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Importance: Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. Objective(s): To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. Design, Setting, and Participant(s): This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks' gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Intervention(s): Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Main Outcomes and Measures: Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Result(s): Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in th

Background: Dopamine is frequently used as inotropic agent in preterm infants. Its cardiovascular actions, as well as effects on neurovascular interactions may be neuroprotective during hypoxic-ischaemic events. Using a preterm lamb model we aimed to test the impact of intravenous dopamine on hypoxic-ischaemic brain injury. Method(s): Nine fetal lambs (91-93d gestation) were instrumented with catheters in carotid artery and jugular vein, and an umbilical cord occluder. Four days after surgery, intravenous dopamine (DA, 10 mug/kg/ min, n = 5) (or saline, n = 4) was commenced. Then a hypoxic-ischaemic insult was induced with umbilical cord occlusion for 25 min. Infusions were continued for another 72 h before euthanasia. Fetal brains were collected for immunohistopathology. Result(s): Dopamine infusion increased fetal heart rate (184 +/- 1 to 203 +/- 1 bpm, P < 0.05) while arterial pressure was unchanged. Three animals in the DA group showed tachycardic response to cord occlusion, while the other two animals showed bradycardic response similar to the saline group. In the periventricular white matter, the saline group had higher number of microglia (lectin positive) than the DA group (10 +/- 3 vs. 6 +/- 2 per 0.04 mm2, P < 0.05). The saline group tended to have shorter myelinated fibre lengths (CNPase) compared with the DA group (15.0 +/- 2.0 vs. 18.4 +/- 5.7 mum respectively, P = ns). No histological differences were evident between DA animals exhibiting a tachycardic or bradycardic response during cord occlusion. Conclusion(s): Intravenous dopamine reduces hypoxic-ischaemic white matter injury in preterm lambs, independent of the cardiovascular response during the hypoxic-ischaemia., F.Y. Wong, Ritchie Centre, MIMR, Monash University, Melbourne, VIC, Australia. E-mail: flora.wong@med.monash.edu.au, CONFERENCE ABSTRACT

Therapeutic hypothermia (TH) is standard care in high-resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 +/- 3 mm Hg in sham controls to 18-20 mm Hg (10.1 +/- 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole-body cooling to 35.1 +/- 0.8degreeC vs. 38.3 +/- 0.17degreeC in sham controls, from 4-28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P =.003) and reduced NAA:Choline (P =.005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P <.05), and increased neuroinflammation and oxidative stress (P <.05). TH and MLT were independently associated with region-specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.Copyright © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background: In the adult brain, increases in neural activity lead to increases in local blood flow. However, in the preterm neonate, studies of cerebral functional haemodynamics have yielded inconsistent results, including negative responses suggesting decreased perfusion and localised tissue hypoxia, probably due to immature neurovascular coupling. Furthermore, the impact of vasoactive medications, such as dopamine and dobutamine used as inotropic therapies in preterm neonates, on cerebrovascular responses to somatosensory input is unknown. We aimed to characterise the cerebral haemodynamic functional response after somatosensory stimulation in the preterm newborn brain, with and without dopamine or dobutamine treatment. Method(s): We studied the cerebral haemodynamic functional response in 13 anaesthetised preterm lambs, using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (DELTAoxyHb, DELTAdeoxyHb) following left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. The 4.8 and 7.8 s stimulations were repeated during dopamine or dobutamine infusion. Result(s): Stimulation always produced a somatosensory evoked response. Majority of preterm lambs demonstrated positive functional responses (i.e. increased DELTAoxyHb) in the contralateral cortex following stimulus trains of all durations. Dopamine increased baseline oxyHb and total Hb, whereas dobutamine increased baseline deoxyHb. Both dopamine and dobutamine reduced the evoked DELTAoxyHb responses to 4.8 and 7.8 s stimulations. Conclusion(s): Somatosensory stimulation increases cerebral oxygenation in the preterm brain, consistent with increased cerebral blood flow due to neurovascular coupling. Notably, our results show that dopamine/dobutamine reduces oxygen delivery relative to consumption in the preterm brain during somatosensory stimulations, suggesting there may be a risk of intermittent localised tissue hypoxia which has clear implications for clinical pr

Background: Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally. Method(s): Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs. Result(s): The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean +/- SEM: 0.445 +/- 0.01 vs 0.388 +/- 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA. Conclusion(s): The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA. Impact: The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear.Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age.Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age.Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.Copyright © 2021, The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.

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 microm 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 microm. 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.Copyright © The Author(s) 2021.

