ORCID Profile
0000-0002-8906-614X
Current Organisations
Monash University
,
Hudson Institute of Medical Research
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Animal Physiology - Systems | Paediatrics and Reproductive Medicine | Respiratory Diseases | Paediatrics |
Respiratory System and Diseases (incl. Asthma) | Expanding Knowledge in the Medical and Health Sciences
Publisher: American Physiological Society
Date: 09-2011
DOI: 10.1152/JAPPLPHYSIOL.00214.2011
Abstract: Perinatal inflammation is associated with adverse neurodevelopmental outcomes, which may be partly due to changes in the cerebral oxygen delivery/consumption relationship. We aimed to determine the critical oxygen delivery threshold of the brain of preterm, ventilated lambs and to determine whether the critical threshold is affected by exposure to inflammation in utero. Pregnant ewes received intra-amniotic injection of lipopolysaccharide or saline at 125 or 127 days of gestation. Pulmonary and systemic flow probes and catheters were surgically positioned in the fetus immediately before delivery at 129 days of gestation. After delivery, lambs were ventilated for 90 min using a positive end-expiratory pressure recruitment strategy. Cardio-respiratory variables and blood gases were measured regularly. Systemic and cerebral oxygen delivery, consumption (Fick), and extraction were calculated, and the relationship between cerebral delivery and consumption analyzed. Linear regression was used to define the transition or “critical” oxygen threshold as the point at which the slope of the oxygen delivery/consumption curve changed to be °. Four subgroups were defined according to the calculated critical threshold. A total of 150 measurements were recorded in 18 lambs. Fetal cerebral oxygen consumption was increased by antenatal lipopolysaccharide ( P 0.05). The postnatal critical oxygen threshold was 3.6 ml·kg −1 ·min −1 , corresponding to cerebral oxygen consumption of 0.73 ml·kg −1 ·min −1 . High oxygen delivery and consumption were associated with increased pulmonary and carotid blood flow and systemic extraction compared with low oxygen delivery and consumption. No postnatal effect of antenatal inflammation was observed. Inflammation in utero increases fetal, but not postnatal, cerebral oxygen consumption. Adverse alterations to pulmonary blood flow can result in reduced cerebral blood flow, oxygen delivery, and consumption. Regardless of exposure to inflammation, there is a consistent postnatal relationship between cerebral oxygen delivery and consumption.
Publisher: Springer Science and Business Media LLC
Date: 07-2007
Publisher: MDPI AG
Date: 27-02-2019
Abstract: Brain injury in the asphyxic newborn infant may be exacerbated by delayed restoration of cardiac output and oxygen delivery. With increasing severity of asphyxia, cerebral autoregulatory responses are compromised. Further brain injury may occur in association with high arterial pressures and cerebral blood flows following the restoration of cardiac output. Initial resuscitation aims to rapidly restore cardiac output and oxygenation whilst mitigating the impact of impaired cerebral autoregulation. Recent animal studies have indicated that the current standard practice of immediate umbilical cord cl ing prior to resuscitation may exacerbate injury. Resuscitation prior to umbilical cord cl ing confers several haemodynamic advantages. In particular, it retains the low-resistance placental circuit that mitigates the rebound hypertension and cerebrovascular injury. Prolonged cerebral hypoxia–ischaemia is likely to contribute to further perinatal brain injury, while, at the same time, tissue hyperoxia is associated with oxidative stress. Efforts to monitor and target cerebral flow and oxygen kinetics, for ex le, using near-infrared spectroscopy, are currently being evaluated and may facilitate development of novel resuscitation approaches.
Publisher: American Physiological Society
Date: 2019
DOI: 10.1152/JAPPLPHYSIOL.00800.2018
Abstract: Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent n = 7) or intravenous 300 ( n = 5), 1,000 (EPO 1000 n = 5), or 3,000 (EPO 3000 n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO 1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar–arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO 3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.
Publisher: Wiley
Date: 30-03-2015
DOI: 10.1002/PPUL.23187
Abstract: Synchronised intermittent mandatory ventilation (SIMV) and high-frequency jet ventilation (HFJV) are accepted ventilatory strategies for treatment of respiratory distress syndrome (RDS) in preterm babies. We hypothesised that SIMV and HFJV both facilitate adequate oxygenation and ventilation but that HFJV is associated with less lung injury. There were no differences in arterial oxygenation or partial pressure of carbon dioxide despite lower mean airway pressure during SIMV for most of the study. There were no consistent significant differences in end systolic and end diastolic PBF, lung injury data and static lung compliance. Preterm lambs of anaesthetised ewes were instrumented, intubated and delivered by caesarean section after intratracheal suction and instillation of surfactant. Each lamb was managed for 3 hr according to a predetermined algorithm for ventilatory support consistent with open lung ventilation. Pulmonary blood flow (PBF) was measured continuously and pulsatility index was calculated. Ventilatory parameters were recorded and arterial blood gases were measured at intervals. At postmortem, in situ pressure-volume deflation curves were recorded, and bronchoalveolar lavage fluid and lung tissue were obtained to assess inflammation. SIMV and HFJV have comparable clinical efficacy and ventilator pressure requirements when applied with a targeted lung volume recruitment strategy.
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/412831
Abstract: Preterm birth is a major cause of perinatal mortality and long-term morbidity. Chorioamnionitis is a common cause of preterm birth. Clinical chorioamnionitis, characterised by maternal fever, leukocytosis, tachycardia, uterine tenderness, and preterm rupture of membranes, is less common than subclinical/histologic chorioamnionitis, which is asymptomatic and defined by inflammation of the chorion, amnion, and placenta. Chorioamnionitis is often associated with a fetal inflammatory response. The fetal inflammatory response syndrome (FIRS) is defined by increased systemic inflammatory cytokine concentrations, funisitis, and fetal vasculitis. Clinical and epidemiological studies have demonstrated that FIRS leads to poor cardiorespiratory, neurological, and renal outcomes. These observations are further supported by experimental studies that have improved our understanding of the mechanisms responsible for these outcomes. This paper outlines clinical and experimental studies that have improved our current understanding of the mechanisms responsible for chorioamnionitis-induced preterm birth and explores the cellular and physiological mechanisms underlying poor cardiorespiratory, neural, retinal, and renal outcomes observed in preterm infants exposed to chorioamnionitis.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/RD12229
Abstract: It is common practice in Australian agriculture to remove the tails of lambs to prevent infection and to castrate males to prevent behavioural problems and unwanted reproduction. We have studied the pain and stress responses to these interventions by measuring changes in the hypothalamic–pituitary–adrenal (HPA) axis and β-endorphin levels. Further, we have evaluated the effects of prenatal exposure to dexamethasone, which is known to affect the developing HPA axis. In control animals that had received prenatal saline treatment, plasma cortisol and adrenocorticotrophin (ACTH) levels increased after the interventions in both females and males. Plasma β-endorphin levels also increased after the interventions, but the responses were less consistent. Prenatal dexamethasone exposure early in pregnancy (dexamethasone 0.14 mg kg–1 ewe weight injection commenced on day 40 of pregnancy for four consecutive intramuscular injections at 12-hourly intervals) blunted the cortisol response to tail docking in female offspring, but not to combined tail docking and castration in males. It had no effect on ACTH or β-endorphin responses in either sex. These findings describe the stress responses to these common agricultural interventions and suggest that long-term development of the HPA axis in females is altered by prenatal exposure to dexamethasone.
Publisher: Public Library of Science (PLoS)
Date: 22-06-2012
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.SINY.2018.07.002
Abstract: Animal models have made and continue to make important contributions to neonatal medicine. For ex le, studies in fetal sheep have taught us much about the physiology of the fetal-to-neonatal transition. However, whereas animal models allow multiple factors to be investigated in a logical and systematic manner, no animal model is perfect for humans and so we need to understand the fundamental differences in physiology between the species in question and humans. Although most physiological systems are well conserved between species, some small differences exist and so wherever possible the knowledge generated from preclinical studies in animals should be tested in clinical trials. However, with the rise of evidence-based medicine the distinction between scientific knowledge generation and evidence gathering has been confused and the two have been lumped together. This misunderstands the contribution that scientific knowledge can provide. Science should be used to guide the gathering of evidence by informing the design of clinical trials, thereby increasing their likelihood of success. While scientific knowledge is not evidence, in the absence of evidence it is likely to be the best option for guiding clinical practice.
Publisher: American Physiological Society
Date: 04-2009
DOI: 10.1152/JAPPLPHYSIOL.91445.2008
Abstract: Increases in positive end-expiratory pressure (PEEP) improve arterial oxygenation in preterm infants, but the effects on cardiopulmonary hemodynamics are understood poorly. We aimed to determine the effect of increased PEEP on cardiopulmonary hemodynamics and to compare measurements from indwelling flow probes with Doppler echocardiography. Preterm lambs (129 ± 1 days) were ventilated initially with a tidal volume of 7 ml/kg and 4 cmH 2 O of PEEP. In r lambs ( n = 7), PEEP was increased by 2-cmH 2 O increments to 10 cmH 2 O and then in decrements back to 4 cmH 2 O. PEEP was unchanged in controls ( n = 6). Doppler echocardiographic flow measurements in the left pulmonary artery (LPA) and ductus arteriosus (DA) were correlated with flow probe measurements. Compared with controls, high PEEP reduced LPA flow from baseline (10-cmH 2 O PEEP: 43 ± 8% vs. control: 83 ± 21% P = 0.029). High PEEP increased the proportion of right-to-left (R-L) shunting through the DA, with a trend to an increased oxygenation index compared with controls (oxygenation index: 44.5 ± 13.5 at 10-cmH 2 O PEEP vs. 19.4 ± 4.5 in controls P = 0.07). Increasing PEEP decreased heart rate (17 beats/min P = 0.03) and tended to lower systolic arterial pressure (5.0 mmHg P = 0.052) compared with controls. Doppler echocardiography measurement of LPA flows correlated strongly with indwelling flow probe ( r 2 = 0.73, P 0.001), except during highly turbulent flows. Increases in PEEP have significant cardiopulmonary consequences in preterm lambs, including reduced LPA flow and increased R-L shunt through the DA. These changes are likely due to the concomitant increase in downstream pulmonary vascular resistance and increased cardiovascular constraint induced by PEEP.
Publisher: S. Karger AG
Date: 2017
DOI: 10.1159/000456542
Abstract: Fetal growth restriction (FGR) is a common complication of pregnancy, principally caused by suboptimal placental function, and is associated with high rates of perinatal mortality and morbidity. Clinical studies suggest that the time of onset of placental insufficiency is an important contributor towards the neurodevelopmental impairments that are evident in children who had FGR. It is however currently unknown how early-onset and late-onset FGR differentially affect brain development. The aim of this study was to examine neuropathology in early-onset and late-onset FGR fetal sheep and to determine whether they differentially alter brain development. We induced placental insufficiency and FGR via single umbilical artery ligation at either 88 days (early-onset) or 105 days (late-onset) of fetal sheep gestation (term is approx. 147 days), reflecting a period of rapid white matter brain development. Fetal blood s les were collected for the first 10 days after surgery, and all fetuses were sacrificed at 125 days' gestation for brain collection and subsequent histopathology. Our results show that early-onset FGR fetuses became progressively hypoxic over the first 10 days after onset of placental insufficiency, whereas late-onset FGR fetuses were significantly hypoxic compared to controls from day 1 after onset of placental insufficiency (Sa smlcap O /smlcap sub /sub 46.7 ± 7.4 vs. 65.7 ± 3.9%, respectively, i /i = 0.03). Compared to control brains, early-onset FGR brains showed widespread white matter injury, with a reduction in both CNPase-positive and MBP-positive density of staining in the periventricular white matter (PVWM), subcortical white matter, intragyral white matter (IGWM), subventricular zone (SVZ), and external capsule ( i /i 0.05 for all). Total oligodendrocyte lineage cell counts (Olig-2-positive) did not differ across groups, but mature oligodendrocytes (MBP-positive) were reduced, and neuroinflammation was evident in early-onset FGR brains with reactive astrogliosis (GFAP-positive) in the IGWM and cortex ( i /i 0.05), together with an increased number of Iba-1-positive activated microglia in the PVWM, SVZ, and cortex ( i /i 0.05). Late-onset FGR was associated with a widespread reduction of CNPase-positive myelin expression ( i /i 0.05) and a reduced number of mature oligodendrocytes in all white matter regions examined ( i /i 0.05). NeuN-positive neuronal cell counts in the cortex were not different across groups however, the morphology of neuronal cells was different in response to placental insufficiency, most notable in the early-onset FGR fetuses, but it was late-onset FGR that induced caspase-3-positive apoptosis within the cortex. This study demonstrates that early-onset FGR is associated with more widespread white matter injury and neuroinflammation however, both early- and late-onset FGR are associated with complex patterns of white and grey matter injury. These results indicate that it is the timing of the onset of fetal compromise relative to brain development that principally mediates altered brain development associated with FGR.
Publisher: Cold Spring Harbor Laboratory
Date: 05-10-2019
DOI: 10.1101/19007708
Abstract: Timing of cord cl ing and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups such as those who usually receive immediate neonatal care. Previous and current trials compare various policies, including immediate cord cl ing, time- or physiology-based deferred cord cl ing, and cord milking. In idual participant data (IPD) enables exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. 1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis and 2) to evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. We will conduct a systematic search of Medline, Embase, clinical trial registries, and other sources for all planned, ongoing and completed randomised controlled trials comparing alternative cord management strategies at preterm birth (before 37 weeks’ gestation). IPD will be sought for all trials. First, deferred cl ing and cord milking will be compared with immediate cl ing in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for pre-specified subgroups of participants. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes intraventricular haemorrhage (any grade) and infant blood transfusions (any). Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Approved by University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline-developers and policy-makers, and will be disseminated via publications, presentations, and media releases. Australian New Zealand Clinical Trials Registry: ACTRN12619001305112. This will be the most comprehensive review to date of interventions for umbilical cord management in preterm infants and the findings will be highly relevant to clinicians and guideline developers The use of in idual participant data will allow assessment of the best treatment option for key subgroups of participants Network meta-analysis will enable the comparison and ranking of all available treatment options using direct and indirect evidence For some of the trials it will not be possible to obtain in idual participant data, so published aggregate results will be used instead Risk of bias in the primary trials will be assessed using Cochrane criteria, and certainty of evidence for the meta-analyses will be appraised using the GRADE approach for the pairwise comparisons, and the CINeMA approach for the network meta-analysis
Publisher: Springer Science and Business Media LLC
Date: 23-11-2022
DOI: 10.1007/S00431-022-04684-5
Abstract: To identify characteristics associated with delivery room clinical instability in at-risk infants. Prospective cohort study. Two perinatal centres in Melbourne, Australia. Infants born at ≥ 35 +0 weeks’ gestation with a first-line paediatric doctor requested to attend. Clinical instability defined as any one of heart rate 100 beats per minute for ≥ 20 s in the first 10 min after birth, maximum fraction of inspired oxygen of ≥ 0.70 in the first 10 min after birth, 5-min Apgar score of 7, intubated in the delivery room or admitted to the neonatal unit for respiratory support. Four hundred and seventy-three infants were included. The median (IQR) gestational age at birth was 39 +4 (38 +4 —40 +4 ) weeks. Eighty (17%) infants met the criteria for clinical instability. Independent risk factors for clinical instability were labour without oxytocin administration, presence of a medical pregnancy complication, difficult extraction at birth and unplanned caesarean section in labour. Decision tree analysis determined that infants at highest risk were those whose mothers did not receive oxytocin during labour (25% risk). Infants at lowest risk were those whose mothers received oxytocin during labour and did not have a medical pregnancy complication (7% risk). Conclusions : We identified characteristics associated with clinical instability that may be useful in alerting less experienced clinicians to call for senior assistance early. The decision trees provide intuitive visual aids but require prospective validation. What is Known: • First-line clinicians attending at-risk births may need to call senior colleagues for assistance depending on the infant’s condition. • Delays in effectively supporting a compromised infant at birth is an important cause of neonatal morbidity and infant-mother separation. What is New: • This study identifies risk factors for delivery room clinical instability in at-risk infants born at ≥ 35 + 0 weeks’ gestation. • The decision trees presented provide intuitive visual tools to aid in determining the need for senior paediatric presence.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JPEDS.2017.05.076
Abstract: To assess cardiac morphology and function in preterm infants with fetal growth restriction (FGR) compared with an appropriate for gestational age cohort, and to ascertain clinical correlation with neonatal sequelae. With informed consent, 20 infants born between 28 and 32 weeks of gestational age and birthweight (BW) <10th percentile were compared using conventional and tissue Doppler echocardiography with 20 preterm appropriate for gestational age infants. Total duration of respiratory support was recorded. The gestational age and BW of the infants with FGR and appropriate for gestational age infants were 29.8 ± 1.3 weeks vs 30 ± 0.9 weeks (P = .78) and 923.4 ± 168 g vs 1403 ± 237 g (P < .001), respectively. Preterm infants with FGR had significantly greater interventricular septal hypertrophy, greater free wall thickening, and lower sphericity indices (1.53 ± 0.15 vs 1.88 ± 0.2 P < .001), signifying globular and hypertrophied hearts. The transmitral E/A ratio and isovolumic relaxation time, markers of diastolic function, were significantly increased in the FGR cohort (0.84 ± 0.05 vs 0.78 ± 0.03 [P < .001] and 61.4 ± 4.1 ms vs 53.2 ± 3.2 ms [P < .001], respectively). Ejection fraction, as measured by the rate corrected mean velocity of circumferential fiber shortening was reduced (1.93 ± 0.4 circ/second vs 2.77 ± 0.5 circ/second P < .001) in the FGR cohort. On follow-up, the total duration of respiratory support was significantly longer in the FGR cohort, and correlated with tissue Doppler E/E' (r = 0.65 P = .001), mean velocity of circumferential fiber shortening (r = -0.64 P = .001) and mitral annular peak systolic excursion (r = -0.57 P = .008). Preterm infants with FGR have altered cardiac function evident within days after birth, which is associated with respiratory sequelae.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.RESUSCITATION.2019.12.007
Abstract: To test whether stabilising very preterm infants while performing physiological-based cord cl ing (PBCC) is at least as effective as the standard approach of time-based delayed cord cl ing (DCC). A randomised controlled non-inferiority study was performed in two centres from May until November 2018, including preterm infants born below 32 weeks of gestational age. Infants were allocated to PBCC or standard DCC. Infants receiving PBCC were stabilised on a purpose-built resuscitation table with an intact umbilical cord. The cord was cl ed when the infant had regular spontaneous breathing, heart rate ≥100 bpm and SpO Thirty-seven infants (mean gestational age 29 + 0 weeks) were included. Mean cord cl ing time was 5:49 ± 2:37 min in the PBCC (n = 20) and 1:02 ± 0:30 min in the DCC group (n = 17). Infants receiving PBCC needed less time to reach respiratory stability (PBCC 5:54 ± 2:27 min DCC 7:07 ± 2:54 min mean difference corrected for gestational age -1:19 min, 95% CI [-3:04-0:27]), showing non-inferiority with the pre-defined limit of 1:15 min. No significant differences between the groups were found for maternal blood loss, postpartum haemorrhage, infant temperature at admission or short-term neonatal outcomes. Stabilisation of very preterm infants with physiological-based cord cl ing is at least as effective as with standard DCC. Netherlands Trial Register (NTR7194/NL7004).
