Red cell infusion but not saline is effective for volume expansion in preterm piglets.

BACKGROUND: A common first-line treatment for supporting cardiovascular function in preterm infants is volume expansion using saline, but this does not improve outcomes. This study aimed to determine if volume expansion with saline increases blood volume, blood pressure and cerebral oxygenation; and if volume expansion with packed red blood cells (RBC) is more effective. We hypothesized that RBC infusion is more effective than saline for increasing blood volume and maintaining cardiovascular function and cerebral oxygenation. METHODS: Five groups of preterm piglets (98/115d gestation) were infused with saline (10 or 20 mL/kg) or RBC (10 or 20 mL/kg) or no treatment. Blood volume, blood pressure, central venous pressure, heart rate, carotid flow, cerebral oxygenation, arterial pH, base excess, and lactate levels were assessed for 6 h after treatment started. RESULTS: Both RBC groups had significant increases in blood volume, and improved measures of cardiovascular function, cerebral oxygenation and metabolic acidosis. Saline infusion did not increase blood volume or measures of cardiovascular function, cerebral oxygenation or metabolic acidosis. CONCLUSIONS: The results suggest that the deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in premature babies, may be reversed or halted by more effective support of blood volume. IMPACT: Blood volume decreases after birth in preterm piglets and this decrease is associated with deteriorating cardiovascular function and cerebral oxygenation. Infusion of saline does not increase blood volume nor prevent deterioration in cardiovascular function. Infusion of packed red blood cells results in an increase in blood volume and improvements in cardiovascular function and cerebral oxygenation. Deteriorating cardiovascular function in the hours after birth in preterm piglets, and possibly in human preterm neonates, may be reversed or halted by more effective support of blood volume.

Trends in the use of non-invasive respiratory support for term infants in tertiary neonatal units in Australia and New Zealand.

OBJECTIVE: To determine whether the use of non-invasive respiratory support, such as continuous positive airway pressure and nasal high flow, to treat term infants in Australian and New Zealand tertiary neonatal intensive care units (NICUs) has changed over time, and if so, whether there are parallel changes in short-term respiratory morbidities. DESIGN: Retrospective database review of patient-level data from the Australian and New Zealand Neonatal Network (ANZNN) from 2010 to 2018. Denominator data on the number of term inborn livebirths in each facility was only available as annual totals. PATIENTS AND SETTING: Term, inborn infants cared for in NICUs within the ANZNN. MAIN OUTCOME MEASURES: The primary outcome was the annual change in hospital-specific rates of non-invasive respiratory support per 1000 inborn livebirths, expressed as a percentage change. Secondary outcomes were the change in rates of mechanical ventilation, pneumothorax requiring drainage, exogenous surfactant treatment and death before hospital discharge. RESULTS: A total of 14 656 term infants from 21 NICUs were included from 2010 to 2018, of whom 12 719 received non-invasive respiratory support. Non-invasive respiratory support use increased on average by 8.7% per year (95% CI: 7.9% to 9.4% per year); the number of term infants receiving non-invasive respiratory support almost doubled from 980 in 2010 (10.8/1000 livebirths) to 1913 in 2018 (20.8/1000). There was no change over time in rate of mechanical ventilation or death. The rate of pneumothorax requiring drainage increased over time, as did surfactant treatment. CONCLUSIONS: Non-invasive respiratory support use to treat term infants cared for in NICUs within the ANZNN is increasing over time. Clinicians should be diligent in selecting infants most likely to benefit from treatment with non-invasive respiratory support in this relatively low-risk population of term newborn infants. Analysis of patient-level data by individual NICUs is recommended to control for potential confounding due to changes in population over time.

Effect of Omega-3 Supplementation on Self-Regulation in Typically Developing Preschool-Aged Children: Results of the Omega Kid Pilot Study-A Randomised, Double-Blind, Placebo-Controlled Trial.