Study Objectives: Preterm infants undergoing intensive care are often placed prone to improve respiratory function. Current clinical guidelines recommend preterm infants are slept supine from 32 weeks' postmenstrual age, regardless of gestational age at birth. However, respiratory function is also related to gestational and chronological ages and is affected by sleep state. We aimed to identify the optimal timing for adopting the supine sleeping position in preterm infants, using a longitudinal design assessing the effects of sleep position and state on cardiorespiratory stability. Method(s): Twenty-three extremely (24-28 weeks' gestation) and 33 very preterm (29-34 weeks' gestation) infants were studied weekly from birth until discharge, in both prone and supine positions, in quiet and active sleep determined by behavioral scoring. Bradycardia (heart rate <=100 bpm), desaturation (oxygen saturation <=80%), and apnea (pause in respiratory rate >=10 s) episodes were analyzed. Result(s): Prone positioning in extremely preterm infants reduced the frequency of bradycardias and desaturations and duration of desaturations. In very preterm infants, prone positioning only reduced the frequency of desaturations. The position-related effects were not related to postmenstrual age. Quiet sleep in both preterm groups was associated with fewer bradycardias and desaturations, and also reduced durations of bradycardia and desaturations in the very preterm group. Conclusion(s): Cardiorespiratory stability is improved by the prone sleep position, predominantly in extremely preterm infants, and the improvements are not dependent on postmenstrual age. In very preterm infants, quiet sleep has a more marked effect than the prone position. This evidence should be considered in individualizing management of preterm infant positioning.Copyright © Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved.

Disturbed fetal haemodynamics often affects cardiac development and leads to congenital cardiac defects. Reduced left ventricular (LV) preload in the fetus may result in hypoplastic LV, mitral and aortic valve, mimicking a moderate form of hypoplastic left heart complex. We aimed to induce LV hypoplasia by occluding the foramen ovale (FO) to reduce LV preload in the fetal sheep heart, using percutaneous trans-hepatic catheterisation. Under maternal anaesthesia and ultrasound guidance, hepatic venous puncture was performed in six fetal lambs (0.7-0.75 gestation). A coronary guidewire was advanced into the fetal inferior vena cava, right and left atrium. A self-expandable stent was positioned across the FO. An Amplatzer Duct Occluder was anchored within the stent for FO occlusion. Euthanasia and post-mortem examination was performed after 3 weeks. Nine fetuses were used as age-matched controls. Morphometric measurements and cardiac histopathology were performed. Compared with controls, fetal hearts with occluded FO had smaller LV chamber, smaller mitral and aortic valves, lower LV-to-RV ratio in ventricular weight and wall volume, and lower number of LV cardiomyocyte nuclei. We conclude that fetal FO occlusion leads to a phenotype simulating LV hypoplasia. This large animal model may be useful for understanding and devising therapies for LV hypoplasia.

Mitochondrial disorders are clinically heterogeneous and comprise over 350 different genetic conditions. However, the molecular diagnosis is unknown in ~50% of cases, partly due to some genomic regions being refractory to standard genomic analysis. One such region is the ATAD3 locus consisting of 3 highly homologous tandemly arrayed genes (ATAD3C, ATAD3B and ATAD3A) encoding mitochondrial proteins implicated in processes including cholesterol metabolism, and mitochondrial replication, dynamics and morphology. Recessive deletions and dominant duplications in this locus have recently been reported to cause rare, lethal perinatal mitochondrial disorders characterised by pontocerebellar hypoplasia or cardiomyopathy, respectively. We report 17 subjects from 16 unrelated families with cardiomyopathy, persistent hyperlactacidemia, encephalopathy and frequently corneal clouding or cataracts due to de novo ATAD3 duplications. The six different 68 Kb duplications were consistently identifiable from whole genome and exome sequencing, but usually missed on microarray. The duplications all resulted in the formation of an identical chimeric ATAD3A/ATAD3C fusion protein, which appears to act in a dominant manner causing altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. In our experience, the ATAD3 locus is one of the five most common causes of nuclear-encoded paediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies.

Positive end-expiratory pressure (PEEP) improves oxygenation in mechanically ventilated preterm neonates by preventing lung collapse. However, high PEEP may alter cerebral blood flow secondarily to the increased intrathoracic pressure, predisposing to brain injury. The precise effects of high PEEP on cerebral hemodynamics in the preterm brain are unknown. We aimed to assess the effect of PEEP on microvessels in the preterm brain by using synchrotron radiation (SR) microangiography, which enables in vivo real-time high-resolution imaging of the cerebral vasculature. Preterm lambs (0.8 gestation, n = 4) were delivered via caesarean section, anesthetized, and ventilated. SR microangiography of the right cerebral hemisphere was performed with iodine contrast administered into the right carotid artery during PEEP ventilation of 5 and 10 cmH2O. Carotid blood flow was measured using an ultrasonic flow probe placed around the left carotid artery. An increase of PEEP from 5 to 10 cmH2O increased the diameter of small cerebral vessels (<150 microm) but decreased the diameter of larger cerebral vessels (>500 microm) in all four lambs. Additionally, the higher PEEP increased the cerebral contrast transit time in three of the four lambs. Carotid blood flow increased in two lambs, which also had increased carbon dioxide levels during PEEP 10. Our results suggest that PEEP of 10 cmH2O alters the preterm cerebral hemodynamics, with prolonged cerebral blood flow transit and engorgement of small cerebral microvessels likely due to the increased intrathoracic pressure. These microvascular changes are generally not reflected in global assessment of cerebral blood flow or oxygenation.NEW & NOTEWORTHY An increase of positive end-expiratory pressure (PEEP) from 5 to 10 cmH2O increased the diameter of small cerebral vessels (<150 microm) but decreased the diameter of larger cerebral vessels (>500 microm). This suggests increased intrathoracic pressure due to high PEEP can drive microvessel