Publisher: Springer Science and Business Media LLC
Date: 31-08-2021
DOI: 10.1186/S12974-021-02238-4
Abstract: Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion ( n = 9). Sheep were euthanized 4 days after starting infusions for histology. LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate ( P 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.
Publisher: Springer Science and Business Media LLC
Date: 09-2009
Publisher: American Physiological Society
Date: 10-2005
DOI: 10.1152/JAPPLPHYSIOL.00055.2005
Abstract: In mature lungs, elevated positive end-expiratory pressure (PEEP) reduces pulmonary blood flow (PBF) and increases pulmonary vascular resistance (PVR). However, the effect of PEEP on PBF in preterm infants with immature lungs and a patent ductus arteriosus is unknown. Fetal sheep were catheterized at 124 days of gestation (term ∼147 days), and a flow probe was placed around the left pulmonary artery to measure PBF. At 127 days, lambs were delivered and ventilated from birth with a tidal volume of 5 ml/kg and 4-cmH 2 O PEEP PEEP was changed to 0, 8, and 12 cmH 2 O in random order, returning to 4 cmH 2 O between each change. Increasing PEEP from 4 to 8 cmH 2 O and from 4 to 12 cmH 2 O decreased PBF by 20.5 and 41.0%, respectively, and caused corresponding changes in PVR reducing PEEP from 4 to 0 cmH 2 O did not affect PBF. Despite decreasing PBF, increasing PEEP from 4 to 8 cmH 2 O and 12 cmH 2 O improved oxygenation of lambs. Increasing and decreasing PEEP from 4 cmH 2 O significantly changed the contour of the PBF waveform at a PEEP of 12 cmH 2 O, end-diastolic flow was reduced by 82.8% and retrograde flow was reestablished. Although increasing PEEP improves oxygenation, it adversely affects PBF and PVR shortly after birth, alters the PBF waveform, and reestablishes retrograde flow during diastole.
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00171.2018
Abstract: Fetal growth restriction (FGR) and prematurity are associated with high risk of brain injury and long-term neurological deficits. FGR infants born preterm are commonly exposed to mechanical ventilation, but it is not known whether ventilation differentially induces brain pathology in FGR infants compared with appropriate for gestational age (AGA) infants. We investigated markers of neuropathology in moderate- to late-preterm FGR lambs, compared with AGA lambs, delivered by caesarean birth and ventilated under standard neonatal conditions for 24 h. FGR was induced by single umbilical artery ligation in fetal sheep at 88-day gestation (term, 150 days). At 125-day gestation, FGR and AGA lambs were delivered, dried, intubated, and commenced on noninjurious ventilation, with surfactant administration at 10 min. A group of unventilated FGR and AGA lambs at the same gestation was also examined. Over 24 h, circulating pH, Po 2 , and lactate levels were similar between groups. Ventilated FGR lambs had lower cerebral blood flow compared with AGA lambs ( P = 0.01). The brain of ventilated FGR lambs showed neuropathology compared with unventilated FGR, and unventilated and ventilated AGA lambs, with increased apoptosis (caspase-3), blood-brain barrier dysfunction (albumin extravasation), activated microglia (Iba-1), and increased expression of cellular oxidative stress (4-hydroxynonenal). The neuropathologies seen in the ventilated FGR brain were most pronounced in the periventricular and subcortical white matter but also evident in the subventricular zone, cortical gray matter, and hippoc us. Ventilation of preterm FGR lambs increased brain injury compared with AGA preterm lambs and unventilated FGR lambs, mediated via increased vascular permeability, neuroinflammation and oxidative stress.
Publisher: Wiley
Date: 04-05-2015
DOI: 10.1111/JPC.12910
Abstract: Intra-uterine growth restriction (IUGR) is an important cause for prematurity as well as a significant risk factor for neurodevelopmental deficits. In this study, we aimed to examine the association between IUGR and early brain injury on neonatal cranial ultrasound in preterm infants. This retrospective cohort study examined the relationship between IUGR and neonatal cranial ultrasound findings in preterm infants <32 weeks gestation with IUGR, compared with gestation and year of birth-matched appropriately grown infants, in a tertiary level neonatal unit. Primary outcome was incidence and severity of intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL) and hydrocephalus detected by cranial ultrasound in the neonatal period. A total of 153 IUGR and 306 non-IUGR preterm infants <32 weeks were included. The rates of IVH (21.6% vs. 23.9%), severe IVH (3.9% vs. 4.6%), PVL (8.4% vs. 9.4%), cystic PVL (2.6% vs. 0%) and hydrocephalus (0.7% vs. 0.3%) were similar in the two groups. Composite outcome of death and severe brain injury (severe IVH, cystic PVL and hydrocephalus) was greater (20.2% vs. 9.1%, P = 0.001) in IUGR infants. IUGR did not lead to increased neonatal brain injury on cranial ultrasound but was associated with increased mortality. Advanced neonatal neuroimaging techniques may be necessary to estimate risk and to provide prognostic information of adverse neurological outcomes in this vulnerable population.
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Publisher: Wiley
Date: 10-09-2016
DOI: 10.1113/JP270926
Publisher: Cold Spring Harbor Laboratory
Date: 20-09-2023
Publisher: Frontiers Media SA
Date: 23-10-2020
Publisher: American Thoracic Society
Date: 15-05-2009
Publisher: S. Karger AG
Date: 2008
DOI: 10.1159/000143721
Abstract: We review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is lified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.
Publisher: Frontiers Media SA
Date: 29-01-2018
Publisher: Public Library of Science (PLoS)
Date: 23-04-2014
Publisher: American Physiological Society
Date: 11-2023
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000334828
Abstract: i Background: /i Conventional mechanical ventilator (CMV) breaths during high-frequency jet ventilation (HFJV) are advocated to recruit and stabilize alveoli. i Objectives: /i To establish if CMV breath duration delivered during HFJV influences gas exchange, lung mechanics and lung injury. i Methods: /i Preterm lambs at 128 days gestational age were studied. HFJV (7 Hz, PEEP 8 cm H sub /sub O, PIP sub HFJV /sub 40 cm H sub /sub O, FiO sub /sub 0.4) with superimposed CMV breaths (PIP sub CMV /sub 25 cm H sub /sub O, rate 5 breaths/min) was commenced after delivery and continued for 2 h. CMV breath inspiratory time ( i t /i sub I /sub ) was either 0.5 s (HFJV+CMV sub .5 /sub n = 8) or 2.0 s (HFJV+CMV sub .0 /sub n = 8). Age-matched unventilated controls (UVC) were included for comparison. i Results: /i Serial arterial blood gas analyses were performed. PIP sub HFJV /sub was adjusted to target a i P /i aCO sub /sub of 45–55 mm Hg. FiO sub /sub was adjusted to target SpO sub /sub 90–95%. Pressure-volume curves, broncho-alveolar lavage (BAL) and lung tissue s les were obtained postmortem. Gas exchange, ventilation parameters, static lung compliance and BAL inflammatory markers were not different between HFJV+CMV sub .5 /sub and HFJV+CMV sub .0 /sub . Both ventilation groups had higher BAL inflammatory markers and increased iNOS-positive cells on histology compared to UVC, whilst lung tissue IL-1β and IL-6 mRNA expression was higher in the HFJV+CMV sub .0 /sub group compared to the UVC group. i Conclusions: /i Preterm lambs were ventilated effectively with HFJV and 5 CMV breaths/min. CMV breath duration did not alter blood gas exchange, ventilation parameters, ex vivo static lung mechanics or markers of lung injury over a 2-hour study, although consistent trends towards increased inflammatory markers with the longer i t /i sub I /sub suggest greater risk of injury.
Publisher: Springer Science and Business Media LLC
Date: 11-2011
Publisher: Elsevier BV
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
DOI: 10.1038/S41598-020-73453-X
Abstract: Hypoxic-ischaemia renders the neonatal brain susceptible to early secondary injury from oxidative stress and impaired autoregulation. We aimed to describe cerebral oxygen kinetics and haemodynamics immediately following return of spontaneous circulation (ROSC) and evaluate non-invasive parameters to facilitate bedside monitoring. Near-term sheep fetuses [139 ± 2 (SD) days gestation, n = 16] were instrumented to measure carotid artery (CA) flow, pressure, right brachial arterial and jugular venous saturation (SaO 2 and SvO 2 , respectively). Cerebral oxygenation (crSO 2 ) was measured using near-infrared spectroscopy (NIRS). Following induction of severe asphyxia, lambs received cardiopulmonary resuscitation using 100% oxygen until ROSC, with oxygen subsequently weaned according to saturation nomograms as per current guidelines. We found that oxygen consumption did not rise following ROSC, but oxygen delivery was markedly elevated until 15 min after ROSC. CrSO 2 and heart rate each correlated with oxygen delivery. SaO 2 remained 90% and was less useful for identifying trends in oxygen delivery. CrSO 2 correlated inversely with cerebral fractional oxygen extraction. In conclusion, ROSC from perinatal asphyxia is characterised by excess oxygen delivery that is driven by rapid increases in cerebrovascular pressure, flow, and oxygen saturation, and may be monitored non-invasively. Further work to describe and limit injury mediated by oxygen toxicity following ROSC is warranted.
Publisher: Wiley
Date: 27-03-2014
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000371415
Abstract: b i Background: /i /b Preterm infants can be inadvertently exposed to high tidal volumes (V sub T /sub ) during resuscitation in the delivery room due to limitations of available equipment. High V sub T /sub ventilation of preterm lambs produces cerebral white matter (WM) pathology similar to that observed in preterm infants who develop cerebral palsy. We hypothesized that human amnion epithelial cells (hAECs), which have anti-inflammatory and regenerative properties, would reduce ventilation-induced WM pathology in neonatal late preterm lamb brains. b i Methods: /i /b Two groups of lambs (0.85 gestation) were used, as follows: (1) ventilated lambs (Vent n = 8) were ventilated using a protocol that induces injury (V sub T /sub targeting 15 ml/kg for 15 min, with no positive end-expiratory pressure) and were then maintained for another 105 min, and (2) ventilated + hAECs lambs (Vent+hAECs n = 7) were similarly ventilated but received intravenous and intratracheal administration of 9 × 10 sup /sup hAECs (18 × 10 sup /sup hAECs total) at birth. Oxygenation and ventilation parameters were monitored in real time cerebral oxygenation was measured using near-infrared spectroscopy. qPCR (quantitative real-time PCR) and immunohistochemistry were used to assess inflammation, vascular leakage and astrogliosis in both the periventricular and subcortical WM of the frontal and parietal lobes. An unventilated control group (UVC n = 5) was also used for qPCR analysis of gene expression. Two-way repeated measures ANOVA was used to compare physiological data. Student's t test and one-way ANOVA were used for immunohistological and qPCR data comparisons, respectively. b i Results: /i /b Respiratory parameters were not different between groups. Interleukin (IL)-6 mRNA levels in subcortical WM were lower in the Vent+hAECs group than the Vent group (p = 0.028). IL-1β and IL-6 mRNA levels in periventricular WM were higher in the Vent+hAECs group than the Vent group (p = 0.007 and p = 0.001, respectively). The density of Iba-1-positive microglia was lower in the subcortical WM of the parietal lobes (p = 0.010) in the Vent+hAECs group but not in the periventricular WM. The number of vessels in the WM of the parietal lobe exhibiting protein extravasation was lower (p = 0.046) in the Vent+hAECs group. Claudin-1 mRNA levels were higher in the periventricular WM (p = 0.005). The density of GFAP-positive astrocytes was not different between groups. b i Conclusions: /i /b Administration of hAECs at the time of birth alters the effects of injurious ventilation on the preterm neonatal brain. Further studies are required to understand the regional differences in the effects of hAECs on ventilation-induced WM pathology and their net effect on the developing brain.
Publisher: Frontiers Media SA
Date: 03-03-2022
DOI: 10.3389/FPHYS.2022.841229
Abstract: Preterm newborns commonly experience apnoeas after birth and require respiratory stimulants and support. Antenatal inflammation is a common antecedent of preterm birth and inflammatory mediators, particularly prostaglandin E2 (PGE 2 ), are associated with inhibition of vital brainstem respiratory centers. In this study, we tested the hypothesis that exposure to antenatal inflammation inhibits fetal breathing movements (FBMs) and increases inflammation and PGE 2 levels in brainstem respiratory centers, cerebrospinal fluid (CSF) and blood plasma. Chronically instrumented late preterm fetal sheep at 0.85 of gestation were randomly assigned to receive repeated intravenous saline ( n = 8) or lipopolysaccharide (LPS) infusions (experimental day 1 = 300 ng, day 2 = 600 ng, day 3 = 1200 ng, n = 8). Fetal breathing movements were recorded throughout the experimental period. Sheep were euthanized 4 days after starting infusions for assessment of brainstem respiratory center histology. LPS infusions increased circulating and cerebrospinal fluid PGE 2 levels, decreased arterial oxygen saturation, increased the partial pressure of carbon dioxide and lactate concentration, and decreased pH ( p & 0.05 for all) compared to controls. LPS infusions caused transient reductions in the % of time fetuses spent breathing and the proportion of vigorous fetal breathing movements ( P & 0.05 vs. control). LPS-exposure increased PGE 2 expression in the RTN FRG ( P & 0.05 vs. control) but not the pBÖTC ( P & 0.07 vs. control) of the brainstem. No significant changes in gene expression were observed for PGE 2 enzymes or caspase 3. LPS-exposure reduced the numbers of GFAP-immunoreactive astrocytes in the RTN FRG, NTS and XII of the brainstem ( P & 0.05 vs. control for all) and increased microglial activation in the RTN FRG, preBÖTC, NTS, and XII brainstem respiratory centers ( P & 0.05 vs. control for all). Chronic LPS-exposure in late preterm fetal sheep increased PGE 2 levels within the brainstem, CSF and plasma, and was associated with inhibition of FBMs, astrocyte loss and microglial activation within the brainstem respiratory centers. Further studies are needed to determine whether the inflammation-induced increase in PGE 2 levels plays a key role in depressing respiratory drive in the perinatal period.
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000496466
Abstract: Antenatal administration of betamethasone (BM) is a common antecedent of preterm birth, but there is limited information about its impact on the acute evolution of preterm neonatal brain injury. We aimed to compare the effects of maternal BM in combination with mechanical ventilation on the white matter (WM) of late preterm sheep. At 0.85 of gestation, pregnant ewes were randomly assigned to receive intra-muscular (i.m.) saline ( i n /i = 9) or i.m. BM ( i n /i = 13). Lambs were delivered and unventilated controls (UVC sub Sal /sub , i n /i = 4 UVC sub BM, /sub i n /i = 6) were humanely killed without intervention ventilated lambs (Vent sub Sal /sub , i n /i = 5 Vent sub BM /sub , i n /i = 7) were injuriously ventilated for 15 min, followed by conventional ventilation for 75 min. Cardiovascular and cerebral haemodynamics and oxygenation were measured continuously. The cerebral WM underwent assessment of inflammation and injury, and oxidative stress was measured in the cerebrospinal fluid (CSF). In the periventricular and subcortical WM tracts, the proportion of amoeboid (activated) microglia, the density of astrocytes, and the number of blood vessels with protein extravasation were higher in UVC sub BM /sub than in UVC sub Sal /sub ( i /i & #x3c 0.05 for all). During ventilation, tidal volume, mean arterial pressure, carotid blood flow, and oxygen delivery were higher in Vent sub BM /sub lambs ( i /i & #x3c 0.05 vs. Vent sub Sal /sub ). In the subcortical WM, microglial infiltration was increased in the Vent sub Sal /sub group compared to UVC sub Sal /sub . The proportion of activated microglia and protein extravasation was higher in the Vent sub BM /sub group compared to Vent sub Sal /sub within the sub /sub periventricular and subcortical WM tracts ( i /i & #x3c 0.05). CSF oxidative stress was increased in the Vent sub BM /sub group compared to UVC sub Sal, /sub UVC sub BM /sub , and Vent sub Sal /sub groups ( i /i & #x3c 0.05). Antenatal BM was associated with inflammation and vascular permeability in the WM of late preterm fetal sheep. During the immediate neonatal period, the increased carotid perfusion and oxygen delivery in BM-treated lambs was associated with increased oxidative stress, microglial activation and microvascular injury.
Publisher: Portland Press Ltd.
Date: 09-07-2014
DOI: 10.1042/CS20140097
Abstract: Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which might be explained by altered cardiomyocyte proliferation and maturation. Pregnant ewes received an ultrasound-guided intra-amniotic injection of lipopolysaccharide (LPS) or saline 7 days prior to delivery at day 127 of pregnancy (term 147 days). Cardiac contractility was recorded in spontaneously beating hearts of the offspring, perfused in a Langendorff apparatus. Saline-filled latex balloons were inserted into the left ventricle (LV) and right ventricle (RV). Responsiveness to isoprenaline and stop-flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed, and cardiomyocyte nuclearity, volume and number were determined. β-Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS-exposed fetuses, contractility in the LV and RV was suppressed by ~40% and cardiomyocyte numbers were reduced by ~25%. Immature mono-nucleated cardiomyocytes had lower volumes (~18%), whereas mature bi-nucleated cardiomyocyte volume was ~77% greater. Although basal coronary flow was significantly increased by 21±7% in LPS-exposed hearts, following ischaemia/reperfusion (IR), end-diastolic pressure was increased 2.4±0.3-fold and infarct area was increased 3.2±0.6-fold compared with those in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in β-adrenoceptor mRNA, suggesting altered second messenger signalling. Intrauterine inflammation altered cardiac growth, suppressed contractile function and enhanced responsiveness to stress. Although these effects may ensure immediate survival, they probably contribute to the increased vulnerability of organ perfusion in preterm neonates.