Supplementation of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) may enhance self-regulation (SR) and executive functioning (EF) in children of preschool age. The aim of the Omega Kid Study was to investigate the effect of n-3 LCPUFA supplementation on SR and EF in typically developing preschool-aged children. A double-blind placebo-controlled pilot trial was undertaken, the intervention was 12 weeks and consisted of 1.6 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day compared to placebo. The HS-Omega-3 Index® was assessed by capillary blood samples at baseline and post-intervention. Seventy-eight children were enrolled and randomised to either the n-3 LCPUFA treatment (n = 39) or placebo (n = 39) group. Post intervention, there was a significant three-fold increase in the HS-Omega-3 Index® in the n-3 LCPUFA group (p < 0.001). There were no improvements in SR or EF outcome variables for the n-3 LCPUFA group post intervention compared to the placebo group determined by linear mixed models. At baseline, there were significant modest positive Spearman correlations found between the HS-Omega-3 index® and both behavioural self-regulation and cognitive self-regulation (r = 0.287, p = 0.015 and r = 0.242, p = 0.015 respectively). Although no treatment effects were found in typically developing children, further research is required to target children with sub-optimal self-regulation who may benefit most from n-3 LCPUFA supplementation.

Plasma Leak From the Circulation Contributes to Poor Outcomes for Preterm Infants: A Working Hypothesis.

Preterm infants are at high risk of death and disability resulting from brain injury. Impaired cardiovascular function leading to poor cerebral oxygenation is a significant contributor to these adverse outcomes, but current therapeutic approaches have failed to improve outcome. We have re-examined existing evidence regarding hypovolemia and have concluded that in the preterm infant loss of plasma from the circulation results in hypovolemia; and that this is a significant driver of cardiovascular instability and thus poor cerebral oxygenation. High capillary permeability, altered hydrostatic and oncotic pressure gradients, and reduced lymphatic return all combine to increase net loss of plasma from the circulation at the capillary. Evidence is presented that early hypovolemia occurs in preterm infants, and that capillary permeability and pressure gradients all change in a way that promotes rapid plasma loss at the capillary. Impaired lymph flow, inflammation and some current treatment strategies may further exacerbate this plasma loss. A framework for testing this hypothesis is presented. Understanding these mechanisms opens the way to novel treatment strategies to support cardiovascular function and cerebral oxygenation, to replace current therapies, which have been shown not to change outcomes.

Cost-Effectiveness of Nasal High Flow Versus CPAP for Newborn Infants in Special-Care Nurseries.

BACKGROUND: Treating respiratory distress in newborns is expensive. We compared the cost-effectiveness of 2 common noninvasive therapies, nasal continuous positive airway pressure (CPAP) and nasal high-flow (nHF), for newborn infants cared for in nontertiary special care nurseries. METHODS: The economic evaluation was planned alongside a randomized control trial conducted in 9 Australian special care nurseries. Costs were considered from a hospital perspective until infants were 12 months of age. A total of 754 infants with respiratory distress, born ≥31 weeks' gestation and with birth weight ≥1200 g, <24 hours old, requiring noninvasive respiratory support and/or supplemental oxygen for >1 hour were recruited during 2015-2017. Inpatient costing records were obtained for 753 infants, of whom 676 were included in the per-protocol analysis. Two scenarios were considered: (1) CPAP versus nHF, with infants in the nHF group having "rescue" CPAP backup available (trial scenario); and (2) CPAP versus nHF, as sole primary support (hypothetical scenario). Effectiveness outcomes were rate of endotracheal intubation and transfer to a tertiary-level NICU. RESULTS: As sole primary support, CPAP is more effective and on average cheaper, and thus is superior. However, nHF with back-up CPAP produced equivalent cost and effectiveness results, and there is no reason to make a decision between the 2 treatments on the basis of the cost or effectiveness outcomes. CONCLUSIONS: Nontertiary special care nurseries choosing to use only 1 of the modes should choose CPAP. In units with both modes available, using nHF as first-line therapy may be acceptable if there is back-up CPAP.

Food anthocyanins decrease concentrations of TNF-α in older adults with mild cognitive impairment: A randomized, controlled, double blind clinical trial.