Background: Preterm infants undergoing intensive care often experience painful procedures such as heel lance for blood sampling. Knowledge of the cerebral hemodynamic response to painful stimuli contributes to understanding of cortical pain processing and the neurovascular network in the preterm brain. Previous research has demonstrated cerebral hemodynamic responses using near-infrared spectroscopy (NIRS) after noxious stimuli in infants appropriately grown for age (AGA). But this has not been studied in infants born small for gestational age after fetal growth restriction (FGR). FGR infants differ in brain development due to utero-placental insufficiency leading to the intrauterine growth restriction, and cerebral response to pain may be altered. Objective(s): We aimed to compare the cerebral hemodynamic response to painful stimuli (heel lance) in FGR and AGA infants. Method(s): Preterm FGR infants (n = 20) and AGA infants (n = 15) born at 28-32 weeks' gestation were studied at mean +/- SD postnatal age of 11.5 +/- 2.4 and 10.5 +/- 2.4 days, respectively. Infants had baseline echocardiographic assessment of ductus arteriosus and stroke volume. They were monitored with NIRS for changes in tissue oxygenation index (TOI, %), and oxygenated, deoxygenated, and total hemoglobin (DELTAO2Hb, DELTAHHb, and DELTATHb) in contralateral and ipsilateral cerebral hemispheres, during a heel lance. Result(s): At baseline, FGR infants had significantly lower TOI, higher heart rate, and lower stroke volume compared to AGA infants. Most infants in both groups showed increase in each of the NIRS parameters in the contralateral hemisphere following heel lance. However, more AGA infants (6/15) showed decreased DELTATHb compared to FGR infants (1/20) (p = 0.016). The magnitude of cerebral hemodynamic response and time to response did not differ between FGR and AGA infants. FGR infants showed larger DELTAO2Hb in the contralateral compared to ipsilateral cortex (p = 0.05). Conclusion(s): P

There are no publications reporting on scan duration and Doppler use during neonatal cranial ultrasound scans. We investigated current practice of neonatal cranial ultrasound at four large tertiary neonatal intensive care units in Australia. Cranial scans were prospectively recorded between March 2015 and November 2016. Variables, including total number of scans, scan duration and frequency and duration of colour and spectral Doppler mode, were extracted. A total of 196 scans formed the final cohort. The median (range) number of scans for each neonate was 1 (1-12). The median (range) overall total scan duration was 309 (119-801) s. Colour mode with or without spectral Doppler mode was used in approximately half of the cohort (106/196, 54%). Our findings comport with our hypotheses. Operators performing neonatal cranial scans in Australia have low overall scan durations. Although the use of Doppler mode during neonatal cranial scans is not standard practice in all neonatal intensive care units, it is used widely irrespective of the degree of prematurity or the presence of brain pathology. Further efforts are required to incorporate recommendations on scan duration and the routine use of Doppler mode during neonatal cranial scans. This is especially imperative given that the most vulnerable neonates with the greater neural tissue sensitivity are likely to be scanned more often.Copyright © 2020

Study Objectives: Preterm infants undergoing intensive care are often placed prone to improve respiratory function. Current clinical guidelines recommend preterm infants are slept supine from 32 weeks' postmenstrual age, regardless of gestational age at birth. However, respiratory function is also related to gestational and chronological ages and is affected by sleep state. We aimed to identify the optimal timing for adopting the supine sleeping position in preterm infants, using a longitudinal design assessing the effects of sleep position and state on cardiorespiratory stability. Method(s): Twenty-three extremely (24-28 weeks' gestation) and 33 very preterm (29-34 weeks' gestation) infants were studied weekly from birth until discharge, in both prone and supine positions, in quiet and active sleep determined by behavioral scoring. Bradycardia (heart rate <=100 bpm), desaturation (oxygen saturation <=80%), and apnea (pause in respiratory rate >=10 s) episodes were analyzed. Result(s): Prone positioning in extremely preterm infants reduced the frequency of bradycardias and desaturations and duration of desaturations. In very preterm infants, prone positioning only reduced the frequency of desaturations. The position-related effects were not related to postmenstrual age. Quiet sleep in both preterm groups was associated with fewer bradycardias and desaturations, and also reduced durations of bradycardia and desaturations in the very preterm group. Conclusion(s): Cardiorespiratory stability is improved by the prone sleep position, predominantly in extremely preterm infants, and the improvements are not dependent on postmenstrual age. In very preterm infants, quiet sleep has a more marked effect than the prone position. This evidence should be considered in individualizing management of preterm infant positioning.Copyright © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society.

Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired autoregulation. There is evidence that systemically administered dopamine crosses the preterm blood-brain barrier. However, the effects of exogenous dopamine and cerebral HI on dopaminergic signaling in the immature brain are unknown. We determined the effect of HI and dopamine on D1 and D2 receptor binding and expressions of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum of the preterm fetal sheep. Fetal sheep (99 days of gestation, term=147days) were unoperated controls (n = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, n = 8) or to HI with dopamine infusion (UCO + dopamine, 10 microg/kg/min, n = 7) for 74 h. D1 and D2 receptor densities were measured by autoradiography in vitro. DAT, TH, and cell death were measured using immunohistochemistry. HI resulted in cell death in the caudate nucleus and putamen, and dopamine infusion started before HI did not exacerbate or ameliorate these effects. HI led to reduced D1 and D2 receptor densities in the caudate nucleus and reduction in DAT protein expression in the caudate and putamen. Fetal brains exposed to dopamine in addition to HI were not different from those exposed to HI alone in these changes in dopaminergic parameters. We conclude that dopamine infusion does not alter the striatal cell death or the reductions in D1 and D2 receptor densities and DAT protein expression induced by HI in the preterm brain.NEW & NOTEWORTHY This is the first study on the effects of hypoxia-ischemia and dopamine treatment on the dopaminergic pathway in the preterm brain. In the striatum of fetal sheep (equivalent to ~26-28 wk of human gestation), we demonstrate that hypoxia-ischemia leads to cell death, reduces D1 and D2 receptors, and reduces dopamine transporter. Intravenous dopamine infusion at clinical d

Background: Neurovascular coupling (NVC) leads to increased local cerebral blood flow and oxygenation to meet the increased metabolic demand of neural activity. We showed that cerebral oxygenation increased after somatosensory stimulations in preterm lambs (Wiersma et al PSANZ 2019). Impaired NVC may lead to reduced cerebral oxygenation and cerebral hypoxic injury when neural activity is increased. Intrauterine inflammation, which manifests as chorioamnionitis, is a major contributor to preterm brain injury. We compared the cerebral haemodynamic functional response in preterm lambs with and without exposure to intra-uterine inflammation, by measuring changes in cerebral oxy-and deoxy-haemoglobin (DELTAoxyHb, DELTAdeoxyHb) using near infrared spectroscopy (NIRS). Method(s): Pregnant ewes (119-121 days' gestation) were given intra-amniotic injection of lipo-polysaccharide (10 mg). After seven days, preterm lambs were delivered and ventilated under isoflurane anaesthesia. Scalp EEG and NIRS optodes were positioned bilaterally over the somatosensory cortex. Using a cuff electrode, the left median nerve was stimulated by trains (1.8, 4.8, 7.8 s duration) of pulses (3-8 mA, 2 msec). TheDELTAoxyHb andDELTAdeoxyHb were recorded. Result(s): Stimulation for 1.8 s, 4.8 s and 7.8 s durations increased DELTAoxyHb in the contralateral cortex in four (50%), three (38%) and four (50%) of the eight preterm lambs respectively, while the remaining lambs showed decreased DELTAoxyHb (negative cerebral haemodynamic response). Conclusion(s): Somatosensory stimulations decreased cerebral oxygenation in 50-60% of preterm lambs exposed to intrauterine inflammation, contrasting with our previous findings in control preterm lambs in which 90% showed increased cerebral oxygenation. Impaired NVC leading to repeated cerebral hypoxia may underlie the neuropathy in infants with chorioamnionitis.

Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine (DB) or dopamine (DA). This may be because of altered cardiac adrenoceptor expression because of tissue HI or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without DB/DA treatment on cardiac adrenoceptor expression in preterm fetal sheep. Fetal sheep (93-95 days) exposed to sham surgery or severe HI induced by umbilical cord occlusion received intravenous DB or saline for 74 h (HI + DB, HI, Sham + DB, Sham). The HI groups were also compared with fetal sheep exposed to HI and DA. Fetal hearts were collected to determine beta-adrenoceptor numbers using [125I]-cyanopindolol binding and mRNA expression of beta1-, beta2-, alpha1A-, alpha2A-, or alpha2B-adrenoceptors. The HI group had increased beta-adrenoceptor numbers compared with all other groups in all four heart chambers ( P < 0.05). This increase in beta-adrenoceptor numbers in the HI group was significantly reduced by DB infusion in all four heart chambers, but DA infusion in the HI group only reduced beta-adrenoceptor numbers in the left atria and ventricle. DB alone did not affect beta-adrenoceptor numbers in the sham animals. Changes in beta1-adrenoceptor mRNA levels trended to parallel the binding results. We conclude that HI upregulates preterm fetal cardiac beta-adrenoceptors, but prolonged exposure to adrenergic agonists downregulates adrenoceptors in the preterm heart exposed to HI and may underpin the frequent failure of inotropic therapy in preterm infants. NEW & NOTEWORTHY This is the first study, to our knowledge, on the effects of hypoxia-ischemia and adrenergic agonists on adrenoceptors in the preterm heart. In fetal sheep, we demonstrate that hypoxia-ischemia increases cardiac beta-adrenoceptor numbe