Publisher: BMJ
Date: 28-06-2017
DOI: 10.1136/ARCHDISCHILD-2017-312818
Abstract: Lung ultrasound (LUS) has shown promise as a diagnostic tool for the evaluation of the newborn with respiratory distress. No study has described LUS during ‘normal’ transition. Our goal was to characterise the appearance of serial LUS in healthy newborns from the first minutes after birth until airway liquid clearance is achieved. Prospective observational study. Single-centre tertiary perinatal centre in Australia. Of 115 infants born at ≥35 weeks gestational age, mean (SD) gestational age of 38 6/7 weeks±11 days, mean birth weight of 3380±555 g, 51 were delivered vaginally, 14 via caesarean section (CS) after labour and 50 infants via elective CS. We obtained serial LUS videos via the right and left axillae at 1–10 min, 11–20 min and 1, 2, 4 and 24 hours after birth. LUS videos were graded for aeration and liquid clearance according to a previously validated system. We analysed 1168 LUS video recordings. As assessed by LUS, lung aeration and airway liquid clearance occurred quickly. All infants had an established pleural line at the first examination (median=2 (1–4) min). Only 14% of infants had substantial liquid retention at 10 min after birth. 49%, 78% and 100% of infants had completed airway liquid clearance at 2, 4 and 24 hours, respectively. In healthy transitioning newborn infants, lung aeration and partial liquid clearance are achieved on the first minutes after birth with complete liquid clearance typically achieved within the first 4 hours of birth. ANZCT 12615000380594.
Publisher: Springer Science and Business Media LLC
Date: 09-2010
Publisher: Wiley
Date: 21-03-2013
DOI: 10.1111/JPC.12133
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/RD11121
Abstract: Males born preterm are at greater risk of illness and death than females, principally due to respiratory disease. Much of the excess morbidity occurs within the first few hours of life. Therefore, the aim of the present study was to investigate whether or not differences in the cardiopulmonary transition soon after birth underlie the increased morbidity in males after preterm birth. Nine female and thirteen male lambs (128 ± 2 days gestation) underwent surgery immediately before delivery for implantation of a pulmonary arterial flow-probe and catheters into the main pulmonary artery and a carotid artery. After birth lambs were ventilated for 30 min (tidal volume 7 mL kg–1) while anaesthetised. Arterial pressures and flows were recorded in real time and left-ventricular output measured using Doppler echocardiography. Before birth, fetal cardiopulmonary haemodynamics, arterial blood gases, pH, glucose and lactate did not differ between sexes. Similarly, in the neonatal period there were no significant differences in arterial blood gas status, ventilation parameters, respiratory indices or cardiopulmonary haemodynamics between the sexes. Our data show that the cardiopulmonary transition at birth in ventilated, anaesthetised preterm lambs is not influenced by sex. Thus, the neonatal ‘male disadvantage’ is not explained by an impaired cardiovascular transition at birth.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.SEMPERI.2022.151621
Abstract: Literature supporting various umbilical management strategies have increased substantially over the past decade. Delayed cord cl ing and umbilical cord milking are increasing embraced by obstetricians and neonatologists, and multiple international governing bodies now endorse these practices. This review summarizes the benefits and limitations of the different umbilical cord management strategies for term, near-term, and preterm neonates. Additional studies are underway to elucidate the safety profile of these practices, long term outcomes, and variations within these strategies that could potentially augment the benefits.
Publisher: Frontiers Media SA
Date: 09-10-2019
Publisher: Springer Science and Business Media LLC
Date: 17-07-2012
DOI: 10.1038/PR.2012.97
Abstract: As compared with constant respiratory rate (RR) and tidal volume (V(T)) during controlled conventional mechanical ventilation (CV), variable ventilation (VV) using the same breath-to-breath minute volume but variable V(T) and RRs enhances ventilation efficiency in preterm lambs. We hypothesized that if V(T) was adjusted to target permissive hypercarbia, VV would result in more efficient gas exchange without increasing inflammatory and injurious responses in the lung. Preterm lambs at 129 d gestation were anesthetized, tracheotomized, and randomized to either CV (n = 8) or VV (n = 8) using the same initial average V(T) and RR. Lung mechanics and gas exchange were measured intermittently, and average V(T) was adjusted to target partial pressure of arterial carbon dioxide (PaCO2) of 40-50 mm Hg for 3 h. Lung injury and inflammation were assessed from bronchoalveolar lavage fluid, lung tissue, and peripheral blood. VV achieved permissive hypercarbia using a lower average V(T), peak inspiratory pressure, and elastance (increased compliance) as compared with CV. Oxygenation and markers of lung tissue inflammation or injury were not different apart from a lower wet:dry tissue ratio in the VV lungs. VV improves ventilation efficiency and in vivo lung compliance in the ovine preterm lung without increasing lung inflammation or lung injury.
Publisher: Public Library of Science (PLoS)
Date: 30-04-2014
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 04-2011
Publisher: Springer Science and Business Media LLC
Date: 18-06-2015
DOI: 10.1038/PR.2015.117
Abstract: Chest compressions (CC) and adrenaline administration are recommended in asphyxiated newborns with persistent bradycardia despite effective ventilation. The effects of CC on cerebral blood flow in newborns at birth are unknown. Our aim was to determine the effects of CC, with or without adrenaline administration, on the return of spontaneous circulation, carotid blood flow (CBF), and carotid arterial pressure (CAP) in asphyxiated near-term lambs. Asphyxia was induced in near-term lambs by cl ing the umbilical cord and delaying ventilation onset until spontaneous circulation ceased. Lambs were then resuscitated by positive pressure ventilation along with CC followed by adrenaline administration. CAP and CBF were continuously recorded. Mean CAP did not increase significantly during CC and only increased following adrenaline administration. CC did not increase mean CBF but increased CBF litude due to increased peak flow and the onset of retrograde flow during diastole. Adrenaline increased mean CBF from 1 ± 2 to 15 ± 5 ml/kg/min and abolished retrograde diastolic CBF, leading to the return in spontaneous circulation. We conclude that CC with adrenaline administration was required to increase CBF and restore spontaneous circulation in asphyxiated lambs. Low CBF and retrograde diastolic CBF during CC indicate hypoperfusion to the brain.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2013
DOI: 10.1038/PR.2013.226
Abstract: Antenatal inflammation and maternal corticosteroids induce fetal lung maturation but interfere with late lung development. Canonical Wingless-Int (Wnt) signaling directs lung development and repair. We showed that intra-amniotic (IA) lipopolysaccharide (LPS) exposure disrupted developmental signaling pathways in the preterm lamb lungs. Therefore, we hypothesized that pulmonary Wnt signaling was altered by exposure to IA LPS and/or antenatal corticosteroids. Ovine fetuses were exposed to IA LPS, maternal intramuscular betamethasone, a control saline injection, or a combination thereof at 107 and/or 114 d gestational age (term = 150 d gestational age) before delivery at 121 d gestational age. IA LPS exposure decreased the lung expression of lymphoid enhancer-binding factor 1 (LEF1), a major Wnt pathway effector. WNT1, WNT4, and downstream messenger β-catenin decreased after LPS exposure. WNT7b mRNA increased fourfold 14 d post-LPS exposure. Betamethasone treatment 7 d before LPS exposure prevented the reduction in LEF1 expression, whereas betamethasone administration after LPS normalized the LPS-induced increase in Wnt7b mRNA. IA LPS exposure decreased canonical Wnt signaling in the developing lung. Antenatal corticosteroids before or after IA inflammation had different effects on pulmonary Wnt signaling. This study provides new insights into possible mechanisms by which prenatal inflammation affects lung development and how corticosteroid can be beneficial in this setting.
Publisher: American Physiological Society
Date: 12-2023
Publisher: S. Karger AG
Date: 2018
DOI: 10.1159/000490943
Abstract: b i Background: /i /b Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. b i Methods: /i /b Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. b i Results: /i /b LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. b i Conclusions: /i /b UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.
Publisher: American Thoracic Society
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 18-08-2016
Publisher: BMJ
Date: 15-05-2019
DOI: 10.1136/ARCHDISCHILD-2018-316044
Abstract: During delayed umbilical cord cl ing, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs. Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs. Pregnant sheep were instrumented at 132–133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes. In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02±2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord cl ing (median difference in body weight 52.3 [−54.9–166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth. Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
DOI: 10.1038/S41598-017-13113-9
Abstract: Mechanical ventilation of preterm neonates causes lung inflammation and injury, with potential life-long consequences. Inert 50-nm polystyrene nanoparticles (PS50G) reduce allergic inflammation in the lungs of adult mice. We aimed to confirm the anti-inflammatory effects of PS50G in a sheep asthma model, and investigate the effects of prophylactic administration of PS50G on ventilation-induced lung injury (VILI) in preterm lambs. We assessed lung inflammatory cell infiltration, with and without PS50G, after airway allergen challenge in ewes sensitised to house dust mite. Preterm lambs (0.83 gestation) were delivered by caesarean section for immediate tissue collection (n = 5) or ventilation either with (n = 6) or without (n = 5) prophylactic intra-tracheal administration of PS50G nanoparticles (3% in 2 ml). Ventilation was continued for a total of 2 h before tissue collection for histological and biomolecular assessment of lung injury and inflammation. In ewes with experimental asthma, PS50G decreased eosinophilic infiltration of the lungs. Ventilated preterm lambs showed molecular and histological signs of lung injury and inflammation, which were exacerbated in lambs that received PSG50G. PS50G treatment decreased established inflammation in the lungs of asthmatic sheep. However, prophylactic administration of PSG50 exacerbated ventilation-induced lung injury and lung inflammation in preterm lambs.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/PR.2017.37
Abstract: Fetal growth restriction (FGR) is a common complication of pregnancy and, in severe cases, is associated with elevated rates of perinatal mortality, neonatal morbidity, and poor neurodevelopmental outcomes. The leading cause of FGR is placental insufficiency, with the placenta failing to adequately meet the increasing oxygen and nutritional needs of the growing fetus with advancing gestation. The resultant chronic fetal hypoxia induces a decrease in fetal growth, and a redistribution of blood flow preferentially to the brain. However, this adaptation does not ensure normal brain development. Early detection of brain injury in FGR, allowing for the prediction of short- and long-term neurodevelopmental consequences, remains a significant challenge. Furthermore, in FGR infants the detection and diagnosis of neuropathology is complicated by preterm birth, the etiological heterogeneity of FGR, timing of onset of growth restriction, its severity, and coexisting complications. In this review, we examine existing and emerging diagnostic tools from human and preclinical studies for the detection and assessment of brain injury in FGR fetuses and neonates. Increased detection rates, and early detection of brain injury associated with FGR, will offer opportunities for developing and assessing interventions to improve long-term outcomes.
Publisher: Public Library of Science (PLoS)
Date: 18-05-2016
Publisher: Springer Science and Business Media LLC
Date: 04-09-2014
DOI: 10.1186/SCRT495
Publisher: Wiley
Date: 25-03-2011
DOI: 10.1111/J.1440-1681.2011.05489.X
Abstract: 1. Early postnatal events might play a critical role in the development of cardiorespiratory diseases of prematurity. Although the exact mechanism is unknown, capillary leakage resulting in increased interstitial fluid volume has been postulated to play a critical role. We investigated the effects of capillary leakage, induced by a volume load, on cardiopulmonary and systemic haemodynamics immediately after preterm delivery. 2. Fetal sheep were instrumented at 129 days gestation, delivered and ventilated. After 15 min, lambs in the volume load group received intravenous saline (50 mL/kg) infused over 10 min control lambs received no infusion. At 30 min, lambs underwent a pulmonary challenge by increasing positive end-expiratory pressure (PEEP) by 2 cmH(2)O every 10 min to 10 cmH(2)O, with similar decrements back to baseline PEEP. Pulmonary blood flow (PBF) and arterial pressures were recorded in real-time and cardiovascular variables were measured by Doppler echocardiography. 3. Total protein concentration in the bronchoalveolar-lavage fluid was higher in volume load lambs compared with controls, and histological interstitial fluid retention was evident in volume load lambs, both indicative of capillary leak. PBF increased immediately after the volume load, but PBF, pulmonary and systemic arterial pressures, and oxygenation all deteriorated during the PEEP challenge compared with controls, coinciding with an increase in downstream pulmonary resistance. Three of six volume load lambs had pulmonary haemorrhage, which was not observed in control lambs. 4. Capillary leakage had moderate effects, but subsequent high levels of PEEP had significant negative effects on cardiopulmonary and respiratory function in preterm lambs. Capillary leakage might contribute to postnatal cardiopulmonary failure in preterm infants.
Publisher: Elsevier BV
Date: 02-2021
Publisher: AMPCo
Date: 26-02-2018
DOI: 10.5694/MJA17.01287
Publisher: Frontiers Media SA
Date: 14-08-2020
Publisher: BMJ
Date: 20-01-2022
DOI: 10.1136/ARCHDISCHILD-2021-323017
Abstract: Animal and observational human studies report that delivery of excessive tidal volume (V T ) at birth is associated with lung and brain injury. Using a respiratory function monitor (RFM) to guide V T delivery might reduce injury and improve outcomes. To determine whether use of an RFM in addition to clinical assessment versus clinical assessment alone during mask ventilation in the delivery room reduces in-hospital mortality and morbidity of infants weeks’ gestation. Randomised controlled trials (RCTs) comparing RFM in addition to clinical assessment versus clinical assessment alone during mask ventilation in the delivery room of infants born weeks’ gestation. Risk of bias was assessed using Covidence Collaboration tool and pooled into a meta-analysis using a random-effects model. The primary outcome was death prior to discharge. Death before hospital discharge. Three RCTs enrolling 443 infants were combined in a meta-analysis. The pooled analysis showed no difference in rates of death before discharge with an RFM versus no RFM, relative risk (RR) 95% (CI) 0.98 (0.64 to 1.48). The pooled analysis suggested a significant reduction for brain injury (a combination of intraventricular haemorrhage and periventricular leucomalacia) (RR 0.65 (0.48 to 0.89), p=0.006) and for intraventricular haemorrhage (RR 0.69 (0.50 to 0.96), p=0.03) in infants receiving positive pressure ventilation with an RFM versus no RFM. In infants weeks, an RFM in addition to clinical assessment compared with clinical assessment during mask ventilation resulted in similar in-hospital mortality, significant reduction for any brain injury and intraventricular haemorrhage. Further trials are required to determine whether RFMs should be routinely available for neonatal resuscitation.
Publisher: Wiley
Date: 13-06-2019
DOI: 10.1113/JP276040
Publisher: BMJ
Date: 24-12-2014
DOI: 10.1136/ARCHDISCHILD-2013-305703
Abstract: Umbilical cord cl ing at birth has a major impact on an infant's cardiovascular system that varies in significance depending upon whether the infant has commenced breathing. As umbilical venous return is a major source of preload for the left ventricle during fetal life, recent experimental evidence has shown that cl ing the umbilical cord severely limits cardiac venous return in the absence of pulmonary ventilation. As a result, cardiac output greatly reduces and remains low until breathing commences. Once the infant begins breathing, aeration of the lung triggers a large increase in pulmonary blood flow, which replaces umbilical venous return as the source of preload for the left ventricle. As a result, cardiac output markedly increases, as indicated by an increase in heart rate immediately after birth. Thus, infants born apnoeic and hypoxic and have their cords immediately cl ed, are likely to have a restricted cardiac output combined with hypoxia. As increased cardiac output is a major physiological defence mechanism that counteracts the effects of hypoxaemia, limiting the increase in cardiac output exposes the infant to ischaemia along with hypoxia. However, if the infant commences breathing, aerates its lungs and increases pulmonary blood flow before the umbilical cord is cl ed, then pulmonary venous return can immediately take over the supply of left ventricular preload upon cord cl ing. As a result, there is no intervening period of reduced preload and cardiac output and the large swings in arterial pressures and flows are reduced leading to a more stable circulatory transition.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.RESUSCITATION.2018.07.020
Abstract: Over five percent of infants born worldwide will need help breathing after birth. Delayed cord cl ing (DCC) has become the standard of care for vigorous infants. DCC in non-vigorous infants is uncommon because of logistical difficulties in providing effective resuscitation during DCC. In Baby-Directed Umbilical Cord Cl ing (Baby-DUCC), the umbilical cord remains patent until the infant's lungs are exchanging gases. We conducted a feasibility study of the Baby-DUCC technique. We obtained antenatal consent from pregnant women to enroll infants born at ≥32 weeks. Vigorous infants received ≥2 min of DCC. If the infant received respiratory support, the umbilical cord was cl ed ≥60 s after the colorimetric carbon dioxide detector turned yellow. Maternal uterotonic medication was administered after umbilical cord cl ing. A paediatrician and researcher entered the sterile field to provide respiratory support during a cesarean birth. Maternal and infant outcomes in the delivery room and prior to hospital discharge were analysed. Forty-four infants were enrolled, 23 delivered via cesarean section (8 unplanned) and 15 delivered vaginally (6 via instrumentation). Twelve infants were non-vigorous. ECG was the preferred method for recording HR. Two infants had a HR 100 BPM by 80 s after birth. Median time to umbilical cord cl ing was 150 and 138 s in vigorous and non-vigorous infants, respectively. Median maternal blood loss was 300 ml. It is feasible to provide resuscitation to term and near-term infants during DCC, after both vaginal and cesarean births, cl ing the umbilical cord only when the infant is physiologically ready.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2012
Publisher: Elsevier BV
Date: 02-2021
Publisher: S. Karger AG
Date: 2019
DOI: 10.1159/000502212
Abstract: b i Background: /i /b The use of intraosseous (IO) access during resuscitation is widely accepted and promoted in paediatric medicine but features less prominently in neonatal training. Whilst umbilical venous catheterization (UVC) is a reliable method of delivering emergency drugs and fluids, it is not always achievable in a timely manner. IO access warrants exploration as an alternative. b i Aim: /i /b Conduct a systematic review of existing literature to examine the evidence for efficacy and safety of IO devices in neonatal patients, from birth to discharge. b i Method: /i /b A search of PubMed, Ovid, Medline, and Embase was carried out. Abstracts were screened for relevance to focus on neonatal-specific literature and studies which carried out separate analyses for neonates (infants & #x3c days of age or resident on a neonatal unit). b i Results: /i /b One case series and 12 case reports describe IO device insertion into 41 neonates, delivering a variety of drugs, including adrenaline (epinephrine) and volume resuscitation. Complications range from none to severe. Cadaveric studies show that despite a small margin for error, IO devices can be correctly sited in neonates. Simulation studies suggest that IO devices may be faster and easier to site than UVC, even in experienced hands. b i Conclusion: /i /b IO access should be available on neonatal units and considered for early use in neonates where other access routes have failed. Appropriate training should be available to staff in addition to existing life support and UVC training. Further studies are required to assess the optimal device, position, and whether medication can be delivered IO as effectively as by UVC. If IO devices provide a faster method of delivering adrenaline effectively than UVC, this may lead to changes in neonatal resuscitation practice.