BACKGROUND & AIMS: Vascular function, blood pressure and inflammation are involved in the pathogenesis of major chronic diseases, including both cardiovascular disease (CVD) and mild cognitive impairment (MCI). This study investigated the effects of food anthocyanins on microvascular function, 24-h ambulatory blood pressure (ABP) and inflammatory biomarkers in older adults with MCI. METHODS AND RESULTS: Thirty-one participants with MCI [19 female, 12 male, mean age 75.3 (SD 6.9) years and body mass index 26.1 (SD 3.3) kg/m2], participated in a randomized, controlled, double-blind clinical trial (Australian New Zealand Clinical Trials Registry: ACTRN12618001184268). Participants consumed 250 mL fruit juice daily for 8 weeks, allocated into three groups: a) high dose anthocyanins (201 mg); b) low dose anthocyanins (47 mg); c) control. Microvascular function (Laser Speckle Contrast Imaging combined with a post-occlusive reactive hyperaemia test), 24h ABP and serum inflammatory biomarkers were assessed before and after the nutritional intervention. RESULTS: Participants in the high anthocyanins group had a reduction in serum tumor necrosis factor alpha (TNF-α) (P = 0.002) compared to controls and the low anthocyanins group (all P's > 0.05). Serum IL-6, IL-1ß, c-reactive protein, and parameters of microvascular function and 24h ABP were not altered by any treatment. CONCLUSION: A daily high dose of fruit-based anthocyanins for 8 weeks reduced concentrations of TNF-α in older adults with MCI. Anthocyanins did not alter other inflammatory biomarkers, microvascular function or blood pressure parameters. Further studies with a larger sample size and longer period of follow-up are required to elucidate whether this change in the immune response will alter CVD risk and progression of cognitive decline.

The Feasibility of the "Omega Kid" Study Protocol: A Double-Blind, Randomised, Placebo-Controlled Trial Investigating the Effect of Omega-3 Supplementation on Self-Regulation in Preschool-Aged Children.

Self-regulation, the regulation of behaviour in early childhood, impacts children's success at school and is a predictor of health, wealth, and criminal outcomes in adulthood. Self-regulation may be optimised by dietary supplementation of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs). The aim of the "Omega Kid" study is to investigate the feasibility of a protocol to investigate whether n-3 LCPUFA supplementation enhances self-regulation in preschool-aged children. The protocol assessed involved a double-blind, randomised, placebo-controlled trial of 12 weeks duration, with an intervention of 1.6 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day (0.3 g EPA and 1.3 g DHA) in a microencapsulated powder compared to placebo. Children (n = 78; 40 boys and 38 girls) aged 3-5 years old were recruited and randomly allocated to the treatment (n = 39) or placebo group (n = 39). The HS-Omega-3 Index® served as a manipulation check on the delivery of either active (n-3 LCPUFAs) or placebo powders. Fifty-eight children (76%) completed the intervention (28-30 per group). Compliance to the study protocol was high, with 92% of children providing a finger-prick blood sample at baseline and high reported-adherence to the study intervention (88%). Results indicate that the protocol is feasible and may be employed in an adequately powered clinical trial to test the hypothesis that n-3 LCPUFA supplementation will improve the self-regulation of preschool-aged children.

Anthocyanins attenuate vascular and inflammatory responses to a high fat high energy meal challenge in overweight older adults: A cross-over, randomized, double-blind clinical trial.