Background: Preterm infants in NICU are often placed prone to improve respiratory function. Clinical guidelines recommend preterm infants are slept supine at >32 weeks of postmentrual age. However, neonatal respiratory disease is related to gestational and postnatal age rather than postmentrual age. We investigated the effects of sleep position on bradycardias and desaturations in preterm infants, in relation to gestational and postnatal age, taking into account the sleep states. Method(s): Twenty-three extremely preterm (24-28 weeks' gestation) and 33 very preterm(29-34 weeks' gestation) infants were studied weekly until discharge, in prone and supine positions, in active (AS) and quiet sleep (QS). Episodes of bradycardia (heart rate <= 100 bpm) and desaturation (arterial oxygen saturation, SaO2 <= 80%) were analysed. Two-way RM ANOVA assessed the effect of sleep position/state at each postnatal week. Mixed-model analysis assessed overall effects of sleep position/state with postnatal age. Result(s): In extremely preterm infants, bradycardias were overall more frequent in supine than prone, and in AS than QS. Desaturations were more frequent and longer when supine during weeks 1, 2 and 6, but were not affected by sleep state. In contrast, in very preterm infants, bradycardia frequency was not affected by sleep position but was higher in AS. Desaturation frequency and duration were greater in supine only at week 3, and desaturation frequency was higher in AS during weeks 1-4. Conclusion(s): In extremely preterm infants, the prone position is associated with less bradycardias and desaturations, whilst in very preterm infants, respiratory events are less affected by sleep position, but increased with AS.

Neonatal hypoxic ischemic encephalopathy (HIE) resulting from intrapartum asphyxia is a global problem that causes severe disabilities and up to 1 million deaths annually. A variant form of activated protein C, 3K3A-APC, has cytoprotective properties that attenuate brain injury in models of adult stroke. In this study, we compared the ability of 3K3A-APC and APC (wild-type (wt)) to attenuate neonatal brain injury, using the spiny mouse (Acomys cahirinus) model of intrapartum asphyxia. Pups were delivered at 38 days of gestation (term = 39 days), with an intrapartum hypoxic insult of 7.5 min (intrapartum asphyxia cohort), or immediate removal from the uterus (control cohort). After 1 h, pups received a subcutaneous injection of 3K3A-APC or wild-type APC (wtAPC) at 7 mg/kg, or vehicle (saline). At 24 h of age, pups were killed and brain tissue was collected for measurement of inflammation and cell death using RT-qPCR and histopathology. Intrapartum asphyxia increased weight loss, inflammation, and apoptosis/necrosis in the newborn brain. 3K3A-APC administration maintained body weight and ameliorated an asphyxia-induced increase of TGFbeta1 messenger RNA expression in the cerebral cortex, immune cell aggregation in the corpus callosum, and cell death in the deep gray matter and hippocampus. In the cortex, 3K3A-APC appeared to exacerbate the immune response to the hypoxic ischemic insult. While wtAPC reduced cell death in the corpus callosum and hippocampus following intrapartum asphyxia, it increased markers of neuro-inflammation and cell death in control pups. These findings suggest 3K3A-APC administration may be a useful therapy to reduce cell death and neonatal brain injury associated with HIE.Copyright © 2018, The American Society for Experimental NeuroTherapeutics, Inc.

Objective: To investigate the relationship between growth, nutritional and fluid intake in the first month of life and the likelihood of developing bronchopulmonary dysplasia. Design & Settings: This is a retrospective case-control study conducted in a tertiary perinatal centre between January 2011 and December 2013. Patient(s): Thirty-three preterm infants without bronchopulmonary dysplasia (BPD) were identified and matched with those with BPD, based on period of birth within a cohort of infants with a birth weight of <=1000 g and gestational age <=28 weeks that were admitted to the unit during the study period. Main Outcome Measure(s): We reported the weekly and 4-week mean daily caloric and fluid intake, and growth status as changes in Fenton z-scores and weight velocity. The predictors of bronchopulmonary dysplasia were identified using multivariable logistic regression analysis. Result(s): The 4-week mean daily caloric and fluid intake were significantly lower in the BPD group. Mean z-scores of weights, weight velocity and proportions of infants with weights below the 10th percentile on day 28 of life were similar in both groups. The odds of developing BPD were increased when invasive ventilatory support was required at day 28 (OR = 16.5), and were decreased with a higher 4-week averaged daily caloric intake (OR = 0.89). Conclusion(s): Infants with BPD received a lower caloric and fluid intake in the first month of life. In multivariable regression analysis, two independent predictors for BPD development were the need for invasive ventilatory support and a lower 4-week averaged daily caloric intake.Copyright © 2019 Elsevier B.V.

