols for increasing bCPAP and intubation criteria. Infants were evaluated for intubation before transport, the safety of transport, and the need for intubation shortly after arrival in the NICU. RESULTS: After initiating the protocols, less infants received mechanical ventilation, and more infants received bCPAP for transport via ground and helicopter. Upon arrival to the NICU, infants using the protocols had lower fraction of inspired oxygen and higher continuous positive airway pressures, and similar numbers required intubations in the first 12 hours. There were no differences in the rate of pneumothoraces. CONCLUSIONS: bCPAP can be used on both ground and helicopter transport of very small infants. Respiratory protocols decreased mechanical ventilation during transport without increasing the need for intubation within 12 hours of arrival.

Surfactant plus budesonide decreases lung and systemic inflammation in mechanically ventilated preterm sheep.

Mechanical ventilation with normal tidal volumes (VT) causes lung and systemic inflammation in preterm sheep. Mechanical ventilation is associated with bronchopulmonary dysplasia (BPD) in preterm infants, and the addition of budesonide to surfactant decreases BPD in clinical trials. Budesonide with surfactant will decrease the lung injury from mechanical ventilation for 24 h in preterm sheep. Lambs at 126 ± 1 day gestational age were delivered and randomized to either: 1) surfactant (200 mg/kg) or 2) surfactant mixed with budesonide (0.25 mg/kg) before mechanical ventilation with VT of 7-8 ml/kg for 2, 6, or 24 h (n = 6 or 7/group). Lung physiology and budesonide levels in the plasma and the lung were measured. Lung tissue, bronchoalveolar lavage fluid (BALF), liver, and brain tissues were evaluated for indicators of injury. High initial budesonide plasma levels of 170 ng/ml decreased to 3 ng/ml at 24 h. Lung tissue budesonide levels were less than 1% of initial dose by 24 h. Although physiological variables were generally similar, budesonide-exposed lambs required lower mean airway pressures, had higher hyperoxia responses, and had more stable blood pressures. Budesonide decreased proinflammatory mRNA in the lung, liver, and brain. Budesonide also decreased total protein and proinflammatory cytokines in BALF, and decreased inducible nitric oxide synthase activation at 24 h. In ventilated preterm lambs, most of the budesonide left the lung within 24 h. The addition of budesonide to surfactant improved physiology, decreased markers of lung injury, and decreased systemic responses in liver and brain.

Mass spectrometry imaging as a tool for evaluating the pulmonary distribution of exogenous surfactant in premature lambs.

BACKGROUND: The amount of surfactant deposited in the lungs and its overall pulmonary distribution determine the therapeutic outcome of surfactant replacement therapy. Most of the currently available methods to determine the intrapulmonary distribution of surfactant are time-consuming and require surfactant labelling. Our aim was to assess the potential of Mass Spectrometry Imaging (MSI) as a label-free technique to qualitatively and quantitatively evaluate the distribution of surfactant to the premature lamb. METHODS: Twelve preterm lambs (gestational age 126-127d, term ~150d) were allocated in two experimental groups. Seven lambs were treated with an intratracheal bolus of the synthetic surfactant CHF5633 (200 mg/kg) and 5 lambs were managed with mechanical ventilation for 120 min, as controls. The right lung lobes of all lambs were gradually frozen while inflated to 20 cmH2O pressure for lung cryo-sections for MSI analysis. The intensity signals of SP-C analog and SP-B analog, the two synthetic peptides contained in the CHF5633 surfactant, were used to locate, map and quantify the intrapulmonary exogenous surfactant. RESULTS: Surfactant treatment was associated with a significant improvement of the mean arterial oxygenation and lung compliance (p < 0.05). Nevertheless, the physiological response to surfactant treatment was not uniform across all animals. SP-C analog and SP-B analog were successfully imaged and quantified by means of MSI in the peripheral lungs of all surfactant-treated animals. The intensity of the signal was remarkably low in untreated lambs, corresponding to background noise. The signal intensity of SP-B analog in each surfactant-treated animal, which represents the surfactant distributed to the peripheral right lung, correlated well with the physiologic response as assessed by the area under the curves of the individual arterial partial oxygen pressure and dynamic lung compliance curves of the lambs. CONCLUSIONS: Applying MSI, we were able to detect, locate and quantify the amount of exogenous surfactant distributed to the lower right lung of surfactant-treated lambs. The distribution pattern of SP-B analog correlated well with the pulmonary physiological outcomes of the animals. MSI is a valuable label-free technique which is able to simultaneously evaluate qualitative and quantitative drug distribution in the lung.

Bronchopulmonary Dysplasia: When the Very Preterm Baby Comes Home.