Publisher: Wiley
Date: 14-02-2017
DOI: 10.1113/JP273682
Publisher: Georg Thieme Verlag KG
Date: 16-01-2018
Abstract: Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.
Publisher: Springer Science and Business Media LLC
Date: 2009
Publisher: The Endocrine Society
Date: 21-10-2009
DOI: 10.1210/EN.2009-0086
Abstract: Fetal exposure to elevated levels of bioactive glucocorticoids early in gestation, as in suspected cases of congenital adrenal hyperplasia, may result in adverse neurological events. Fetal hypothalamic-pituitary-adrenal development and function may be involved. We investigated immediate and long-term effects of maternal dexamethasone (DEX) administration early in pregnancy on fetal growth and pituitary-adrenal activity in sheep. Pregnant ewes carrying singleton fetuses (total n = 119) were randomized to control (2 ml saline/ewe) or DEX-treated groups (im injections of 0.14 mg/kg ewe weight · 12 h) at 40–41 d gestation (dG). At 50, 100, 125, and 140 dG, fetal plasma and tissues were collected. DEX-exposed fetuses were lighter than controls at 100 dG (P & 0.05) but not at any other times. Fetal plasma ACTH levels and pituitary POMC and PC-1 mRNA levels were similar between groups. Fetal plasma cortisol levels were significantly reduced after DEX exposure in both male and female fetuses at 50 dG (P & 0.05), were similar at 100 and 125 dG, but were significantly higher than controls at 140 dG. At 140 dG, there was increased adrenal P450C17 and 3β-HSD mRNA in female fetuses and reduced expression of ACTH-R mRNA in males. Fetal hepatic CBG mRNA levels mimicked plasma cortisol patterns. DEX exposure reduced CBG only in males at 50 dG (P & 0.05). Placental mRNA levels of 11β-HSD2 were increased after DEX in males (P & 0.05). Therefore, in sheep, early DEX may alter the developmental trajectory of the fetal hypothalamic-pituitary-adrenal axis, directly increasing fetal adrenal activation but not anterior pituitary function. In females, this effect may be attributed, in part, to increased fetal adrenal steroidogenic activity.
Publisher: American Physiological Society
Date: 08-2008
DOI: 10.1152/JAPPLPHYSIOL.00041.2008
Abstract: The effects of lung volume recruitment manouvres on pulmonary blood flow (PBF) during high-frequency oscillatory ventilation (HFOV) in preterm neonates are unknown. Since increased airway pressure adversely affects PBF, we compared the effects of two HFOV recruitment strategies on PBF and oxygenation index (OI). Preterm lambs (128 ± 1 day gestation term ∼150 days) were anesthetized and ventilated using HFOV (10 Hz, 33% t I ) with a mean airway pressure (Pao) of 15 cmH 2 O. Lung volume was recruited by either increasing Pao to 25 cmH 2 O for 1 min, repeated five times at 5-min intervals (Sigh group n = 5) or stepwise (5 cmH 2 O) changes in Pao at 5-min intervals incrementing up to 30 cmH 2 O then decrementing back to 15 cmH 2 O (R group n = 6). Controls ( n = 5) received constant HFOV at 15 cmH 2 O. PBF progressively decreased (by 45 ± 4%) and OI increased (by 15 ± 6%, indicating reduced oxygenation) in controls during HFOV, which was similar to the changes observed in the Sigh group of lambs. In the R group, PBF fell (by 54 ± 10%) as airway pressure increased ( r 2 = 0.99), although the PBF did not increase again as the Pao was subsequently reduced. The OI decreased (by 47 ± 9%), reflecting improved oxygenation at high Pao levels during HFOV in the R group. However, high Pao restored retrograde PBF during diastole in four of six lambs, indicating the restoration of right-to-left shunting through the ductus arteriosus. Thus the choice of volume recruitment maneuvre influences the magnitude of change in OI and PBF that occurs during HFOV. Despite significantly improving OI, the r recruitment approach causes sustained changes in PBF.
Publisher: Frontiers Media SA
Date: 02-06-2020
Publisher: Wiley
Date: 12-07-2022
DOI: 10.1113/JP283359
Publisher: American Physiological Society
Date: 07-2006
DOI: 10.1152/JAPPLPHYSIOL.01544.2005
Abstract: Prolonged increases in fetal lung expansion stimulate fetal lung growth and development, but the effects on pulmonary hemodynamics are unknown. Our aim was to determine the effect of increased fetal lung expansion, induced by tracheal obstruction (TO), on pulmonary blood flow (PBF) and vascular resistance (PVR). Chronically catheterized fetal sheep ( n = 6) underwent TO from 120 to 127 days of gestational age (term ∼147 days) tracheas were not obstructed in control fetuses ( n = 6). PBF, PVR, and changes to the PBF waveform were determined. TO significantly increased lung wet weight compared with control (166.3 ± 20.2 vs. 102.0 ± 18.8 g P 0.05). Despite the increase in intraluminal pressure caused by TO (5.0 ± 0.9 vs. 2.4 ± 1.0 mmHg P 0.001), PBF and PVR were similar between groups after 7 days (TO 28.1 ± 3.2 vs. control 34.1 ± 10.0 ml·min −1 ·100 g lung wt −1 ). However, TO markedly altered pulmonary hemodynamics associated with accentuated fetal breathing movements, causing a reduction rather than an increase in PBF at 7 days of TO. To account for the increase in intraluminal pressure, the pressure was equalized by draining the lungs of liquid on day 7 of TO. Pressure equalization increased PBF from 36.8 ± 5.2 to 112.4 ± 22.8 ml/min ( P = 0.01) and markedly altered the PBF waveform. These studies provide further evidence to indicate that intraluminal pressure is an important determinant of PBF and PVR in the fetus. We suggest that the increase in PBF associated with pressure equalization following TO reflects an increase in growth of the pulmonary vascular bed, leading to an increase in its cross-sectional area.
Publisher: Wiley
Date: 20-08-2013
Publisher: Cambridge University Press (CUP)
Date: 10-12-2020
DOI: 10.1017/S2040174420001208
Abstract: Preterm birth (delivery weeks of gestation) is associated with impaired glomerular capillary growth in neonates if this persists, it may be a contributing factor in the increased risk of hypertension and chronic kidney disease in people born preterm. Therefore, in this study, we aimed to determine the long-term impact of preterm birth on renal morphology, in adult sheep. Singleton male sheep were delivered moderately preterm at 132 days (~0.9) of gestation ( n = 6) or at term (147 days gestation n = 6) and euthanised at 14.5 months of age (early adulthood). Stereological methods were used to determine mean renal corpuscle and glomerular volumes, and glomerular capillary length and surface area, in the outer, mid and inner regions of the renal cortex. Glomerulosclerosis and interstitial collagen levels were assessed histologically. By 14.5 months of age, there was no difference between the term and preterm sheep in body or kidney weight. Renal corpuscle volume was significantly larger in the preterm sheep than the term sheep, with the preterm sheep exhibiting enlarged Bowman’s spaces however, there was no difference in glomerular volume between groups, with no impact of preterm birth on capillary length or surface area per glomerulus. There was also no difference in interstitial collagen levels or glomerulosclerosis index between groups. Findings suggest that moderate preterm birth does not adversely affect glomerular structure in early adulthood. The enlarged Bowman’s space in the renal corpuscles of the preterm sheep kidneys, however, is of concern and merits further research into its cause and functional consequences.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2015
Publisher: Wiley
Date: 08-10-2015
DOI: 10.1113/JP271376
Publisher: Frontiers Media SA
Date: 27-05-2020
Publisher: American Physiological Society
Date: 15-02-2012
DOI: 10.1152/AJPLUNG.00338.2011
Abstract: The proinflammatory stimulus of chorioamnionitis is commonly associated with preterm delivery. Women at risk of preterm delivery receive antenatal glucocorticoids to functionally mature the fetal lung. However, the effects of the combined exposures of chorioamnionitis and antenatal glucocorticoids on the fetus are poorly understood. Time-mated ewes with singleton fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) either preceding or following maternal intramuscular betamethasone 7 or 14 days before delivery, and the fetuses were delivered at 120 days gestational age (GA) (term = 150 days GA). Gestation matched controls received intra-amniotic and maternal intramuscular saline. Compared with saline controls, intra-amniotic LPS increased inflammatory cells in the bronchoalveolar lavage and myeloperoxidase, Toll-like receptor 2 and 4 mRNA, PU.1, CD3, and Foxp3-positive cells in the fetal lung. LPS-induced lung maturation measured as increased airway surfactant and improved lung gas volumes. Intra-amniotic LPS-induced inflammation persisted until 14 days after exposure. Betamethasone treatment alone induced modest lung maturation but, when administered before intra-amniotic LPS, suppressed lung inflammation. Interestingly, betamethasone treatment after LPS did not counteract inflammation but enhanced lung maturation. We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Elsevier BV
Date: 06-2015
Publisher: BMJ
Date: 05-12-2017
DOI: 10.1136/ARCHDISCHILD-2017-314005
Abstract: Umbilical cord milking (UCM) at birth may benefit preterm infants, but the physiological effects of UCM are unknown. We compared the physiological effects of two UCM strategies with immediate umbilical cord cl ing (UCC) and physiological-based cord cl ing (PBCC) in preterm lambs. At 126 days’ gestational age, fetal lambs were exteriorised, intubated and instrumented to measure umbilical, pulmonary and cerebral blood flows and arterial pressures. Lambs received either (1) UCM without placental refill (UCMwoPR) (2) UCM with placental refill (UCMwPR) (3) PBCC, whereby ventilation commenced prior to UCC or (4) immediate UCC. UCM involved eight milks along a 10 cm length of cord, followed by UCC. A net volume of blood was transferred into the lamb during UCMwPR (8.8 mL/kg, IQR 8–10, P=0.01) but not during UCMwoPR (0 mL/kg, IQR −2.8 to 1.7) or PBCC (1.1 mL/kg, IQR −1.3 to 4.3). UCM had no effect on pulmonary blood flow, but caused large fluctuations in mean carotid artery pressures (MBP) and blood flows (CABF). In UCMwoPR and UCMwPR lambs, MBP increased by 12%±1% and 8%±1% and CABF increased by 32%±2% and 15%±2%, respectively, with each milk. Cerebral oxygenation decreased the least in PBCC lambs (17%, IQR 13–26) compared with UCMwoPR (26%, IQR 23–25, P=0.03), UCMwPR (35%, IQR 27–44, P=0.02) and immediate UCC (34%, IQR 28–41, P=0.02) lambs. UCMwoPR failed to provide placental transfusion, and UCM strategies caused considerable haemodynamic disturbance. UCM does not provide the same physiological benefits of PBCC. Further review of UCM is warranted before adoption into routine clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 03-2012
Abstract: We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippoc us, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2012
DOI: 10.1038/PR.2012.49
Publisher: Public Library of Science (PLoS)
Date: 07-11-2014
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPLUNG.90547.2008
Abstract: Chorioamnionitis, a risk factor for bronchopulmonary dysplasia in preterm infants, causes an influx of inflammatory cells into the fetal lung. Using a fetal sheep model, we evaluated the time course of activation, functional maturity, and apoptosis of the leukocytes recruited to the fetal air spaces by lipopolysaccharide (LPS). Time-mated sheep were given intra-amniotic injections with 10 mg of Escherichia coli LPS or saline 2 or 7 days before preterm delivery at 124 days of gestation (term is 150 days). Both neutrophils and monocytes in bronchoalveolar lavage fluid (BALF) had activated NF-κB after 2- and 7-day LPS exposures. These neutrophils and monocytes expressed the activation factor CD11b and the maturation factor PU.1 at 2 days, and increased PU.1 expression was detected in macrophages at 7 days. Leukocyte oxidative burst activity was greatest at 7 days. BALF lipid peroxidation increased fivefold at 2 days, while protein carbonyls increased eightfold at 7 days. Nitrative stress was not detected in the BALF, but leukocytes in the lung expressed nitric oxide synthase (NOS)II (inducible NOS). BALF leukocytes expressed the antioxidant peroxiredoxin V. Lung glutathione peroxidase was also increased with LPS exposure. There was minimal apoptosis of airway and lung leukocytes assessed by caspase-3 activation. Intra-amniotic LPS recruits leukocytes to the fetal air space that have a persistent activation. These results have implications for the pathogenesis of lung inflammatory disorders in the preterm.
Publisher: American Thoracic Society
Date: 15-09-2007
Publisher: American Physiological Society
Date: 09-2014
DOI: 10.1152/JAPPLPHYSIOL.01358.2013
Abstract: At birth, the transition to newborn life is triggered by lung aeration, which stimulates a large increase in pulmonary blood flow (PBF). Current theories predict that the increase in PBF is spatially related to ventilated lung regions as they aerate after birth. Using simultaneous phase-contrast X-ray imaging and angiography we investigated the spatial relationships between lung aeration and the increase in PBF after birth. Six near-term (30-day gestation) rabbits were delivered by caesarean section, intubated and an intravenous catheter inserted, before they were positioned for X-ray imaging. During imaging, iodine was injected before ventilation onset, after ventilation of the right lung only, and after ventilation of both lungs. Unilateral ventilation increased iodine levels entering both left and right pulmonary arteries (PAs) and significantly increased heart rate, iodine ejection per beat, diameters of both left and right PAs, and number of visible vessels in both lungs. Within the 6th intercostal space, the mean gray level (relative measure of iodine level) increased from 68.3 ± 11.6 and 70.3 ± 7.5%·s to 136.3 ± 22.6 and 136.3 ± 23.7%·s in the left and right PAs, respectively. No differences were observed between vessels in the left and right lungs, despite the left lung not initially being ventilated. The increase in PBF at birth is not spatially related to lung aeration allowing a large ventilation erfusion mismatch, or pulmonary shunting, to occur in the partially aerated lung at birth.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2009
DOI: 10.1007/S00134-009-1624-Z
Abstract: The relative contributions of factors influencing lung injury immediately after birth are poorly understood. We hypothesized that oxygen content and humidity of inspired air would influence markers of pulmonary inflammation in ventilated lambs. Lambs delivered at 140 days gestation (term = 150 days) were assigned to one of five groups (n = 5-6/group): unventilated controls, or ventilation with 21 or 100% O(2) that was either heated and humidified or cold and dry. Lambs were ventilated gently for 3 h: blood gases were recorded regularly. Bronchoalveolar lavage and s les of tracheal mucosa and lung were collected post mortem. Arterial pH was lower [mean difference (95% CI): -0.07 (-0.13, -0.03)], while there was an increase in PaCO(2) [mean difference (95% CI): 10.2 (2.4, 17.9)] and fold change in lung pro-inflammatory IL-1beta cytokine mRNA [mean difference (95% CI): 28.3 (0.3, 56.2)] or IL-8 [mean difference (95% CI): 27.8 (7.9, 47.7)] cytokine mRNA expression with 100% O(2) relative to 21% O(2). Cold dry inspired gas did not influence gas exchange or dynamic mechanics at 3 h compared to heated humidified gas. Compared to 100% inspired O(2), cold dry inspired gas had less marked effect on fold change in lung pro-inflammatory IL-1beta cytokine mRNA [mean difference (95% CI): 27.2 (-0/8, 55.1)] or IL-8 [mean difference (95% CI): 14.5 (5.5, 34.4)] cytokine mRNA expression, although cilial dysfunction/damage was evident on electron microscopy, especially when exposure to cold dry gas was combined with hyperoxia. In near-term neonatal lambs ventilated for 3 h, hyperoxia was associated a more powerful stimulus for pulmonary dysfunction and upregulation of inflammatory cytokines than cold dry gas.
Publisher: American Physiological Society
Date: 02-2016
DOI: 10.1152/AJPLUNG.00328.2015
Abstract: Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.
Publisher: American Thoracic Society
Date: 07-2007
Publisher: Frontiers Media SA
Date: 07-02-2019
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.RESUSCITATION.2017.02.017
Abstract: Lung ultrasound (LUS) has shown promise for evaluation of newborns with respiratory distress. However, no study has described the appearance of LUS during the initiation of breathing. We used LUS to describe the appearance of the lungs in healthy infants immediately after birth, starting with the infant's first breath, through the first 20min after birth. This was a single-center observational study enrolling neonates born at ≥35 weeks. We obtained LUS video recordings with the initiation of breathing. Recordings that captured one of the 1st four breaths after birth were included. We also obtained recordings at 1-10 and 11-20min after birth. Recordings were graded using a modified version of a previously published system, with additional grades to describe the appearance of the lungs prior to establishment of the pleural line. We studied 63 infants, mean gestational age=39 Establishment of the pleural line, indicating lung aeration and substantial liquid clearance is achieved with the first few breaths after birth in term and near term infants.
Publisher: American Academy of Pediatrics (AAP)
Date: 03-2021
Abstract: The transition from intrauterine life to extrauterine existence encompasses significant cardiorespiratory adaptations. These include rapid lung aeration and increase in pulmonary blood flow (PBF). Perinatal asphyxia and fetal growth restriction can severely h er this transition. Hypoxia is the common denominator in these 2 disease states, with the former characterized by acute insult and the latter by utero-placental insufficiency and a chronic hypoxemic state. Both may manifest as hemodynamic instability. In this review, we emphasize the role of physiologic-based cord cl ing in supplementing PBF during transition. The critical role of lung aeration in initiating pulmonary gas exchange and increasing PBF is discussed. Physiologic studies in animal models have enabled greater understanding of the mechanisms and effects of various therapies on transitional circulation. With data from sheep models, we elaborate instrumentation for monitoring of cardiovascular and pulmonary physiology and discuss the combined effect of chest compressions and adrenaline in improving transition at birth. Lastly, physiologic adaptation influencing management in human neonatal cohorts with respect to cardiac and vascular impairments in hypoxic-ischemic encephalopathy and growth restriction is discussed. Impairments in right ventricular function and vascular mechanics hold the key to prognostication and understanding of therapeutic rationale in these critically ill cohorts. The right ventricle and pulmonary circulation seem to be especially affected and may be explored as therapeutic targets. The role of comprehensive assessments using targeted neonatal echocardiography as a longitudinal, reliable, and easily accessible tool, enabling precision medicine facilitating physiologically appropriate treatment choices, is discussed.