Background: Neurovascular coupling (NVC) leads to increased local cerebral blood flow and oxygenation to meet the increased metabolic demand of neural activity. Immature NVC in the preterm newborn may predispose the brain to cerebral hypoxia when neural activity is increased. We reported that prolonged somatosensory stimulation in fetal sheep reduced cerebral oxygenation (negative cerebral haemodynamic response) (Nakamura et al. 2017). We now characterise the cerebral haemodynamic response after somatosensory stimulation in the preterm newborn lamb, by measuring changes in cerebral oxy- and deoxy-haemoglobin (DELTAoxyHb, DELTAdeoxyHb) using near infrared spectroscopy (NIRS). Method(s): Preterm lambs (126-128 days gestation) were delivered and ventilated under isoflurane anaesthesia. Scalp EEG and NIRS optodes were positioned bilaterally over the somatosensory cortex. Using a cuff electrode, the left median nerve was stimulated by trains (1.8, 4.8, 7.8 s duration) of pulses (3-8 mA, 2 msec). The DELTAoxyHb and DELTAdeoxyHb were recorded. Result(s): Stimulation for 1.8 s, 4.8 s and 7.8 s durations increased DELTAoxyHb in the contralateral cortex in 9 of 10 (90%), 8 of 11 (73%) and 9 of 10 (90%) preterm lambs respectively, while the remaining lambs showed decreased DELTAoxyHb. The DELTAoxyHb did not correlate with changes in arterial blood pressure. Conclusion(s): Somatosensory stimulation increased cerebral oxygenation in the preterm newborn brain, contrasting with our published findings in age-matched fetal sheep in which prolonged stimulation decreased cerebral oxygenation. Ex-utero NVC responses in the postnatal and fetal brain may be different because of loss of endogenous neurosteroids (e.g.progesterone, allopregnanolone) of placental origin which contribute to fetal sleep and suppress somatosensory neural responses.

The authors regret that there was a typographic error in Table 3 under Univariate analyses, in the row of "4-week averaged CVR (Cal/ml)". The coefficient should be 6.75e-09, the lower and upper limits of the 95% confidence intervals (CI)should be 1.09e-13 and 0.00042 respectively. The p-value is the same at <0.05. The rest of the results regarding the 4-week averaged CVR are all correct. The error does not affect the Multivariable logistic regression analysis, results and conclusions. The authors would like to apologise for any inconvenience caused.Copyright © 2019 Elsevier B.V.

Perinatal asphyxia remains a principal cause of infant mortality and long-term neurological morbidity, particularly in low-resource countries. No neuroprotective interventions are currently available. Melatonin (MLT), a potent antioxidant, anti-inflammatory and antiapoptotic agent, offers promise as an intravenous (IV) or transdermal therapy to protect the brain. We aimed to determine the effect of melatonin (IV or transdermal patch) on neuropathology in a lamb model of perinatal asphyxia. Asphyxia was induced in newborn lambs via umbilical cord occlusion at birth. Animals were randomly allocated to melatonin commencing 30 minutes after birth (60 mg in 24 hours; IV or transdermal patch). Brain magnetic resonance spectroscopy (MRS) was undertaken at 12 and 72 hours. Animals (control n = 9; control+MLT n = 6; asphyxia n = 16; asphyxia+MLT [IV n = 14; patch n = 4]) were euthanised at 72 hours, and cerebrospinal fluid (CSF) and brains were collected for analysis. Asphyxia resulted in severe acidosis (pH 6.9 +/- 0.0; lactate 9 +/- 2 mmol/L) and altered determinants of encephalopathy. MRS lactate:N-acetyl aspartate ratio was 2.5-fold higher in asphyxia lambs compared with controls at 12 hours and 3-fold higher at 72 hours (P <.05). Melatonin prevented this rise (3.5-fold reduced vs asphyxia; P =.02). Asphyxia significantly increased brain white and grey matter apoptotic cell death (activated caspase-3), lipid peroxidation (4HNE) and neuroinflammation (IBA-1). These changes were significantly mitigated by both IV and patch melatonin. Systemic or transdermal neonatal melatonin administration significantly reduces the neuropathology and encephalopathy signs associated with perinatal asphyxia. A simple melatonin patch, administered soon after birth, may improve outcome in infants affected by asphyxia, especially in low-resource settings.Copyright © 2018 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd

Objective: To determine the effect of prone sleeping on cerebral oxygenation in preterm infants in the neonatal intensive care unit. Study design: Preterm infants, divided into extremely preterm (gestational age 24-28 weeks; n = 23) and very preterm (gestational age 29-34 weeks; n = 33) groups, were studied weekly until discharge in prone and supine positions during active and quiet sleep. Cerebral tissue oxygenation index (TOI) and arterial oxygen saturation (SaO2) were recorded. Cerebral fractional tissue extraction (CFOE) was calculated as CFOE = (SaO2 - TOI)/SaO2. Result(s): In extremely preterm infants, CFOE increased modestly in the prone position in both sleep states at age 1 week, in no change in TOI despite higher SaO2. In contrast, the very preterm infants did not have position-related differences in CFOE until the fifth week of life. In the very preterm infants, TOI decreased and CFOE increased with active sleep compared with quiet sleep and with increasing postnatal age. Conclusion(s): At 1 week of age, prone sleeping increased CFOE in extremely preterm infants, suggesting reduced cerebral blood flow. Our findings reveal important physiological insights in clinically stable preterm infants. Further studies are needed to verify our findings in unstable preterm infants regarding the potential risk of cerebral injury in the prone sleeping position in early postnatal life.Copyright © 2018 Elsevier Inc.