BACKGROUND & AIMS: Postprandial metabolic imbalances are important indicators of later developing cardiovascular disease (CVD). This study investigated the effects of food anthocyanins on vascular and microvascular function, and CVD associated biomarkers following a high fat high energy (HFHE) meal challenge in overweight older adults. METHODS: Sixteen subjects (13 female, 3 male, mean age 65.9 SD 6.0 and body mass index 30.6 kg/m2 SD 3.9) participated in a crossover, randomized, controlled, double-blind clinical trial (registered under Australian New Zealand Clinical Trials Registry, identifier no. ACTRN12620000437965). Participants consumed a HFHE meal with a 250 mL dose of either intervention (anthocyanins-rich Queen Garnet Plum) or control (apricot) juice. Blood samples and blood pressure measures were collected at baseline, 2 h and 4 h following the HFHE meal. Vascular and microvascular function were evaluated at baseline and 2 h after the HFHE meal. RESULTS: Participants had a higher 2 h postprandial flow-mediated dilatation (+1.14%) and a higher microvascular post-occlusive reactive hyperaemia (+0.10 perfusion units per mmHg) when allocated to the anthocyanin compared to the control arm (P = 0.019 and P = 0.049, respectively). C-reactive protein was lower 4 h postprandially in the anthocyanins (1.80 mg/L, IQR 0.90) vs control arm (2.30 mg/L, IQR 1.95) (P = 0.026), accompanied by a trend for lower concentrations of interleukin-6 (P = 0.075). No significant postprandial differences were observed between treatments for blood pressure, triacylglycerol, total cholesterol, serum derivatives of reactive oxidative metabolites, tumor necrosis factor alpha, interleukin-1 beta, or maximum microvascular perfusion following iontophoresis of acetylcholine. CONCLUSION: Fruit-based anthocyanins attenuated the potential postprandial detrimental effects of a HFHE challenge on parameters of vascular and microvascular function, and inflammatory biomarkers in overweight older adults. Anthocyanins may reduce cardiovascular risk associated with endothelial dysfunction and inflammatory responses to a typical high fat 'Western' meal. Further studies are required to better elucidate the clinical implications of postprandial biomarkers of CVD.

Predicting Nasal High-Flow Treatment Success in Newborn Infants with Respiratory Distress Cared for in Nontertiary Hospitals.

OBJECTIVE: To evaluate demographic and clinical variables as predictors of nasal high-flow treatment success in newborn infants with respiratory distress cared for in Australian nontertiary special care nurseries. STUDY DESIGN: A secondary analysis of the HUNTER trial, a multicenter, randomized controlled trial evaluating nasal high-flow as primary respiratory support for newborn infants with respiratory distress who were born ≥31 weeks of gestation and with birth weight ≥1200 g, and cared for in Australian nontertiary special care nurseries. Treatment success within 72 hours after randomization to nasal high-flow was determined using objective criteria. Univariable screening and multivariable analysis was used to determine predictors of nasal high-flow treatment success. RESULTS: Infants (n = 363) randomized to nasal high-flow in HUNTER were included in the analysis; the mean gestational age was 36.9 ± 2.7 weeks and birth weight 2928 ± 782 g. Of these infants, 290 (80%) experienced nasal high-flow treatment success. On multivariable analysis, nasal high-flow treatment success was predicted by higher gestational age and lower fraction of inspired oxygen immediately before randomization, but not strongly. The final model was found to have an area under the curve of 0.65, which after adjustment for optimism was found to be 0.63 (95% CI, 0.57-0.70). CONCLUSIONS: Gestational age and supplemental oxygen requirement may be used to guide decisions regarding the most appropriate initial respiratory support for newborn infants in nontertiary special care nurseries. Further prospective research is required to better identify which infants are most likely to be successfully treated with nasal high-flow. TRIAL REGISTRATION: ACTRN12614001203640.

The impact of maternal asthma during pregnancy on offspring retinal microvascular structure and its relationship to placental growth factor production in utero.

Asthma is a common chronic disease in pregnancy that affects placental function and fetal growth and associated with cardio-metabolic disorders in the offspring but the mechanisms are unknown. This study explored whether maternal asthma in pregnancy is associated with the development of offspring microvascular structure and whether it was related to biomarkers of angiogenesis in utero. Children aged 4 to 6 years, born to either asthmatic mothers (n = 38) or healthy controls (n = 25), had their retinal microvascular structure examined. Maternal plasma PlGF concentrations at 18 and 36 weeks' gestation were measured. There was a significant global difference in all retinal microvascular measures between children of asthmatic mothers relative to controls and increased retinal venular tortuosity in children born to asthmatic mothers (7.1 (95% CI 0.7-13.5); P = .031). A rise in plasma PlGF from 18 to 36 weeks' gestation was observed in the control population which was significantly lower in the asthma group by 190.9 pg/mL. PlGF concentrations were correlated with microvascular structure including arteriolar branching and venular tortuosity. These exploratory findings indicate that exposure to maternal asthma during pregnancy is associated with persistent changes in microvascular structure in childhood that may be driven by alterations to angiogenic mechanisms in utero.