Publisher: Public Library of Science (PLoS)
Date: 17-02-2015
Publisher: Cold Spring Harbor Laboratory
Date: 28-08-2023
DOI: 10.1101/2023.08.25.23294627
Abstract: To determine the causal relationship between exposure to early hyperoxaemia and death/disability in infants with hypoxic-ischemic encephalopathy (HIE). We analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks’ gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO 2 measured within 2 h of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO 2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO 2 and death/disability. Among 221 infants, 116 (56%) had arterial pO 2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO 2 and death/disability. Among hyperoxaemic infants (pO 2 100–500 mmHg) the risk of death/disability was 40/58 (0.69), while the risk in normoxaemic infants (pO 2 40 – 99mmHg) was 20/48 (0.42). In the adjusted model, hyperoxaemia increased the risk of death/disability (adjusted risk ratio 1.61, 95% CI 1.07 – 2.00, p= 0.03) in relation to normoxaemia. Early hyperoxaemia increased the risk of death/disability among infants who had an early arterial pO 2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2019
DOI: 10.1038/S41390-019-0398-4
Abstract: Efficacy of surfactant therapy in fetal growth restricted (FGR) preterm neonates is unknown. Twin-bearing ewes underwent surgery at 105 days gestation to induce FGR in one twin by single umbilical artery ligation. At 123-127 days, catheters and flow probes were implanted in pulmonary and carotid arteries to measure flow and pressure. Lambs were delivered, intubated and mechanically ventilated. At 10 min, surfactant (100 mg kg FGR preterm lambs were 26% lighter than appropriate for gestational age (AGA) lambs and had baseline differences in lung mechanics and pulmonary blood flows. Surfactant therapy reduced ventilator and oxygen requirements and improved lung mechanics in both groups, although a more rapid improvement in compliance and tidal volume was observed in AGA lambs. Surfactant administration was associated with decreased mean pulmonary and carotid blood flow in FGR but not AGA lambs. No major differences in surfactant protein mRNA or PC levels were noted. Surfactant therapy was associated with an altered pulmonary and cerebral hemodynamic response in preterm FGR lambs.
Publisher: Public Library of Science (PLoS)
Date: 27-03-2017
Publisher: Public Library of Science (PLoS)
Date: 25-06-2021
DOI: 10.1371/JOURNAL.PONE.0253456
Abstract: Lung inflammation and impaired alveolarization are hallmarks of bronchopulmonary dysplasia (BPD). We hypothesize that human amnion epithelial cells (hAECs) are anti-inflammatory and reduce lung injury in preterm lambs born after antenatal exposure to inflammation. Pregnant ewes received either intra-amniotic lipopolysaccharide (LPS, from E . coli 055:B5 4mg) or saline (Sal) on day 126 of gestation. Lambs were delivered by cesarean section at 128 d gestation (term ~150 d). Lambs received intravenous hAECs (LPS/hAECs: n = 7 30x10 6 cells) or equivalent volumes of saline (LPS/Sal, n = 10 or Sal/Sal, n = 9) immediately after birth. Respiratory support was gradually de-escalated, aimed at early weaning from mechanical ventilation towards unassisted respiration. Lung tissue was collected 1 week after birth. Lung morphology was assessed and mRNA levels for inflammatory mediators were measured. Respiratory support required by LPS/hAEC lambs was not different to Sal/Sal or LPS/Sal lambs. Lung tissue:airspace ratio was lower in the LPS/Sal compared to Sal/Sal lambs (P .05), but not LPS/hAEC lambs. LPS/hAEC lambs tended to have increased septation in their lungs versus LPS/Sal (P = 0.08). Expression of inflammatory cytokines was highest in LPS/hAECs lambs. Postnatal administration of a single dose of hAECs stimulates a pulmonary immune response without changing ventilator requirements in preterm lambs born after intrauterine inflammation.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 19-03-2013
Publisher: American Physiological Society
Date: 09-2011
DOI: 10.1152/AJPLUNG.00446.2010
Abstract: Clinical and epidemiological studies implicate IL-1 as an important mediator of perinatal inflammation. We tested the hypothesis that intra-amniotic IL-1α would induce pulmonary and systemic fetal inflammatory responses. Sheep with singleton fetuses were given an intra-amniotic injection of recombinant sheep IL-1α (100 μg) and were delivered 1, 3, or 7 days later, at 124 ± 1 days gestation ( n=5–8/group). A separate group of sheep were given two intra-amniotic IL-1α injections (100 μg dose each): 7 days and again 1 day prior to delivery. IL-1α induced a robust increase in monocytes, neutrophils, lymphocytes, and IL-8 protein in bronchoalveolar lavage fluid. H 2 O 2 secretion was increased in inflammatory cells isolated from lungs of IL-1α-exposed lambs upon LPS challenge in vitro compared with control monocytes. T lymphocytes were recruited to the lung. IL-1β, cyclooxygenase-1, and cyclooxygenase-2 mRNA expression increased in the lung 1 day after intra-amniotic IL-1α exposure. Lung volumes increased 7 days after intra-amniotic IL-1α exposure, with minimal anatomic changes in air space morphology. The weight of the posterior mediastinal lymph node draining the lung and the gastrointestinal tract doubled, inducible nitric oxide synthase (NOSII)-positive cells increased, and Foxp3-positive T-regulatory lymphocytes decreased in the lymph node after IL-1α exposure. In the blood, neutrophil counts and plasma haptoglobin increased after IL-1α exposure. Compared with a single exposure, exposure to intra-amniotic IL-1α 7 days and again 1 day before delivery had a variable effect (increases in some inflammatory markers, but not pulmonary cytokines). IL-1α is a potent mediator of the fetal inflammatory response syndrome.
Publisher: SAGE Publications
Date: 22-09-2021
DOI: 10.1177/0271678X211045848
Abstract: Neurovascular coupling has been well-defined in the adult brain, but variable and inconsistent responses have been observed in the neonatal brain. The mechanisms that underlie functional haemodynamic responses in the developing brain are unknown. Synchrotron radiation (SR) microangiography enables in vivo high-resolution imaging of the cerebral vasculature. We exploited SR microangiography to investigate the microvascular changes underlying the cerebral haemodynamic response in preterm (n = 7) and 7–10-day old term lambs (n = 4), following median nerve stimulation of 1.8, 4.8 and 7.8 sec durations. Increasing durations of somatosensory stimulation significantly increased the number of cortical microvessels of ≤200 µm diameter in 7–10-day old term lambs (p 0.05) but not preterm lambs where, in contrast, stimulation increased the diameter of cerebral microvessels with a baseline diameter of ≤200 µm. Preterm lambs demonstrated positive functional responses with increased oxyhaemoglobin measured by near infrared spectroscopy, while 7–10-day old term lambs demonstrated both positive and negative responses. Our findings suggest the vascular mechanisms underlying the functional haemodynamic response differ between the preterm and 7–10-day old term brain. The preterm brain depends on vasodilatation of microvessels without recruitment of additional vessels, suggesting a limited capacity to mount higher cerebral haemodynamic responses when faced with prolonged or stronger neural stimulation.
Publisher: Springer Science and Business Media LLC
Date: 07-2007
Publisher: Springer Science and Business Media LLC
Date: 09-11-2018
DOI: 10.1038/JP.2017.135
Abstract: To assess arterial morphology and mechanics in preterm infants with fetal growth restriction (FGR) compared with those appropriate for gestational age (AGA) in the early neonatal period. This observational study involved 20 preterm FGR infants (28 to 32 weeks) of gestational age (GA) and birth weight (BW) <10th centile and 20 preterm AGA infants. Vascular ultrasound was performed to measure aortic properties. GA and BW of FGR and AGA infants were 29.8±1.3 vs 30±0.9 weeks (P=0.78) and 923.4±168 vs 1403±237 g (P<0.001), respectively. At 10.5±1.3 (s.d.) days after birth, blood pressure (systolic 51±3 vs 46±4 mm Hg, P<0.001) and maximum aorta intima-media thickness (621±76 vs 479±54 μm P<0.001) were significantly higher in FGR infants. Arterial wall stiffness and peripheral resistance were also increased in the FGR infants (2.36±0.24 vs 2.14±0.24, P=0.008 and 22.2±5 vs 13.7±2.3 mm Hg min ml Maladaptive arterial-ventricular coupling was noted. Early detection may aid in early therapeutic strategies such as afterload reduction.
Publisher: Frontiers Media SA
Date: 30-04-2020
Publisher: BMJ
Date: 02-03-2018
DOI: 10.1136/ARCHDISCHILD-2017-314064
Abstract: In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings. We compared PEEP delivery to intubated preterm lambs using four commonly available models of paired SIBs and PEEP valves, with a T-piece, with gas flow of 8 L/min. Peak inspiratory pressure inflations of 30 cmH 2 O, combined with set PEEP of 5, 7 and 10 cmH 2 O, were delivered at rates of 20, 40 and 60/min. These combinations were repeated without gas flow. We measured mean PEEP, maximum and minimum PEEP, and its difference (PEEP reduction). A total of 3288 inflations were analysed. The mean PEEP delivered by all SIBs was lower than set PEEP (P .001), although some differences were .5 cmH 2 O. In 55% of combinations, the presence of gas flow resulted in increased PEEP delivery (range difference 0.3–2 cmH 2 O). The mean PEEP was closer to set PEEP with faster inflation rates and higher set PEEPs. The mean (SD) PEEP reduction was 3.9 (1.6), 8.2 (1.8), 2 (0.6) and 1.1 (0.6) cmH 2 O with the four SIBs, whereas it was 0.5 (0.2) cmH 2 O with the T-piece. PEEP delivery with SIBs depends on the set PEEP, inflation rate, device model and gas flow. At recommended inflation rates of 60/min, some devices can deliver PEEP close to the set level, although the reduction in PEEP makes some SIBs potentially less effective for lung recruitment than a T-piece.
Publisher: BMJ
Date: 29-11-2021
DOI: 10.1136/ARCHDISCHILD-2021-322881
Abstract: The feasibility and benefits of continuous sustained inflations (SIs) during chest compressions (CCs) during delayed cord cl ing (physiological-based cord cl ing PBCC) are not known. We aimed to determine whether continuous SIs during CCs would reduce the time to return of spontaneous circulation (ROSC) and improve post-asphyxial blood pressures and flows in asystolic newborn lambs. Fetal sheep were surgically instrumented immediately prior to delivery at ~139 days’ gestation and asphyxia induced until lambs reached asystole. Lambs were randomised to either immediate cord cl ing (ICC) or PBCC. Lambs then received a single SI (SI sing 30 s at 30 cmH 2 O) followed by intermittent positive pressure ventilation, or continuous SIs (SI cont : 30 s duration with 1 s break). We thus examined 4 groups: ICC +SI sing , ICC +SI cont , PBCC +SI sing , and PBCC +SI cont . Chest compressions and epinephrine administration followed international guidelines. PBCC lambs underwent cord cl ing 10 min after ROSC. Physiological and oxygenation variables were measured throughout. The time taken to achieve ROSC was not different between groups (mean (SD) 4.3±2.9 min). Mean and diastolic blood pressure was higher during chest compressions in PBCC lambs compared with ICC lambs, but no effect of SIs was observed. SI cont significantly reduced pulmonary blood flow, diastolic blood pressure and oxygenation after ROSC compared with SI sing . We found no significant benefit of SI cont over SI sing during CPR on the time to ROSC or on post-ROSC haemodynamics, but did demonstrate the feasibility of continuous SIs during advanced CPR on an intact umbilical cord. Longer-term studies are recommended before this technique is used routinely in clinical practice.
Publisher: Cambridge University Press (CUP)
Date: 17-02-2012
Publisher: American Physiological Society
Date: 08-2011
DOI: 10.1152/AJPRENAL.00066.2011
Abstract: Chorioamnionitis is an antecedent of preterm birth. We aimed to determine the effect of experimental chorioamnionitis in fetal sheep during late gestation on 1) nephron number, 2) renal corpuscle volume, and 3) renal inflammation. We hypothesized that exposure to chorioamnionitis would lead to inflammation in fetal kidneys and adversely impact on the development of nephrons, leading to a reduction in nephron number. At ∼121 days of gestation (term ∼147 days), pregnant ewes bearing twin or singleton fetuses received a single intra-amniotic injection of lipopolysaccharide ( n = 6 3 singletons, 3 twins) controls were either untreated or received an intra-amniotic injection of saline ( n = 8 4 singletons, 4 twins). One twin was used from each twin-bearing ewe. At ∼128 days of gestation, fetuses were delivered via Caesarean section. Kidneys were collected and stereologically analyzed to determine nephron number and renal corpuscle volume. Renal inflammation was assessed using immunohistochemistry. Experimental chorioamnionitis did not affect body weight or relative kidney weight. There was a significant reduction in nephron number but no change in renal corpuscle volume in LPS-exposed fetuses relative to controls. On average, nephron number was significantly reduced by 23 and 18% in singleton and twin LPS-exposed fetuses, respectively. The degree of renal inflammation did not differ between groups. Importantly, this study demonstrates that exposure to experimental chorioamnionitis adversely impacts on nephron number in the developing fetus.
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 08-01-2020
DOI: 10.1186/S13287-019-1526-0
Abstract: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs. Surgery was performed in twin-bearing pregnant ewes at 88 days’ gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 10 6 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized. FGR ( n = 6) and FGR+UCBC ( n = 6) lambs were growth restricted compared to AGA ( n = 6) and AGA+UCBC ( n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs ( p 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs. Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.
Publisher: Frontiers Media SA
Date: 04-07-2022
DOI: 10.3389/FPHYS.2022.904144
Abstract: Initiation of respiratory support in the delivery room increases the risk and severity of brain injury in preterm neonates through two major pathways: an inflammatory pathway and a haemodynamic pathway. The relative contribution of each pathway on preterm brain injury is not known. We aimed to assess the role of the inflammatory and haemodynamic pathway on ventilation-induced brain injury (VIBI) in the preterm lamb. Fetal lambs (125 ± 1 day gestation) were exteriorised, instrumented and ventilated with a high tidal-volume (V T ) injurious strategy for 15 min either with placental circulation intact to induce the inflammatory pathway only (INJ INF n = 7) or umbilical cord occluded to induce both the inflammatory and haemodynamic pathways (INJ INF+HAE n = 7). Sham controls were exteriorised but not ventilated (SHAM n = 5) while unoperated controls (UNOP n = 7) did not undergo fetal instrumentation. Fetuses were returned in utero following intervention and the ewe allowed to recover. Arterial blood gases and plasma were s led periodically. Twenty-four hours following intervention, lambs were delivered and maintained on non-injurious ventilation for ∼40 min then brains were collected post-mortem for immunohistochemistry and RT-qPCR to assess inflammation, vascular pathology and cell death within white matter regions. Compared to INJ INF lambs, INJ INF+HAE lambs achieved a consistently higher V T during injurious ventilation and carotid blood flow was significantly lower than baseline by the end of ventilation. Throughout the 24 h recovery period, systemic arterial IL-6 levels of INJ INF+HAE lambs were significantly higher than SHAM while there was no difference between INJ INF and SHAM animals. At 24 h, mRNA expression levels of pro-inflammatory cytokines, tight junction proteins, markers of cell death, and histological injury indices of gliosis, blood vessel protein extravasation, oligodendrocyte injury and cell death were not different between groups. Injurious ventilation, irrespective of strategy, did not increase brain inflammation or injury 24 h later when compared to control animals. However, the haemodynamic pathway did influence carotid blood flow adaptations during injurious ventilation and increased systemic arterial IL-6 that may underlie long-term pathology. Future studies are required to further characterise the pathways and their long-term effects on VIBI.
Publisher: SAGE Publications
Date: 2013
Abstract: The absorption of medetomidine released by continuous infusion from an osmotic pump in the abdominal cavity was studied in pregnant sheep during the 24 h postoperative period. Additionally pain and sedation was assessed. Eleven sheep were studied: six were treated with a medetomidine loaded osmotic pump delivering 10 μL/h (3 μg/kg/h medetomidine) and five with a saline loaded osmotic pump (control). Serial blood s les were taken and analysed to determine plasma medetomidine levels. Medetomidine was absorbed from the peritoneal cavity and a steady plasma concentration was achieved within 10 h, mean (SD) peak concentration was 2.87 (0.22) ng/mL. Sheep receiving medetomidine analgesia had significantly lower pain scores at 10 h than controls. Four control sheep required rescue analgesia, compared with 0 in the treatment group. Delivery of 3 μg/kg/h medetomidine by an intraperitoneal osmotic pump to pregnant sheep in the 24 h postoperative period provides adequate plasma concentrations of medetomidine for analgesia without sedation.
Publisher: BMJ
Date: 20-01-2019
DOI: 10.1136/ARCHDISCHILD-2017-313864
Abstract: Delivery of inadvertent high tidal volume (V T ) during positive pressure ventilation (PPV) in the delivery room is common. High V T delivery during PPV has been associated with haemodynamic brain injury in animal models. We examined if V T delivery during PPV at birth is associated with brain injury in preterm infants weeks’ gestation. A flow-sensor was placed between the mask and the ventilation device. V T values were compared with recently described reference ranges for V T in spontaneously breathing preterm infants at birth. Infants were ided into two groups: V T mL/kg or V T mL/kg (normal and high V T , respectively). Brain injury (eg, intraventricular haemorrhage (IVH)) was assessed using routine ultrasound imaging within the first days after birth. A total of 165 preterm infants were included, 124 (75%) had high V T and 41 (25%) normal V T . The mean (SD) gestational age and birth weight in high and normal V T group was similar, 26 (2) and 26 (1) weeks, 858 (251) g and 915 (250) g, respectively. IVH in the high V T group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal V T group (P=0.008). Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high V T group and 2/41 (6%) in the normal V T group (P=0.01). High V T delivery during mask PPV at birth was associated with brain injury. Strategies to limit V T delivery during mask PPV should be used to prevent high V T delivery.