Key points: Periodic breathing and apnoea were more common in preterm compared to age-matched term-born infants across the first 6 months after term-corrected age. Periodic breathing decreased with age in both term and preterm infants. Apnoea duration was not different between groups; however, the decline in apnoea index with postnatal age observed in the term infants was not seen in the preterm infants. Falls in tissue oxygenation index (brain TOI) associated with apnoeas were greater in the preterm infants at all three ages studied. The clinical significance of falls in brain TOI during periodic breathing and apnoea on neurodevelopmental outcome is unknown and warrants further investigations. Abstract: Periodic breathing and short apnoeas are common in infants, particularly those born preterm, but are thought to be benign. The aim of our study was to assess the incidence and impact of periodic breathing and apnoea on heart rate, oxygen saturation and brain tissue oxygenation index (TOI) in infants born at term and preterm over the first 6 months after term equivalent age. Nineteen term-born infants (38-42 weeks gestational age) and 24 preterm infants (born at 27-36 weeks gestational age) were studied at 2-4 weeks, 2-3 months and 5-6 months post-term-corrected age during sleep. Periodic breathing episodes were defined as three or more sequential apnoeas each lasting >=3 s and apnoeas as >=3 s in duration. The mean duration of periodic breathing episodes was longer in term infants than in preterm infants at 2-4 weeks (P < 0.05) and at 5-6 months (P < 0.05); however, the nadir in TOI was significantly less in the term infants at 2-3 months (P < 0.001). Apnoea duration was not different between groups; however, the decline in apnoea index with postnatal age observed in the term infants was not seen in the preterm infants. Falls in TOI associated with apnoeas were greater in the preterm infants at all three ages studied. In conclusion, periodic breathing and short apno

Background: Impaired cerebral autoregulation in preterm infants makes circulatory management important to avoid cerebral hypoxic-ischemic injury. Dobutamine is frequently used as inotropic treatment in preterm neonates, but its effects on the brain exposed to cerebral hypoxia are unknown. We hypothesized that dobutamine would protect the immature brain from cerebral hypoxic injury. Method(s): In preterm (0.6 gestation) fetal sheep, dobutamine (Dob, 10 mug/kg/min) or saline (Sal) was infused intravenously for 74 h. Two hours after the beginning of the infusion, umbilical cord occlusion (UCO) was performed to produce fetal asphyxia (Sal+UCO: n = 9, Dob+UCO: n = 7), or sham occlusion (Sal+sham: n = 7, Dob+sham: n = 6) was performed. Brains were collected 72 h later for neuropathology. Result(s): Dobutamine did not induce cerebral changes in the sham UCO group. UCO increased apoptosis and microglia density in white matter, hippocampus, and caudate nucleus, and astrocyte density in the caudate nucleus. Dobutamine commenced before UCO reduced microglia infiltration in the white matter, and microglial and astrocyte density in the caudate. Conclusion(s): In preterm hypoxia-induced brain injury, dobutamine decreases neuroinflammation in the white matter and caudate, and reduces astrogliosis in the caudate. Early administration of dobutamine in preterm infants for cardiovascular stabilization appears safe and may be neuroprotective against unforeseeable cerebral hypoxic injury.Copyright © 2018, International Pediatric Research Foundation, Inc.

Background: Commonly the magnitude and frequency of bradycardia is underestimated in the neonatal unit due to the long averaging time used in bedside oximeters. We aimed to assess the frequency and severity of bradycardia in preterm infants using the lowest averaging time (2 s) available on a clinical oximeter, compared with bradycardia detected using electrocardiogram (ECG), and whether bradycardia severity and postmenstrual age affected cerebral oxygenation. Method(s): Preterm infants (10 M/9F) were studied longitudinally at 26-31 (very preterm) and 32-38 weeks (late preterm) postmenstrual age. Heart rate falls calculated from ECG were used to determine mild or moderate/severe (MS) bradycardias. Cerebral tissue oxygenation index (TOI, %) was recorded and fractional tissue oxygen extraction (FTOE) calculated. Result(s): Of the 615 bradycardias scored using ECG criteria, 10% were not detected by oximetry. TOI falls associated with bradycardias were greater for MS bradycardias compared with Mild for both groups (p < 0.001 for both). The FTOE associated with MS bradycardias was higher for the very preterm compared with the late preterm group (p < 0.001). In very preterm infants 61% of MS and 35% Mild bradycardias were associated with TOI nadirs below 55%. Conclusion(s): Even the most sensitive oximeter setting underestimates bradycardias. The cerebral effect from bradycardias in very preterm infants is more severe than in late preterm infants. Even the mild bradycardias are associated with falls in cerebral oxygenation. Routine NIRS monitoring of cerebral oxygenation in NICUs may increase staff awareness for interventions to reduce the repetitive falls in cerebral oxygenation in preterm infants.Copyright © 2018 Elsevier B.V.