Nasal High-Flow Therapy for Newborn Infants in Special Care Nurseries.

BACKGROUND: Nasal high-flow therapy is an alternative to nasal continuous positive airway pressure (CPAP) as a means of respiratory support for newborn infants. The efficacy of high-flow therapy in nontertiary special care nurseries is unknown. METHODS: We performed a multicenter, randomized, noninferiority trial involving newborn infants (<24 hours of age; gestational age, ≥31 weeks) in special care nurseries in Australia. Newborn infants with respiratory distress and a birth weight of at least 1200 g were assigned to treatment with either high-flow therapy or CPAP. The primary outcome was treatment failure within 72 hours after randomization. Infants in whom high-flow therapy failed could receive CPAP. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome, with a noninferiority margin of 10 percentage points. RESULTS: A total of 754 infants (mean gestational age, 36.9 weeks, and mean birth weight, 2909 g) were included in the primary intention-to-treat analysis. Treatment failure occurred in 78 of 381 infants (20.5%) in the high-flow group and in 38 of 373 infants (10.2%) in the CPAP group (risk difference, 10.3 percentage points; 95% confidence interval [CI], 5.2 to 15.4). In a secondary per-protocol analysis, treatment failure occurred in 49 of 339 infants (14.5%) in the high-flow group and in 27 of 338 infants (8.0%) in the CPAP group (risk difference, 6.5 percentage points; 95% CI, 1.7 to 11.2). The incidences of mechanical ventilation, transfer to a tertiary neonatal intensive care unit, and adverse events did not differ significantly between the groups. CONCLUSIONS: Nasal high-flow therapy was not shown to be noninferior to CPAP and resulted in a significantly higher incidence of treatment failure than CPAP when used in nontertiary special care nurseries as early respiratory support for newborn infants with respiratory distress. (Funded by the Australian National Health and Medical Research Council and Monash University; HUNTER Australian and New Zealand Clinical Trials Registry number, ACTRN12614001203640.).

Microvascular circulatory dysregulation driven in part by cystathionine gamma-lyase: A new paradigm for cardiovascular compromise in the preterm newborn.

OBJECTIVE: H2 S may explain the dysregulation of microvascular tone associated with poor outcome following preterm birth. In adult vasculature, H2 S is predominantly produced by CSE. We hypothesized that vascular CSE activity contributes to microvascular tone regulation during circulatory transition. METHODS: Preterm (GA62) and full-term (GA69) guinea pig fetuses and neonates were studied. Microvascular blood flow was assessed by laser Doppler flowmetry. Thiosulfate, primary urinary metabolite of H2 S, was determined by high-performance liquid chromatography. Real-time H2 S production was assessed using a microrespiration system in fetal and postnatal (10, 24 hours) skin and heart samples. CSE contribution was investigated by inhibition via propargylglycine. RESULTS: In preterm animals, postnatal H2 S production capacity in peripheral vasculature increased significantly and was significantly reduced by the inhibition of CSE. Urinary thiosulfate correlated with both microvascular blood flow and capacity of the vasculature to produce H2 S. H2 S produced via CSE did not correlate directly with microvascular blood flow. CONCLUSIONS: In preterm neonates, H2 S production increases during fetal-to-neonatal transition and CSE contribution to total H2 S increases postnatally. CSE-dependent mechanisms may therefore underpin the increase in H2 S production over the first 72 hours of life in preterm human neonates, associated with both central and peripheral cardiovascular instability.

Supporting preterm cardiovascular function.

Preterm infants are at higher risk of adverse neurodevelopmental outcomes. Inadequate cerebral oxygen delivery resulting from poor cardiovascular function is likely to be a significant contributor to preterm brain injury. In this context, improved support of cardiovascular function is integral to improving preterm outcomes. Many of the treatments used to support preterm cardiovascular function are based on adult physiology and may not be appropriate for the unique physiology of the preterm infant. The preterm heart is structurally immature with reduced contractility and low cardiac output. However, there is limited evidence that inotropic support with dopamine and/or dobutamine is effective in preterm babies. Hypovolemia may also contribute to poor preterm cardiovascular function; there is evidence that capillary leakage results in considerable loss of plasma from the circulation of newborn preterm babies. In addition, the vasoconstrictor response to acute stimuli does not develop until quite late in gestation and is limited in the preterm infant. This may lead to inappropriate vasodilatation adding to functional hypovolemia. The first line treatment for hypotension in preterm infants is volume expansion with crystalloid solutions, but this has limited efficacy in the preterm infant. More effective methods of volume expansion are required. Effective support of preterm cardiovascular function requires better understanding of preterm cardiovascular physiology so that treatments can target mechanisms that are sufficiently mature to respond.