Publisher: Wiley
Date: 12-06-2020
DOI: 10.1113/EP088117
Abstract: What is the central question of this study? What is the immediate impact of moderate preterm birth on the structure and function of major conduit arteries using a pre‐clinical sheep model? What is the main finding and its importance? Postnatal changes in conduit arteries, including a significant decrease in collagen within the thoracic aortic wall (predominately males), narrowed carotid arteries, reduced aortic systolic blood flow, and upregulation of the mRNA expression of cell adhesion and inflammatory markers at 2 days of age in preterm lambs compared to controls, may increase the risk of cardiovascular impairment in later life. The aim of this work was to compare the structure and function of the conduit arteries of moderately preterm and term‐born lambs and to determine whether vascular injury‐associated genes were upregulated. Time‐mated ewes were induced to deliver either preterm (132 ± 1 days of gestation n = 11 females and n = 10 males) or at term (147 ± 1 days of gestation n = 10 females and n = 5 males). Two days after birth, ultrasound imaging of the proximal ascending aorta, main, right and left pulmonary arteries, and right and left common carotid arteries was conducted in anaesthetized lambs. Lambs were then killed and segments of the thoracic aorta and left common carotid artery were either snap frozen for real‐time PCR analyses or immersion‐fixed for histological quantification of collagen, smooth muscle and elastin within the medial layer. Overall there were few differences in vascular structure between moderately preterm and term lambs. However, there was a significant decrease in the proportion of collagen within the thoracic aortic wall (predominantly in males), narrowing of the common carotid arteries and a reduction in peak aortic systolic blood flow in preterm lambs. In addition, there was increased mRNA expression of the cell adhesion marker P‐selectin in the thoracic aortic wall and the pro‐inflammatory marker IL‐1β in the left common carotid artery in preterm lambs, suggestive of postnatal vascular injury. Early postnatal differences in the function and structure of conduit arteries and evidence of vascular injury in moderately preterm offspring may place them at greater risk of cardiovascular impairment later in life.
Publisher: BMJ
Date: 10-06-2021
DOI: 10.1136/ARCHDISCHILD-2020-321503
Abstract: To identify risk factors associated with delivery room respiratory support in at-risk infants who are initially vigorous and received delayed cord cl ing (DCC). Prospective cohort study. Two perinatal centres in Melbourne, Australia. At-risk infants born at ≥35 +0 weeks gestation with a paediatric doctor in attendance who were initially vigorous and received DCC for s. Delivery room respiratory support defined as facemask positive pressure ventilation, continuous positive airway pressure and/or supplemental oxygen within 10 min of birth. Two hundred and ninety-eight infants born at a median (IQR) gestational age of 39 +3 (38 +2 –40 +2 ) weeks were included. Cord cl ing occurred at a median (IQR) of 128 (123–145) s. Forty-four (15%) infants received respiratory support at a median of 214 (IQR 156–326) s after birth. Neonatal unit admission for respiratory distress occurred in 32% of infants receiving delivery room respiratory support vs 1% of infants who did not receive delivery room respiratory support (p .001). Risk factors independently associated with delivery room respiratory support were average heart rate (HR) at 90–120 s after birth (determined using three-lead ECG), mode of birth and time to establish regular cries. Decision tree analysis identified that infants at highest risk had an average HR of beats per minute at 90–120 s after birth following caesarean section (risk of 39%). Infants with an average HR of ≥165 beats per minute at 90–120 s after birth were at low risk (5%). We present a clinical decision pathway for at-risk infants who may benefit from close observation following DCC. Our findings provide a novel perspective of HR beyond the traditional threshold of 100 beats per minute.
Publisher: BMJ
Date: 30-08-2021
DOI: 10.1136/ARCHDISCHILD-2021-322638
Abstract: Intraosseous access is recommended as a reasonable alternative for vascular access during newborn resuscitation if umbilical access is unavailable, but there are minimal reported data in newborns. We compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth. Near-term lambs (139 days’ gestation) were instrumented antenatally for measurement of carotid and pulmonary blood flow and systemic blood pressure. Intrapartum asphyxia was induced by umbilical cord cl ing until asystole. Resuscitation commenced with positive pressure ventilation followed by chest compressions and the lambs received either intraosseous or central intravenous epinephrine (10 μg/kg) epinephrine administration was repeated every 3 min until return of spontaneous circulation (ROSC). The lambs were maintained for 30 min after ROSC. Plasma epinephrine levels were measured before cord cl ing, at end asphyxia, and at 3 and 15 min post-ROSC. ROSC was successful in 7 of 9 intraosseous epinephrine lambs and in 10 of 12 intravenous epinephrine lambs. The time and number of epinephrine doses required to achieve ROSC were similar between the groups, as were the achieved plasma epinephrine levels. Lambs in both groups displayed a similar marked overshoot in systemic blood pressure and carotid blood flow after ROSC. Blood gas parameters improved more quickly in the intraosseous lambs in the first 3 min, but were otherwise similar over the 30 min after ROSC. Intraosseous epinephrine administration results in similar outcomes to intravenous epinephrine during resuscitation of asphyxiated newborn lambs. These findings support the inclusion of intraosseous access as a route for epinephrine administration in current guidelines.
Publisher: Frontiers Media SA
Date: 20-10-2014
Publisher: Public Library of Science (PLoS)
Date: 11-07-2018
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.RESUSCITATION.2008.10.007
Abstract: Recent literature suggests hypothermia may protect against lung injury. We evaluated body temperature as a variable in lung inflammation due to oxygenation and mechanical ventilation following delivery of near-term lambs. Twin fetuses were randomized prior to delivery at 140 d GA (term 150 d): unventilated controls, normothermic ventilated with room air, normothermic ventilated with 100% oxygen, low temperature ventilated (target 35 degrees C) with 100% oxygen, and high temperature (target 40 degrees C) with 100% oxygen. Lambs were intubated for gentle mechanical ventilation (tidal volume 7-8ml/kg). Temperature targeting was with radiant warmers and plastic wrap for normothermia, with heat l s for hyperthermia, and with ice packs for hypothermia. Lambs were euthanized after 2h mechanical ventilation. Post-mortem, bronchoalveolar lavage fluid and lung tissue s les were evaluated for inflammatory responses by measuring inflammatory cell counts, protein, myeloperoxidase, protein carbonyl, and pro-inflammatory cytokine mRNA. Target temperatures were achieved by 30min of age and tightly maintained for the 2h study. There were no differences in physiologic variables among groups except those directly resulting from study protocol-PaO2 from air vs. 100% oxygen and body temperature. Indicators of inflammation increased similarly in all ventilated groups compared to unventilated controls. Moderate hyperthermia or hypothermia did not affect lung injury responses to the initiation of ventilation at birth in near-term lambs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
DOI: 10.1161/CIRCGENETICS.115.001225
Abstract: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm 95% confidence interval 0.19 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg 95% confidence interval 0.02 0.08) and systolic blood pressure (0.08 mm Hg 95% confidence interval 0.03 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele 95% confidence interval 0.18 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.AJOG.2010.11.015
Abstract: We hypothesized that fetal innate immune responses to lipopolysaccharide-induced chorioamnionitis would alter postnatal systemic immune and airway responsiveness. Ewes received intraamniotic injections with saline or lipopolysaccharide at 90, 100, and 110 days of gestation. Immune status and airway responsiveness were evaluated at term and at 7 weeks of age. At term, lymphocytes, monocytes, and neutrophils were significantly increased (respectively, 24-fold, 127-fold, and 31,000-fold) in lungs and blood monocytes became Toll-like receptor 2 responsive after lipopolysaccharide exposures. Furthermore, CD4 and CD4/CD25 lymphocytes were increased in thymus and lymph nodes. At 7 weeks, airway reactivity decreased and concentrations of CD8 cytotoxic T lymphocytes changed in the lungs and thymus relative to controls. Early gestational lipopolysaccharide exposure increased leukocyte responsiveness at term. Decreased airway reactivity and changes in lymphocytes at 7 weeks postnatal demonstrate persistent effects of fetal exposure to LPS.
Publisher: Frontiers Media SA
Date: 29-10-2014
Publisher: Frontiers Media SA
Date: 12-04-2019
Publisher: Springer Science and Business Media LLC
Date: 11-2008
Publisher: Wiley
Date: 06-04-2018
DOI: 10.1113/JP275654
Publisher: BMJ
Date: 08-11-2016
Publisher: Springer Science and Business Media LLC
Date: 12-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2018
Publisher: Frontiers Media SA
Date: 03-03-2020
Publisher: Bentham Science Publishers Ltd.
Date: 11-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
DOI: 10.1161/ATVBAHA.119.312366
Abstract: The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.
Publisher: American Physiological Society
Date: 11-2012
DOI: 10.1152/AJPLUNG.00280.2011
Abstract: Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin ( ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.
Publisher: CRC Press
Date: 09-09-2021
Publisher: American Physiological Society
Date: 11-2017
DOI: 10.1152/JAPPLPHYSIOL.00783.2016
Abstract: Oxidative stress arising from suboptimal placental function contributes to a multitude of pathologies in infants compromised by fetal growth restriction (FGR). FGR infants are at high risk for respiratory dysfunction after birth and poor long-term lung function. Our objective was to investigate the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. Placental insufficiency and FGR was surgically induced in 13 fetal sheep at ∼105 days of gestation by ligation of a single umbilical artery. Maternal intravenous melatonin infusion was commenced in seven of the ewes 4 h after surgery and continued until birth. Lambs delivered normally at term and lungs were collected 24 h after birth for histological assessment of lung structure and injury and compared with appropriately grown control lambs ( n = 8). FGR fetuses were hypoxic and had lower glucose during gestation compared with controls. Melatonin administration prevented chronic hypoxia. Within the lung, FGR caused reduced secondary septal crest density and altered elastin deposition compared with controls. Melatonin administration had no effect on the changes to lung structure induced by FGR. We conclude that chronic FGR disrupts septation of the developing alveoli, which is not altered by melatonin administration. These findings suggest that oxidative stress is not the mechanism driving altered lung structure in FGR neonates. Melatonin administration did not prevent disrupted airway development but also had no apparent adverse effects on fetal lung development. NEW & NOTEWORTHY Fetal growth restriction (FGR) results in poor respiratory outcomes, which may be caused by oxidation in utero. We investigated the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. FGR disrupted septation of the developing alveoli, which is not altered by melatonin administration. Oxidative stress may not be the mechanism driving altered lung structure in FGR neonates.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.RESUSCITATION.2018.07.008
Abstract: Over 5% of infants worldwide receive breathing support immediately after birth. Our goal was to define references ranges for exhaled carbon dioxide (ECO This was a single-centre, observational study at the Royal Women's Hospital in Melbourne, Australia, a busy perinatal referral centre. Immediately after the infant's head was delivered, we used a face mask to measure ECO We analysed 14,731 breaths in 101 spontaneously breathing infants, 51 born via planned caesarean section and 50 born vaginally with a median (IQR) gestational age of 39 This study provides reference ranges of exhaled carbon dioxide, exhaled tidal volumes, and respiratory rate for the first ten minutes after birth in term infants who transition without resuscitation.
Publisher: Elsevier BV
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 08-2016
Abstract: Preterm births account for approximately 10% of births worldwide, with the majority (∼80%) being moderate preterm. Our aim was to determine the effects of moderate preterm birth on survival and long-term growth of male and female offspring using an ovine model of preterm birth that was preceded by a clinically relevant dose of corticosteroids. Ewes were induced to deliver preterm or at term those assigned to deliver preterm were administered antenatal betamethasone (11.4 mg, 2 doses, 24 hours apart). The growth (body weight and body dimensions) of offspring was monitored to adulthood (62 weeks) when the animals were humanely killed for organ collection. Survival in the immediate period following preterm birth was high (75% for both sexes). However, there were unexpected deaths between 5 and 12 weeks of age, as a result of vitamin E/selenium deficiency this only occurred in preterm offspring. From birth until adolescence, preterm lambs were lighter than term lambs (controls). After this time, there was gradual catch-up in body weight in preterm females, whereas in preterm males, body weight remained lower than in controls. Preterm sheep were smaller in stature than controls throughout life. This clinically relevant model of preterm birth leads to equally high survival rates in both sexes and is an excellent animal model in which to examine the effects of moderate preterm birth on growth and development of organ systems into adulthood.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2010
Publisher: Wiley
Date: 29-09-2009
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Publisher: Frontiers Media SA
Date: 02-2018
Publisher: Public Library of Science (PLoS)
Date: 29-03-2011
Publisher: S. Karger AG
Date: 2017
DOI: 10.1159/000459620
Abstract: Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO lified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT i n /i = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300 i n /i = 5), 1,000 IU/kg (EPO 1,000 i n /i = 5), or 3,000 IU/kg (EPO 3,000 i n /i = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 ( i /i = 0.006) and caspase-3 ( i /i = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 ( i /i = 0.010) and EPO 3,000 ( i /i = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.
Publisher: Frontiers Media SA
Date: 15-06-2018
Publisher: BMJ
Date: 28-04-2015
DOI: 10.1136/ARCHDISCHILD-2014-307319
Abstract: At birth, an initial sustained inflation (SI) uniformly aerates the lungs, increases arterial oxygenation and rapidly improves circulatory recovery in asphyxiated newborns. We hypothesised that lung aeration, in the absence of an increase in arterial oxygenation, can increase heart rate (HR) in asphyxiated near-term lambs. Lambs were delivered and instrumented at 139±2 days of gestation. Asphyxia was induced by umbilical cord cl ing and then delaying the onset of ventilation until mean carotid arterial pressures (CAPs) had decreased <20 mm Hg. Lambs then received a single 30-s SI using nitrogen (N2 n=6), 5% oxygen (O2 n=6), 21% O2 (n=6) or 100% O2 (n=6) followed by ventilation in air for 30 min. HR, CAP and pulmonary blood flow (PBF) were continuously recorded. HR and PBF increased more quickly in lambs resuscitated with 100% and 21% O2 than with 5% O2 or N2. HR and PBF recovery in the 5% O2 group was delayed relative to all other oxygen SI groups. HR in 5%, 21% and 100% O2 groups reached 100 bpm before the SI was complete. HR and PBF in the N2 group did not increase until 10 s after the SI was completed and ventilation was initiated with air. CAP tended to increase quicker in all O2 groups than in N2 group. Oxygen content during an SI is important for circulatory recovery in asphyxiated lambs. This increase in HR is likely driven by the increase in PBF and venous return to the heart.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2013
DOI: 10.1038/PR.2013.70
Abstract: Intrauterine inflammation adversely affects cardiopulmonary, systemic, and cerebral hemodynamics in preterm neonates, but its impact on responses to endotracheal tube (ETT) suction, known to affect hemodynamics, is unknown. We hypothesized that intrauterine inflammation would alter the cardiopulmonary and cerebral hemodynamic response to open ETT suction in preterm lambs. Chronically instrumented fetuses received intra-amniotic lipopolysaccharide (LPS to induce intrauterine inflammation) or saline at 118 d of gestation (term ~147 d). At 125 d of gestation, lambs were delivered and mechanically ventilated. Open ETT suction was performed 30 min after delivery. Pulmonary and cerebral arterial pressures and flows were recorded continuously. Intrauterine inflammation reduced pulmonary blood flow (PBF) and increased pulmonary vascular resistance (PVR) after preterm birth. PBF and left-ventricular output (LVO) increased during and immediately after ETT suction in both groups, but the values were higher in LPS-exposed lambs. Preductal oxygenation significantly decreased during ETT suction but to a greater extent in LPS-exposed lambs. Cerebral blood flow and systemic arterial pressure were increased by open ETT suction similarly in the two groups. Intrauterine inflammation exacerbates the neonatal hemodynamic response to open ETT suction.
Publisher: Wiley
Date: 18-04-2016
DOI: 10.1111/JPC.13154
Abstract: Pneumothorax is a common emergency affecting extremely preterm. In adult studies, lung ultrasound has performed better than chest x-ray in the diagnosis of pneumothorax. The purpose of this study was to determine the efficacy of lung ultrasound (LUS) examination to detect pneumothorax using a preterm animal model. This was a prospective, observational study using newborn Border-Leicester lambs at gestational age = 126 days (equivalent to gestational age = 26 weeks in humans) receiving mechanical ventilation from birth to 2 h of life. At the conclusion of the experiment, LUS was performed, the lambs were then euthanised and a post-mortem exam was immediately performed. We used previously published ultrasound techniques to identify pneumothorax. Test characteristics of LUS to detect pneumothorax were calculated, using the post-mortem exam as the 'gold standard' test. Nine lambs (18 lungs) were examined. Four lambs had a unilateral pneumothorax, all of which were identified by LUS with no false positives. This was the first study to use post-mortem findings to test the efficacy of LUS to detect pneumothorax in a newborn animal model. Lung ultrasound accurately detected pneumothorax, verified by post-mortem exam, in premature, newborn lambs.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
DOI: 10.1007/S00431-022-04475-Y
Abstract: Randomised trials in emergency settings must quickly confirm eligibility and allocate participants to an intervention group without delaying treatment. We report rapid randomisation during two neonatal resuscitation trials using the non-commercial REDCap platform accessed via smartphone. This simple, reliable method has wide applicability for trials in emergency settings. What is Known: • Randomised trials in emergency settings need to rapidly allocate participants to an intervention group. • This process should not delay treatment. What is New: • This non-commercial, smartphone-accessible application enabled rapid, accurate randomisation at the bedside. • This has broad applicability for emergency setting trials.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2014
DOI: 10.1038/PR.2014.40
Abstract: The transition to newborn life in preterm infants is complicated by immature cardiovascular and respiratory systems. Consequently, preterm infants often require respiratory support immediately after birth. Although aeration of the lung underpins the circulatory transition at birth, positive pressure ventilation can adversely affect cardiorespiratory function during this vulnerable period, reducing pulmonary blood flow and left ventricular output. Furthermore, pulmonary volutrauma is known to initiate pulmonary inflammatory responses, resulting in remote systemic involvement. This review focuses on the downstream consequences of positive pressure ventilation, in particular, interactions between cardiovascular output and the initiation of a systemic inflammatory cascade, on the immature brain. Recent studies have highlighted that positive pressure ventilation strategies are precursors of cerebral injury, probably mediated through cerebral blood flow instability. The presence of, or initiation of, an inflammatory cascade accentuates adverse cerebral blood flow, in addition to being a direct source of brain injury. Importantly, the degree of brain injury is dependent on the nature of the initial ventilation strategy used.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2021
Publisher: Springer Science and Business Media LLC
Date: 11-03-2019
DOI: 10.1038/S41390-019-0366-Z
Abstract: Chorioamnionitis and fetal inflammation are principal causes of neuropathology detected after birth, particularly in very preterm infants. Preclinical studies show that umbilical cord blood (UCB) cells are neuroprotective, but it is uncertain if allogeneic UCB cells are a feasible early intervention for preterm infants. In contrast, mesenchymal stem cells (MSCs) are more readily accessible and show strong anti-inflammatory benefits. We aimed to compare the neuroprotective benefits of UCB versus MSCs in a large animal model of inflammation-induced preterm brain injury. We hypothesized that MSCs would afford greater neuroprotection. Chronically instrumented fetal sheep at 0.65 gestation received intravenous lipopolysaccharide (150 ng 055:B5, n = 8) over 3 consecutive days or saline for controls (n = 8). Cell-treated animals received 10 Lipopolysaccharide induced neuroinflammation and apoptosis, and reduced the number of mature oligodendrocytes. MSCs reduced astrogliosis, but UCB did not have the same effect. UCB significantly decreased cerebral apoptosis and protected mature myelinating oligodendrocytes, but MSCs did not. UCB appears to better protect white matter development in the preterm brain in response to inflammation-induced brain injury in fetal sheep.