Aim: To investigate the effects of foetal growth restriction (FGR) and prematurity on cardiac morphology and function in infancy. We hypothesised that FGR and prematurity would both alter cardiac development. Method(s): Cardiac morphology and function were evaluated in 24 preterm FGR infants (p-FGR) and 23 preterm and 19 term appropriately grown for gestational age infants (p-AGA and t-AGA, respectively) by conventional echocardiography and Tissue Doppler Imaging. p-FGR and p-AGA infants were studied on postnatal day 1 and all groups were studied at one-and six-months post-term age. Result(s): p-FGR infants demonstrated increased cardiac sphericity compared to AGA peers on postnatal day 1 (p = 0.004) and at one-month post-term age (p = 0.004). Posterior and relative wall thickness increased overtime in the p-FGR group only (p < 0.05). Systolic function was not different between groups. E/e' ratio was higher in both preterm groups compared to the term group at one-month post-term age (p = 0.01). No statistically significant group differences were found at six-months post-term age. Conclusion(s): Foetal growth restriction was associated with subtle cardiac morphological changes, whereas both prematurity and FGR were associated with subclinical alterations in diastolic function.Copyright ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd

Aim: Management of congenital pulmonary airway malformations (CPAM) is controversial, especially for asymptomatic patients. We aim to describe the clinical manifestations and management of CPAM at a tertiary paediatric hospital using a retrospective audit. Method(s): Infants with CPAM were identified on the Fetal Diagnostic Unit database from 2007 to 2014. Information on antenatal and post-natal management was collected from medical record. Result(s): Thirty-five infants with antenatally diagnosed CPAM were included. Fetal CPAM volume ratio (CVR) was calculated from antenatal ultrasound measurement and used to categorise the infants into three groups of large (CVR >= 1.6, n = 8), medium (CVR of 0.5-1.6, n = 12) and small CPAM (CVR of <=0.5, n = 15), respectively. Ten infants (10/35 = 29%) were symptomatic in the neonatal period. Overall, nine infants (26%) had surgical resection, among whom eight had large or medium-sized CPAM lesions as defined by the antenatal CVR. Three infants had neonatal emergency surgery and the remaining six had late elective surgery. Histology of eight cases showed CPAM, but one case showed congenital lobar emphysema. Criteria for surgery varied and included persistent symptoms after birth, complications during childhood and persistently abnormal chest X-ray. Most asymptomatic infants with CPAM were safely managed using a conservative approach, with no significant increase in late symptoms or complications. Conclusion(s): Conservative management of CPAM may be considered for infants/children who remain asymptomatic, especially those with a small lesion. For large and medium-sized CPAM, delineation using computed tomography is required, and surgery may be beneficial to prevent late symptoms and the risk of emergency surgery.Copyright © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Advances in neonatal care have improved the survival rates of preterm infants, however, the likelihood of brain injury and neurodevelopmental disability remains a significant problem. Whilst the etiology of preterm brain injury is complex, impairments in the cardio- and cerebro-vascular function have been implicated. During infancy, sleep is vital for brain development. However, instabilities in cardio- and cerebro-vascular function are most marked during sleep. Sleeping position is an important part of a safe sleeping environment. Prone sleeping increases the risk of sudden infant death syndrome and is associated with reduced blood pressure, cerebral oxygenation and impaired autonomic cardiovascular control in infants born at term. Importantly, these effects are amplified by preterm birth. Hospitalized preterm infants are often slept in the prone position to improve respiratory function. However, there is little consensus regarding the sustained benefits of prone sleeping in this population. In light of the impaired cardio- and cerebro-vascular function during prone sleeping in term and preterm infants after hospital discharge, the likely adverse effects of prone sleeping in hospitalized preterm infants are concerning. This review examines the cardiovascular and cerebrovascular effects of prone sleeping in infants born at term, those born preterm after term equivalent age and whilst hospitalized.Copyright © 2017 Elsevier Ltd

Introduction: The preterm born infant's ability to regulate its cerebral blood flow (CBF) is crucial in preventing secondary ischemic and hemorrhagic damage in the developing brain. The relationship between arterial blood pressure (ABP) and CBF estimates, such as regional cerebral oxygenation as measured by near-infrared spectroscopy (NIRS), is an attractive option for continuous non-invasive assessment of cerebrovascular autoregulation. Areas covered: The authors performed a literature search to provide an overview of the current literature on various current clinical practices and methods to measure cerebrovascular autoregulation in the preterm infant by NIRS. The authors focused on various aspects: Characteristics of patient cohorts, surrogate measures for cerebral perfusion pressure, NIRS devices and their accompanying parameters, definitions for impaired cerebrovascular autoregulation, methods of measurements and clinical implications. Expert commentary: Autoregulation research in preterm infants has reported many methods for measuring autoregulation using different mathematical models, signal processing and data requirements. At present, it remains unclear which NIRS signals and algorithms should be used that result in the most accurate and clinically relevant assessment of cerebrovascular autoregulation. Future studies should focus on optimizing strategies for cerebrovascular autoregulation assessment in preterm infants in order to develop autoregulation-based cerebral perfusion treatment strategies.Copyright © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.