Many infants with severe bronchopulmonary dysplasia (BPD) can be safely managed with oxygen at home. This review covers criteria for home oxygen therapy, monitoring, and weaning protocols for oxygen therapy in the outpatient setting. Although most infants with BPD are weaned from oxygen within a year, they continue to have pulmonary function abnormalities into adolescence. These infants also require evaluation for pulmonary hypertension, systemic hypertension, and a strong focus on adequate nutritional needs for growth.

Effects of budesonide and surfactant in preterm fetal sheep.

Mechanical ventilation causes lung injury and systemic inflammatory responses in preterm sheep and is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Budesonide added to surfactant decreased BPD by 20% in infants. We wanted to determine the effects of budesonide and surfactant on injury from high tidal volume (VT) ventilation in preterm lambs. Ewes at 125 ± 1 days gestational age had fetal surgery to expose fetal head and chest with placental circulation intact. Lambs were randomized to 1) mechanical ventilation with escalating VT to target 15 ml/kg by 15 min or 2) continuous positive airway pressure (CPAP) of 5 cmH2O. After the 15-min intervention, lambs were given surfactant 100 mg/kg with saline, budesonide 0.25 mg/kg, or budesonide 1 mg/kg. The fetuses were returned to the uterus for 24 h and then delivered and ventilated for 30 min to assess lung function. Budesonide levels were low in lung and plasma. CPAP groups had improved oxygenation, ventilation, and decreased injury markers compared with fetal VT lambs. Budesonide improved ventilation in CPAP lambs. Budesonide decreased lung weights and lung liquid and increased lung compliance and surfactant protein mRNA. Budesonide decreased proinflammatory and acute-phase responses in lung. Airway thickness increased in animals not receiving budesonide. Systemically, budesonide decreased monocyte chemoattractant protein-1 mRNA and preserved glycogen in liver. Results with 0.25 and 1 mg/kg budesonide were similar. We concluded that budesonide with surfactant matured the preterm lung and decreased the liver responses but did not improve lung function after high VT injury in fetal sheep.

Brief mechanical ventilation causes differential epithelial repair along the airways of fetal, preterm lambs.

Mechanical ventilation of preterm lambs causes lung inflammation and injury to the airway epithelium, which is repaired by 15 days after ventilation. In mice, activated basal cells (p63+, KRT14+, KRT8+) initiate injury repair to the trachea, whereas club cells coordinate distal airway repair. In both human and sheep, basal cells line the pseudostratified airways to the distal bronchioles with club cells only present in terminal bronchioles. Mechanical ventilation causes airway epithelial injury that is repaired through basal cell activation in the fetal lung. Ewes at 123 ± 1 day gestational age had the head and chest of the fetus exteriorized and tracheostomy placed. With placental circulation intact, fetal lambs were mechanically ventilated with up to 15 ml/kg for 15 min with 95% N2/5% CO2 Fetal lambs were returned to the uterus for up to 24 h. The trachea, left mainstem bronchi, and peripheral lung were evaluated for epithelial injury and cellular response consistent with repair. Peripheral lung tissue had inflammation, pro-inflammatory cytokine production, epithelial growth factor receptor ligand upregulation, increased p63 expression, and proliferation of pro-SPB, TTF-1 positive club cells. In bronchi, KRT14 and KRT8 mRNA increased without increases in Notch pathway mRNA or proliferation. In trachea, mRNA increased for Notch ligands, SAM pointed domain-containing Ets transcription factor and mucin 5B, but not for basal cell markers. A brief period of mechanical ventilation causes differential epithelial activation between trachea, bronchi, and peripheral lung. The repair mechanisms identified in adult mice occur at different levels of airway branching in fetal sheep with basal and club cell activation.

Sustained inflation at birth did not protect preterm fetal sheep from lung injury.

Sustained lung inflations (SI) at birth may recruit functional residual capacity (FRC). Clinically, SI increase oxygenation and decrease need for intubation in preterm infants. We tested whether a SI to recruit FRC would decrease lung injury from subsequent ventilation of fetal, preterm lambs. The preterm fetus (128±1 day gestation) was exteriorized from the uterus, a tracheostomy was performed, and fetal lung fluid was removed. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: 1) positive end-expiratory pressure (PEEP) 8 cmH2O (n=4), 2) 20 s SI to 50 cmH2O then PEEP 8 cmH2O (n=10), 3) mechanical ventilation at tidal volume (VT) 7 ml/kg (n=13), or 4) 20 s SI then ventilation at VT 7 ml/kg (n=13). Lambs were ventilated with 95% N2/5% CO2 and PEEP 8 cmH2O. Volume recruitment was measured during SI, and fetal tissues were collected after an additional 30 min on placental support. SI achieved a mean FRC recruitment of 15 ml/kg (range 8-27). Fifty percent of final FRC was achieved by 2 s, 65% by 5 s, and 90% by 15 s, demonstrating prolonged SI times are needed to recruit FRC. SI alone released acute-phase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines and acute-phase response genes in the lung. Mechanical ventilation further increased all markers of lung injury. SI before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth.

Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep.

The chorioamnionitis associated with preterm delivery is often polymicrobial with ureaplasma being the most common isolate. To evaluate interactions between the different proinflammatory mediators, we hypothesized that ureaplasma exposure would increase fetal responsiveness to LPS. Fetal sheep were given intra-amniotic (IA) injections of media (control) or Ureaplasma parvum serovar 3 either 7 or 70 d before preterm delivery. Another group received an IA injection of Escherichia coli LPS 2 d prior to delivery. To test for interactions, IA U. parvum-exposed animals were challenged with IA LPS and delivered 2 d later. All animals were delivered at 124 ± 1-d gestation (term = 150 d). Compared with the 2-d LPS exposure group, the U. parvum 70 d + LPS group had 1) decreased lung pro- and anti-inflammatory cytokine expression and 2) fewer CD3(+) T lymphocytes, CCL2(+), myeloperoxidase(+), and PU.1(+) cells in the lung. Interestingly, exposure to U. parvum for 7 d did not change responses to a subsequent IA LPS challenge, and exposure to IA U. parvum alone induced mild lung inflammation. Exposure to U. parvum increased pulmonary TGF-ß1 expression but did not change mRNA expression of either the receptor TLR4 or some of the downstream mediators in the lung. Monocytes from fetal blood and lung isolated from U. parvum 70 d + LPS but not U. parvum 7 d + LPS animals had decreased in vitro responsiveness to LPS. These results are consistent with the novel finding of downregulation of LPS responses by chronic but not acute fetal exposures to U. parvum. The findings increase our understanding of how chorioamnionitis-exposed preterm infants may respond to lung injury and postnatal nosocomial infections.

Preterm lung and brain responses to mechanical ventilation and corticosteroids.

Mechanical ventilation is necessary to maintain oxygenation and ventilation in many preterm infants. Unfortunately, even short periods of mechanical ventilation can cause lung and airway injury, and initiate the lung inflammation that contributes to the development of bronchopulmonary dysplasia (BPD). The mechanical stretch leads to airway cell differentiation and simplification of the alveoli, and releases cytokines that cause systemic response in other organs. Mechanical ventilation also leads to brain injury (IVH, white and gray matter) and neuronal inflammation that can affect the neurodevelopment of preterm infants. In efforts to decrease BPD, corticosteroids have been used for both prevention and treatment of lung inflammation. Corticosteroids have also been demonstrated to cause neuronal injury, so the clinician must balance the negative effects of both mechanical ventilation and steroids on the brain and lungs. Predictive models for BPD can help assess the infants who will benefit most from corticosteroid exposure. This review describes the lung and brain injury from mechanical ventilation in the delivery room and chronic mechanical ventilation in animal models. It provides updates on the current guidelines for use of postnatal corticosteroids (dexamethasone, hydrocortisone, budesonide, budesonide with surfactant) for the prevention and treatment of BPD, and the effects the timing of each steroid regimen has on neurodevelopment.

Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep.

BACKGROUND: Preterm infants often receive mechanical ventilation and oxygen at birth. Exposure to large tidal volumes (V(T)s) at birth causes lung inflammation, and oxygen may amplify the injury. We hypothesized that normal V(T) ventilation at birth causes lung injury that is exacerbated by 95% oxygen. METHODS: The head and chest of anesthetized preterm fetal sheep (129 ± 1 d gestation) were surgically exteriorized while maintaining the placental circulation. Fetuses were randomized to four groups with either V(T) ventilation to 6 ml/kg or continuous positive airway pressure of 5 cm H2O, and either 95%O2/5%CO2 or 95%N2/5%CO2. Age-matched fetuses were used as controls. After a 15-min intervention, the fetal lamb was returned to the uterus for 1 h 45 min. RESULTS: In ventilated lambs, V(T) was 6.2 ± 0.4 ml/kg at 15 min. Ventilation increased proinflammatory cytokines as compared with controls and lambs on continuous positive airway pressure, with recruitment of primarily monocytes to bronchoalveolar lavage fluid. Early response protein 1 was activated around the bronchioles in V(T)-ventilated animals. The 15-min oxygen exposure did not change inflammatory mediators or other markers of lung and oxidative stress. CONCLUSION: A V(T) of 6-7 ml/kg at birth increased early markers of injury and lung inflammation. Brief exposure to 95% oxygen did not alter lung inflammation.