Publisher: Public Library of Science (PLoS)
Date: 06-12-2017
Publisher: Wiley
Date: 15-10-2015
DOI: 10.1111/APA.13220
Abstract: Intrauterine growth restriction (IUGR) is an important cause for prematurity and adversely influences prematurity-related morbidities. This study evaluates the impact of IUGR on respiratory outcomes in infants <32 weeks with IUGR and birthweight <10th centile (SGA) compared to matched appropriate for gestation (AGA) controls. The primary outcomes of this retrospective study are short-term pulmonary outcomes of chronic lung disease (CLD), CLD or death, and need for home oxygen at discharge. Subgroup analysis by gestation-based stratification (<28 and ≥28 <32 weeks) was decided a priori. Total of 153 IUGR and 306 non-IUGR infants were enrolled. The rate of CLD (45% vs. 17%, p = 0.0001), death (16% vs. 4.6%, p = 0.0001), CLD or death (46% vs. 21.5%, p = 0.0001), home oxygen rates (13.7% vs. 6.5%, p = 0.01) and duration of respiratory support was significantly higher in the IUGR group. IUGR emerged as the strongest predictor of CLD (adjusted OR, 95%CI: (8.4 [2, 35]) and CLD or death (12.7 [3, 54]) across all gestation. IUGR is a major risk factor for adverse short-term pulmonary outcomes as reflected by higher rates of CLD, CLD or death, and oxygen dependency at discharge in preterm infants.
Publisher: BMJ
Date: 08-04-2016
DOI: 10.1136/ARCHDISCHILD-2015-309596
Abstract: A sustained bradycardia is used as a major indicator of severe perinatal asphyxia. However, lambs asphyxiated ex utero do not exhibit the same bradycardic response as lambs asphyxiated in utero. It is possible that the local in utero environment may influence the initial cardiovascular response to asphyxia. We assessed the effect of facial immersion in water on the cardiovascular response to birth asphyxia. Pregnant ewes (138±1 days gestation) were anaesthetised and fetuses were exteriorised and instrumented for measurement of cardiopulmonary haemodynamics. The lamb's head either remained in air (n=5) or was placed in water that was either warm (40±1°C n=5) or at room temperature (21±1°C n=5) before the umbilical cord was cl ed to induce asphyxia. Heart rate after bradycardia onset was reduced in lambs asphyxiated with their head in cool water (-34±2%) and warm water (-25±4%) compared with those in air (-11±5% p<0.05). Similarly, the decrease in blood pressure was faster in lambs with water around the face compared with those in air. From 75 s after asphyxia onset, mean and end-diastolic carotid blood flow was higher in the group asphyxiated in air (25±4 mL/kg/min), compared with the groups in water (13±3 mL/kg/min, warm water 16±2 mL/kg/min, cool water p<0.05). The cardiovascular response to birth asphyxia is altered by the presence and temperature of water surrounding the head. The previous understanding of the vagally mediated bradycardia associated with birth asphyxia may include components of the ing reflex.
Publisher: Public Library of Science (PLoS)
Date: 13-11-2014
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000444918
Abstract: Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth.
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: American Physiological Society
Date: 04-2015
DOI: 10.1152/JAPPLPHYSIOL.00985.2014
Abstract: Support of the mechanically complex preterm lung needs to facilitate aeration while avoiding ventilation heterogeneities: whether to achieve this gradually or quickly remains unclear. We compared the effect of gradual vs. constant tidal inflations and a pressure-limited sustained inflation (SI) at birth on gas exchange, lung mechanics, gravity-dependent lung volume distribution, and lung injury in 131-day gestation preterm lambs. Lambs were resuscitated with either 1) a 20-s, 40-cmH 2 O pressure-limited SI (PressSI), 2) a gradual increase in tidal volume (Vt) over 5-min from 3 ml/kg to 7 ml/kg (IncrVt), or 3) 7 ml/kg Vt from birth. All lambs were subsequently ventilated for 15 min with 7 ml/kg Vt with the same end-expiratory pressure. Lung mechanics, gas exchange and spatial distribution of end-expiratory volume (EEV), and tidal ventilation (electrical impedance tomography) were recorded regularly. At 15 min, early mRNA tissue markers of lung injury were assessed. The IncrVt group resulted in greater tissue hysteresivity at 5 min ( P = 0.017 two-way ANOVA), higher alveolar-arterial oxygen difference from 10 min ( P 0.01), and least uniform gravity-dependent distribution of EEV. There were no other differences in lung mechanics between groups, and the PressSI and 7 ml/kg Vt groups behaved similarly throughout. EEV was more uniformly distributed, but Vt least so, in the PressSI group. There were no differences in mRNA markers of lung injury. A gradual increase in Vt from birth resulted in less recruitment of the gravity-dependent lung with worse oxygenation. There was no benefit of a SI at birth over mechanical ventilation with 7 ml/kg Vt.
Publisher: Wiley
Date: 20-03-2013
Publisher: Springer Science and Business Media LLC
Date: 10-2022
DOI: 10.1186/S13063-022-06789-6
Abstract: International guidelines recommend delayed umbilical cord cl ing (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, cl ing the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord cl ing until lung aeration and ventilation have been established (physiological-based cord cl ing, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord cl ing (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. The Aeriation, Breathing, Cl ing 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is cl ed after the infant is stabilised, defined as reaching heart rate 100 bpm and SpO 2 85% while using supplemental oxygen 40%. In the control TBCC group, cord cl ing is time based at 30–60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required s le size is 660 infants. The findings of this trial will provide evidence for future clinical guidelines on optimal cord cl ing management in very preterm infants at birth. ClinicalTrials.gov NCT03808051. First registered on January 17, 2019.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Public Library of Science (PLoS)
Date: 17-06-2021
DOI: 10.1371/JOURNAL.PONE.0253306
Abstract: Delayed umbilical cord cl ing (UCC) after birth is thought to cause placental to infant blood transfusion, but the mechanisms are unknown. It has been suggested that uterine contractions force blood out of the placenta and into the infant during delayed cord cl ing. We have investigated the effect of uterine contractions, induced by maternal oxytocin administration, on umbilical artery (UA) and venous (UV) blood flows before and after ventilation onset to determine whether uterine contractions cause placental transfusion in preterm lambs. At ~128 days of gestation, UA and UV blood flows, pulmonary arterial blood flow (PBF) and carotid arterial (CA) pressures and blood flows were measured in three groups of fetal sheep during delayed UCC maternal oxytocin following mifepristone, mifepristone alone, and saline controls. Each successive uterine contraction significantly (p .05) decreased UV (26.2±6.0 to 14.1±4.5 mL.min -1 .kg -1 ) and UA (41.2±6.3 to 20.7 ± 4.0 mL.min -1 .kg -1 ) flows and increased CA pressure and flow (47.1±3.4 to 52.8±3.5 mmHg and 29.4±2.6 to 37.3±3.4 mL.min -1 .kg -1 ). These flows and pressures were partially restored between contractions, but did not return to pre-oxytocin administration levels. Ventilation onset during DCC increased the effects of uterine contractions on UA and UV flows, with retrograde UA flow (away from the placenta) commonly occurring during diastole. We found no evidence that lification of uterine contractions with oxytocin increase placental transfusion during DCC. Instead they decreased both UA and UV flow and caused a net loss of blood from the lamb. Uterine contractions did, however, have significant cardiovascular effects and reduced systemic and cerebral oxygenation.
Publisher: Frontiers Media SA
Date: 21-02-2020
Publisher: Wiley
Date: 04-10-2018
DOI: 10.1111/JPC.14251
Abstract: Approximately 6-9% pregnancies are affected by fetal growth restriction (FGR). Placental alterations related to utero-placental insufficiency in FGR may induce placental vascular remodelling to the detriment of the fetus. The objective of this article was to study histopathological features of placentae in a cohort of preterm growth-restricted infants in comparison to a cohort of preterm appropriately grown infants. In a cohort of 40 preterm infants of 28-32 weeks' gestation, placental histopathology was evaluated by a histopathologist, who was blinded to the identity of the grouping. Twenty infants had FGR, while 20 were appropriate for gestational age (AGA). Predefined histopathological characteristics were assessed based on the Amsterdam Placental Workshop Group Consensus Statement. The gestational age and birthweight of the FGR and AGA cohorts were 29.8 ± 1.3 versus 30 ± 0.9 weeks, P = 0.78 and 923 ± 168 versus 1403 ± 237 g, <0.001, respectively. Maternal vascular malperfusion, accelerated villous maturation and fetal vascular malperfusion were features that were significantly more common in FGR placentae. Based on the results of the present study, specific placental histopathological changes may be present in FGR placentae, which may reflect the effects of utero-placental insufficiency.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2015
Publisher: Wiley
Date: 15-12-2017
DOI: 10.1111/JPC.13808
Abstract: Fetal growth restriction (FGR) is associated with increased perinatal morbidity, mortality and long-term neurodevelopmental sequelae. The objective of this study was to examine whether information about early neurodevelopmental deficits was evident using three-dimensional head ultrasound and developmental assessments in preterm infants with FGR, compared with appropriate for gestational age (AGA) infants in the early post-natal period. Twenty preterm FGR infants weighing <10th centile and born between 28 and 32 weeks were compared with age-matched AGA infants. In the second post-natal week after birth, we used three-dimensional ultrasound to assess cerebral ventricular volumes. Prechtl General Movement Assessments were performed at 4-6 weeks after birth. Test of Infant Motor Performance (TIMP) to measure functional motor behaviour was performed at 4-6 and 12-14 weeks corrected age. There was no statistically significant difference in the combined cerebral ventricular volume between the two groups (FGR, 0.81 ± 0.42 vs. AGA 0.72 ± 0.38 cm Ultrasound in the early weeks may be useful to detect the neuropathology which could then mediate functional consequences.
Publisher: Frontiers Media SA
Date: 25-10-2018
Publisher: Frontiers Media SA
Date: 04-06-2018
Publisher: BMJ
Date: 23-11-2022
DOI: 10.1136/ARCHDISCHILD-2022-324695
Abstract: Antenatal inflammation, usually associated with chorioamnionitis, is a major cause of premature birth. As inflammation could depress respiratory drive, we have examined the effect of clinical chorioamnionitis (CCA) on spontaneous breathing in premature infants at birth. Infants with CCA born weeks’ gestation were matched with control infants based on gestational age (±6 days), birth weight (±300 g), antenatal corticosteroids, sex and general anaesthesia. The primary outcome was breathing effort, assessed as minute volume (MV) of spontaneous breathing. We also measured tidal volume (Vt), respiratory rate (RR) and apnoea in the first 5 min and additional physiological parameters in the first 10 min after start of respiratory support. Ninety-two infants were included (n=46 CCA infants vs n=46 controls median (IQR) gestational age 26 +4 (25 +0 –27 +6 ) vs 26 +6 (25 +1 –28 +3 ) weeks). MV and Vt were significantly lower (MV: 43 (17–93) vs 70 (31–119) mL/kg/min, p=0.043 Vt: 2.6 (1.9–3.6) vs 2.9 (2.2–4.8) mL/kg/breath, p=0.046), whereas RR was similar in CCA infants compared with controls. Incidence of apnoea was higher (5 (2-6) vs 2 (1-4), p=0.002), and total duration of apnoea was longer (90 (21-139) vs 35 (12-98) s, p=0.025) in CCA infants. CCA infants took significantly longer to reach an oxygen saturation % (3:37 (2:10–4:29) vs 2:25 (1:06–3:52) min, p=0.016) and had a lower oxygen saturation at 5 min (77 (66–92) vs 91 (68–94) %, p=0.028), despite receiving more oxygen (62 (48-76) vs 54 (43-73) %, p=0.036). CCA is associated with reduced breathing effort and oxygenation in premature infants at birth.
Publisher: Cambridge University Press (CUP)
Date: 23-01-2013
DOI: 10.1017/S204017441200075X
Abstract: Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40–42 days of gestation (dG). There was no consistent effect on fetal weight, or in idual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.
Publisher: Cambridge University Press (CUP)
Date: 09-08-2017
DOI: 10.1017/S204017441700037X
Abstract: Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGR VENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGR VENT and AG VENT lambs. Abnormalities in the neurovascular unit and increased blood–brain barrier permeability were observed in FGR VENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero .
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/JAPPLPHYSIOL.01336.2009
Abstract: Chorioamnionitis increases the risk and severity of persistent pulmonary hypertension of the newborn in preterm infants. Exposure of preterm fetal lambs to intra-amniotic (IA) lipopolysaccharide (LPS) induces chorioamnionitis, causes hypertrophy of pulmonary resistance arterioles, and alters expression of pulmonary vascular growth proteins. We investigated the cardiopulmonary and systemic hemodynamic consequences of IA LPS in preterm lambs. Pregnant ewes received IA injection of LPS ( n = 6) or saline (controls n = 8) at 122 days gestation, 7 days before exteriorization, instrumentation, and delivery of the fetus with pulmonary and systemic flow probes and catheters at 129 days gestation. Newborn lambs were ventilated, targeting a tidal volume of 6–7 ml/kg and a positive end-expiratory pressure (PEEP) of 4 cmH 2 O. At 30 min, all lambs underwent a PEEP challenge: PEEP was increased by 2 cmH 2 O at 10-min intervals to 10 cmH 2 O and then decreased similarly to 4 cmH 2 O. Ventilation parameters, arterial blood flows, and pressures were recorded in real-time for 90 min. LPS lambs had higher total protein in bronchoalveolar lavage fluid ( P 0.002), increased medial thickness of arteriolar walls ( P = 0.013), and right ventricular hypertrophy ( P = 0.012). Compared with controls, LPS lambs had worse oxygenation ( P 0.001), decreased pulmonary blood flow ( P = 0.05), and higher pulsatility index ( P 0.001) and pulmonary ( P 0.001) and systemic arterial pressures ( P = 0.005) than controls. Intra-amniotic LPS increased right-to-left shunting across the ductus arteriosus ( P = 0.018) and decreased left ventricular output ( P 0.001). We conclude that inflammation and pulmonary remodeling induced by IA LPS adversely alters pulmonary hemodynamics with subsequent cardiovascular and systemic sequelae, which may predispose the preterm lamb to persistent pulmonary hypertension of the newborn.
Publisher: American Physiological Society
Date: 02-2012
DOI: 10.1152/JAPPLPHYSIOL.00995.2011
Abstract: Cerebral blood flow disturbance is a major contributor to brain injury in the preterm infant. The initiation of ventilation may be a critical time for cerebral hemodynamic disturbance leading to brain injury in preterm infants, particularly if they are exposed to inflammation in utero. We aimed to determine whether exposure to inflammation in utero alters cardiopulmonary hemodynamics, resulting in cerebral hemodynamic disturbance and related brain injury during the initiation of ventilation. Furthermore, we aimed to determine whether inflammation in utero alters the cerebral hemodynamic response to challenge induced by high mean airway pressures. Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) or saline either 2 or 4-days before preterm delivery (at 128 ± 1 days of gestation). Lambs were surgically instrumented for assessment of pulmonary and cerebral hemodynamics before delivery and positive pressure ventilation. After 30 min, lambs were challenged hemodynamically by incrementing and decrementing positive end-expiratory pressure. Blood gases, arterial pressures, and blood flows were recorded. The brain was collected for biochemical and histological assessment of inflammation, brain damage, vascular extravasation, hemorrhage, and oxidative injury. Carotid arterial pressure was higher and carotid blood flow was more variable in 2-day LPS lambs than in controls during the initial 15 min of ventilation. All lambs responded similarly to the hemodynamic challenge. Both 2- and 4-day LPS lambs had increased brain interleukin (IL)-1β, IL-6, and IL-8 mRNA expression increased number of inflammatory cells in the white matter increased incidence and severity of brain damage and vascular extravasation relative to controls. Microvascular hemorrhage was increased in 2-day LPS lambs compared with controls. Cerebral oxidative injury was not different between groups. Antenatal inflammation causes adverse cerebral hemodynamics and increases the incidence and severity of brain injury in ventilated preterm lambs.
Publisher: Springer Science and Business Media LLC
Date: 15-12-2014
DOI: 10.1038/PR.2014.174
Publisher: Springer Science and Business Media LLC
Date: 17-01-2014
DOI: 10.1038/PR.2014.3
Abstract: Intra-amniotic lipopolysaccharide (LPS) exposure may affect neonatal outcome by altering fetal lung and immune system development. We hypothesized that intra-amniotic LPS exposure would cause persistent fetal pulmonary responses as the lungs develop in utero. Fetal lambs were exposed to intra-amniotic LPS at 118 or at 118 and 123 d of gestational age (GA) with delivery at 125, 133, or 140 d (term = 147 d). Immune responses, PU.1 expression, Toll-like receptor (TLR)-1,2,4,6 mRNA levels, mast cell levels, and pulmonary elastin deposition were evaluated. After a single dose of LPS, pulmonary inflammatory responses were observed with increases of (i) PU.1 and TLR1 at 125 d GA and (ii) monocytes, lymphocytes, TLR2, and TLR6 at 133 d GA. Repetitive LPS exposure resulted in (i) increases of neutrophils, monocytes, PU.1, and TLR1 at 125 d GA (ii) increases of neutrophils, PU.1, and TLR2 at 133 d GA and (iii) decreases of mast cells, elastin foci, TLR4, and TLR6 at early gestation. At 140 d GA, only PU.1 was increased after repetitive LPS exposure. The preterm fetal lung can respond to a single exposure or repeated exposures from intra-amniotic LPS in multiple ways, but the absence of inflammatory and structural changes in LPS-exposed fetuses delivered near term suggest that the fetus can resolve an inflammatory stimulus in utero with time.
Publisher: Public Library of Science (PLoS)
Date: 14-01-2016
Publisher: American Physiological Society
Date: 11-2020
DOI: 10.1152/JAPPLPHYSIOL.00652.2020
Abstract: An increase of positive end-expiratory pressure (PEEP) from 5 to 10 cmH2O increased the diameter of small cerebral vessels ( µm) but decreased the diameter of larger cerebral vessels ( µm). This suggests increased intrathoracic pressure due to high PEEP can drive microvessel engorgement in the preterm brain, which may play a role in cerebrovascular injury.
Publisher: Bioscientifica
Date: 02-2017
DOI: 10.1530/JOE-16-0300
Abstract: Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic cl ) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, β-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males ( P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 ( P = 0.019), PRKAA2 ( P = 0.021) and PRKAG2 ( P = 0.049) expression was greater in preterm than in term overall and in males, while INSR ( P = 0.047) and AKT2 ( P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se .
Publisher: Frontiers Media SA
Date: 30-07-2020
Publisher: Springer Science and Business Media LLC
Date: 15-02-2014
Abstract: Sustained inflations (SI) are advocated for the rapid establishment of FRC after birth in preterm and term infants requiring resuscitation. However, the most appropriate way to deliver a SI is poorly understood. We investigated whether a volume-limited SI improved the establishment of FRC and ventilation homogeneity and reduced lung inflammation/injury compared to a pressure-limited SI. 131 d gestation lambs were resuscitated with either: i) pressure-limited SI (PressSI: 0-40 cmH 2 O over 5 s, maintained until 20 s) or ii) volume-limited SI (VolSI: 0-15 mL/kg over 5 s, maintained until 20 s). Following the SI, all lambs were ventilated using volume-controlled ventilation (7 mL/kg tidal volume) for 15 min. Lung mechanics, regional ventilation distribution (electrical impedance tomography), cerebral tissue oxygenation index (near infrared spectroscopy), arterial pressures and blood gas values were recorded regularly. Pressure-volume curves were performed in-situ post-mortem and early markers of lung injury were assessed. Compared to a pressure-limited SI, a volume-limited SI had increased pressure variability but reduced volume variability. Each SI strategy achieved similar end-inflation lung volumes and regional ventilation homogeneity. Volume-limited SI increased heart-rate and arterial pressure faster than pressure-limited SI lambs, but no differences were observed after 30 s. Volume-limited SI had increased arterial-alveolar oxygen difference due to higher FiO 2 at 15 min (p = 0.01 and p = 0.02 respectively). No other inter-group differences in arterial or cerebral oxygenation, blood pressures or early markers of lung injury were evident. With the exception of inferior oxygenation, a sustained inflation targeting delivery to preterm lambs of 15 mL/kg volume by 5 s did not influence physiological variables or early markers of lung inflammation and injury at 15 min compared to a standard pressure-limited sustained inflation.
Publisher: Wiley
Date: 09-11-2018
DOI: 10.1113/EP086494
Publisher: BMJ
Date: 30-11-2018
DOI: 10.1136/ARCHDISCHILD-2017-313657
Abstract: Physiologically based cord cl ing (PBCC) has advantages over immediate cord cl ing (ICC) during preterm delivery, but its efficacy in asphyxiated infants is not known. We investigated the physiology of PBCC following perinatal asphyxia in near-term lambs. Near-term sheep fetuses (139±2 (SD) days’ gestation) were instrumented to measure umbilical, carotid, pulmonary and femoral arterial flows and pressures. Systemic and cerebral oxygenation was recorded using pulse oximetry and near-infrared spectroscopy, respectively. Fetal asphyxia was induced until mean blood pressure reached ~20 mm Hg, where lambs underwent ICC and initiation of ventilation (n=7), or ventilation for 15 min prior to umbilical cord cl ing (PBCC n=8). Cardiovascular parameters were measured and white and grey matter microvascular integrity assessed using qRT-PCR and immunohistochemistry. PBCC restored oxygenation and cardiac output at the same rate and in a similar fashion to lambs resuscitated following ICC. However, ICC lambs had a rapid and marked overshoot in mean systemic arterial blood pressure from 1 to 10 min after ventilation onset, which was largely absent in PBCC lambs. ICC lambs had increased cerebrovascular injury, as indicated by reduced expression of blood–brain barrier proteins and increased cerebrovascular protein leakage in the subcortical white matter (by 86%) and grey matter (by 47%). PBCC restored cardiac output and oxygenation in an identical time frame as ICC, but greatly mitigated the postasphyxia rebound hypertension measured in ICC lambs. This likely protected the asphyxiated brain from cerebrovascular injury. PBCC may be a more suitable option for the resuscitation of the asphyxiated newborn compared with the current standard of ICC.
Publisher: BMJ
Date: 03-2020
DOI: 10.1136/BMJOPEN-2019-034595
Abstract: Timing of cord cl ing and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord cl ing, and cord milking. In idual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks’ gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials aggregate summary data will be included where IPD are unavailable. First, deferred cl ing and cord milking will be compared with immediate cl ing in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases. Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640).
Publisher: Frontiers Media SA
Date: 16-10-2018
Publisher: Springer Science and Business Media LLC
Date: 16-05-2016
DOI: 10.1038/PR.2016.104
Abstract: Cardiovascular dysfunction at birth may underlie poor outcomes after fetal growth restriction (FGR) in neonates. We compared the cardiovascular transition between FGR and appropriately grown (AG) preterm lambs and examined possible mechanisms underlying any cardiovascular dysfunction in FGR lambs. FGR was induced in ewes bearing twins at 0.7 gestation the twin was used as an internal control (AG). At 0.8 gestation, lambs were delivered and either euthanized with their arteries isolated for in vitro wire myography, or ventilated for 2 h. At 60 min, inhaled nitric oxide (iNO) was administered in a subgroup for 30 min. Molecular assessment of the nitric oxide (NO) pathway within lung tissue was conducted. FGR lambs had lower left ventricular output and cerebral blood flow (CBF) and higher systemic vascular resistance compared with AG lambs. INO administration to FGR lambs rapidly improved cardiovascular and systemic hemodynamics but resulted in decreased CBF in AG lambs. Isolated arteries from FGR lambs showed impaired sensitivity to NO donors, but enhanced vasodilation to Sildenafil and Sodium nitroprusside, and altered expression of components of the NO pathway. Cardiovascular dysfunction at birth may underlie the increased morbidity and mortality observed in preterm FGR newborns. Impaired NO signaling likely underlies the abnormal vascular reactivity.
Publisher: Public Library of Science (PLoS)
Date: 23-06-2022
DOI: 10.1371/JOURNAL.PMED.1004029
Abstract: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord cl ed early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord cl ing (PBCC) is cl ing the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. Between 4 July 2018 and 18 May 2021, infants born at ≥32 +0 weeks’ gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord cl ing. The comparator was early cord cl ing (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord cl ing (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised ( n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord cl ing occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference −6 bpm, 95% confidence interval (CI) −17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal–infant bonding and higher iron stores. In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32 +0 weeks’ gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213 .
Publisher: BMJ
Date: 10-07-2013
DOI: 10.1136/ARCHDISCHILD-2012-301787
Abstract: The 2010 ILCOR neonatal resuscitation guidelines do not specify appropriate inflation times for the initial lung inflations in apnoeic newborn infants. The authors compared three ventilation strategies immediately after delivery in asphyxiated newborn lambs. Experimental animal study. Facility for animal research. Eighteen near-term lambs (weight 3.5-3.9 kg) delivered by caesarean section. Asphyxia was induced by occluding the umbilical cord and delaying ventilation onset (10-11 min) until mean carotid blood pressure (CBP) was ≤22 mm Hg. Animals were ided into three groups (n=6) and ventilation started with: (1) inflation times of 0.5 s at a ventilation rate 60/min, (2) five 3 s inflations or (3) a single 30 s inflation. Subsequent ventilation used inflations at 0.5 s at 60/min for all groups. Times to reach a heart rate (HR) of 120 bpm and a mean CBP of 40 mm Hg. Secondary outcome was change in lung compliance. Median time to reach HR 120 bpm and mean CBP 40 mm Hg was significantly shorter in the single 30 s inflation group (8 s and 74 s) versus the 5×3 s inflation group (38 s and 466 s) and the conventional ventilation group (64 s and 264 s). Lung compliance was significantly better in the single 30 s inflation group. A single sustained inflation of 30 s immediately after birth improved speed of circulatory recovery and lung compliance in near-term asphyxiated lambs. This approach for neonatal resuscitation merits further investigation.
Publisher: Frontiers Media SA
Date: 22-01-2021
Abstract: Objective: Continuous positive airway pressures (CPAP) used to assist preterm infants at birth are limited to 4–8 cmH 2 O due to concerns that high-CPAP may cause pulmonary overexpansion and adversely affect the cardiovascular system. We investigated the effects of high-CPAP on pulmonary (PBF) and cerebral (CBF) blood flows and jugular vein pressure (JVP) after birth in preterm lambs. Methods: Preterm lambs instrumented with flow probes and catheters were delivered at 133/146 days gestation. Lambs received low-CPAP (LCPAP: 5 cmH 2 O), high-CPAP (HCPAP: 15 cmH 2 O) or dynamic HCPAP (15 decreasing to 8 cmH 2 O at ~2 cmH 2 O/min) for up to 30 min after birth. Results: Mean PBF was lower in the LCPAP [median (Q1–Q3) 202 (48–277) mL/min, p = 0.002] compared to HCPAP [315 (221–365) mL/min] and dynamic HCPAP [327 (269–376) mL/min] lambs. CBF was similar in LCPAP [65 (37–78) mL/min], HCPAP [73 (41–106) mL/min], and dynamic HCPAP [66 (52–81) mL/min, p = 0.174] lambs. JVP was similar at CPAPs of 5 [8.0 (5.1–12.4) mmHg], 8 [9.4 (5.3–13.4) mmHg], and 15 cmH 2 O [8.6 (6.9–10.5) mmHg, p = 0.909]. Heart rate was lower in the LCPAP [134 (101–174) bpm p = 0.028] compared to the HCPAP [173 (139–205)] and dynamic HCPAP [188 (161–207) bpm] groups. Ventilation or additional caffeine was required in 5/6 LCPAP, 1/6 HCPAP, and 5/7 dynamic HCPAP lambs ( p = 0.082), whereas 3/6 LCPAP, but no HCPAP lambs required intubation ( p = 0.041), and 1/6 LCPAP, but no HCPAP lambs developed a pneumothorax ( p = 0.632). Conclusion: High-CPAP did not impede the increase in PBF at birth and supported preterm lambs without affecting CBF and JVP.
Publisher: CSIRO Publishing
Date: 2006
DOI: 10.1071/RD05163
Abstract: Increased fetal lung expansion induces lung growth, cell differentiation and extracellular matrix remodelling, although the mechanisms involved are unknown. Platelet-derived growth factor (PDGF)-B, vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-II are mitogens activating the mitogen-activated protein kinase (MAPK) pathway, whereas transforming growth factor (TGF)-β1 induces differentiation and extracellular matrix remodelling. In the present study, we investigated the mRNA levels of PDGF-B, VEGF, IGF-II and TGF-β1, as well as active MAPK levels, during increased fetal lung expansion induced by tracheal obstruction (TO) in sheep for 0 (controls), 36 h or 2, 4, or 10 days (n = 5 in each group). The 3.7-kb VEGF transcript increased by 30% (P 0.05) at 36 h TO. The expression of PDGF-B decreased by approximately 25% (P 0.01) at 2–10 days TO. In contrast, TGF-β1 mRNA increased by 96% (P 0.05) at 10 days TO, when bioactive TGF-β1 decreased by 55% (P 0.05). Insulin-like growth factor-II mRNA tended to increase at 10 days TO (37% above controls P = 0.07), whereas mRNA for its receptor, IGF1R, was reduced by TO. There was no change in active MAPK levels preceding or at the time of a TO-induced 800% increase in cell proliferation. We conclude that VEGF is likely to promote expansion-induced endothelial cell proliferation, but the mechanisms underlying expansion-induced proliferation of fibroblasts and alveolar epithelial cells are unlikely to be mediated by increases in PDGF-B or IGF-II expression or activation of the MAPK pathway.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2010
Publisher: Wiley
Date: 11-08-2020
DOI: 10.1113/JP279248
Abstract: Fetal growth restriction induces a haemodynamic response that aims to maintain blood flow to vital organs such as the brain, in the face of chronic hypoxaemia Maternal sildenafil treatment impairs the hypoxaemia‐driven haemodynamic response and potentially compromises fetal development. Inadequate substrate delivery to a fetus results in hypoxaemia and fetal growth restriction (FGR). In response, fetal cardiovascular adaptations redirect cardiac output to essential organs to maintain oxygen delivery and sustain development. However, FGR infants remain at risk for cardiovascular and neurological sequelae. Sildenafil citrate (SC) has been examined as a clinical therapy for FGR, but also crosses the placenta and may exert direct effects on the fetus. We investigated the effects of maternal SC administration on maternal and fetal cardiovascular physiology in growth‐restricted fetal sheep. Fetal sheep (0.7 gestation) underwent sterile surgery to induce growth restriction by single umbilical artery ligation (SUAL) or sham surgery (control, AG). Fetal catheters and flow probes were implanted to measure carotid and femoral arterial blood flows. Ewes containing SUAL fetuses were randomized to receive either maternal administration of saline or SC (36 mg i.v . per day) beginning 4 days after surgery, and continuing for 20 days. Physiological recordings were obtained throughout the study. Antenatal SC treatment reduced body weight by 32% and oxygenation by 18% in SUAL compared to AG. SC did not alter maternal or fetal heart rate or blood pressure. Femoral blood flow and peripheral oxygen delivery were increased by 49% and 30% respectively in SUAL SC compared to SUAL, indicating impaired cardiovascular adaptation to chronic hypoxaemia. Antenatal SC directly impairs the fetal haemodynamic response to chronic hypoxaemia. Consideration of the consequences upon the fetus should be paramount when administering interventions to the mother during pregnancy.
Publisher: American Physiological Society
Date: 02-2011
DOI: 10.1152/AJPLUNG.00294.2010
Abstract: Mechanical ventilation is a risk factor for the development of bronchopulmonary dysplasia in premature infants. Fifteen minutes of high tidal volume (Vt) ventilation induces inflammatory cytokine expression in small airways and lung parenchyma within 3 h. Our objective was to describe the temporal progression of cytokine and maturation responses to lung injury in fetal sheep exposed to a defined 15-min stretch injury. After maternal anesthesia and hysterotomy, 129-day gestation fetal lambs ( n = 7–8/group) had the head and chest exteriorized. Each fetus was intubated, and airway fluid was gently removed. While placental support was maintained, the fetus received ventilation with an escalating Vt to 15 ml/kg without positive end-expiratory pressure (PEEP) for 15 min using heated, humidified 100% nitrogen. The fetus was then returned to the uterus for 1, 6, or 24 h. Control lambs received a PEEP of 2 cmH 2 O for 15 min. Tissue s les from the lung and systemic organs were evaluated. Stretch injury increased the early response gene Egr-1 and increased expression of pro- and anti-inflammatory cytokines within 1 h. The injury induced granulocyte/macrophage colony-stimulating factor mRNA and matured monocytes to alveolar macrophages by 24 h. The mRNA for the surfactant proteins A, B, and C increased in the lungs by 24 h. The airway epithelium demonstrated dynamic changes in heat shock protein 70 (HSP70) over time. Serum cortisol levels did not increase, and induction of systemic inflammation was minimal. We conclude that a brief period of high Vt ventilation causes a proinflammatory cascade, a maturation of lung monocytic cells, and an induction of surfactant protein mRNA.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2011
DOI: 10.1007/S00134-011-2237-X
Abstract: In adult animals, ventilation with variable tidal volume and rate improves lung mechanics, arterial oxygenation and ventilation compared to a monotonously controlled ventilation pattern. We assessed the physiological consequences of variable ventilation in the immature lung. Lambs delivered at 129 days (term = 150 days) were euthanised (n = 9) or anaesthetised, tracheostomised and suctioned prior to prophylactic intra-tracheal surfactant instillation (Curosurf(®), 100 mg/kg) and commencement of controlled ventilation (50 breaths/min, tidal volume 7.7 ± 0.8 mL/kg). Volume history was standardised at 20 min with two sustained (3 s) inflations to 30 cmH(2)O followed immediately by measurement of baseline dynamic lung mechanics (FlexiVent, Scireq, Canada). Ventilation was continued according to prior randomisation (variable or conventional ventilation). For variable ventilation (n = 9), breath-to-breath tidal volume and respiratory rate varied but intra-breath minute volume (MV) and average tidal volume were equivalent to the conventional ventilation group with fixed tidal volume and rate (n = 7). Lung mechanics and gas exchange were measured at intervals. Lambs were euthanised at 2 h. Inflammatory cell counts and protein from bronchoalveolar lavage fluid and lung tissue cytokine mRNA were quantified. At study completion, PaCO(2) (p = 0.026) and mean airway pressure (p = 0.002) were lower and pH (p = 0.047), ventilation efficiency index (p = 0.021) and dynamic compliance were higher (p = 0.003) in lambs on variable rather than conventional ventilation. However, oxygenation indices and post-mortem static compliances were not different between groups. Variable ventilation improves ventilation efficiency and in vivo lung compliance in the preterm lung, but unlike adult models, had no effect on arterial oxygenation.
Publisher: Frontiers Media SA
Date: 10-11-2015
Publisher: Frontiers Media SA
Date: 05-04-2017
Start Date: 07-2012
End Date: 12-2014
Amount: $67,476.00
Funder: Australian Research Council
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