Reduced blood volume decreases cerebral blood flow in preterm piglets.

KEY POINTS: Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes. Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries. Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets. Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets. Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. ABSTRACT: Preterm infants often have impaired cardiovascular function that may contribute to poor neurodevelopmental outcomes. The study aimed to determine the effects of reduced blood volume on cardiovascular function, including cerebral blood flow, in preterm and term piglets. In preterm (97/115 days) and term piglets, up to 10% of the estimated blood volume was removed. Removal of blood was stopped if MAP dropped below 20 mmHg. Heart rate, cardiac contractility and relaxation, cardiac output, mean arterial pressure (MAP), and cerebral blood flow were measured at baseline and again after blood volume reduction. The volume of blood removed was less in preterm piglets than in term piglets (5.1 ± 1.8 vs. 7.7 ± 0.9 mL kg-1 , mean ± SD, P < 0.001). Cardiac output and MAP decreased to the same extent in term and preterm piglets. Cerebral blood flow decreased in preterm but not term piglets and cerebral vascular conductance increased in term piglets only. Compensatory responses to maintain cerebral blood flow after blood volume reduction are active in term piglets but not in preterm piglets. As a result, even a small reduction in blood volume, or an increase in the capacity of the circulatory system leading to functional hypovolaemia, may lead to a significant reduction in cerebral blood flow and contribute to brain injury in preterm neonates.

Influence of early childhood burns on school performance: an Australian population study.

OBJECTIVES: To determine the influence of burn injuries on childhood performance in national standardised curriculum-based school tests. DESIGN: Birth and health records of 977 children who were hospitalised with a burn injury between 2000 and 2006 in the state of New South Wales, Australia, were linked to performance scores in the National Assessment Program: Literacy and Numeracy test, a compulsory nationwide curriculum-based test (CBT) and compared with children who were not hospitalised for burns and who were matched for birth year, gender, gestation and socioeconomic status. MAIN OUTCOME MEASURES: Test scores in years 3 (ages 8-9), 5 (ages 10-11) and 7 (ages 13-14) in numeracy, writing, reading, spelling, grammar and punctuation. RESULTS: Mean age at first burn injury was 28 months (median: 20, range: 0-140). Children with burns were significantly more likely to have younger mothers (28.5 vs 29.6 years) (P<0.001), be indigenous (OR 2.5 (95% CI 2.1 to 3.1)) (P<0.001) and have siblings (OR 1.2 (95% CI 1.1 to 1.4)) (P<0.001). They were also less likely to meet national minimum standards in most domains of testing until year 5, even after adjustment for parental education levels, parental smoking, maternal age and indigenous status. Each 10% increase in total body surface area burnt was associated with a decrease in year 5 scores by 37.0% in numeracy and 71.9% in writing. CONCLUSIONS: Most childhood burn injuries occur before the start of formal schooling. Children who are hospitalised for burns perform more poorly in CBT even after accounting for family and socioeconomic disadvantage. Rehabilitation of children with burn injuries must address school performance to decrease any long-term negative societal impact of burns.

A multicentre, randomised controlled, non-inferiority trial, comparing nasal high flow with nasal continuous positive airway pressure as primary support for newborn infants with early respiratory distress born in Australian non-tertiary special care nurseries (the HUNTER trial): study protocol.

INTRODUCTION: Nasal high-flow (nHF) therapy is a popular mode of respiratory support for newborn infants. Evidence for nHF use is predominantly from neonatal intensive care units (NICUs). There are no randomised trials of nHF use in non-tertiary special care nurseries (SCNs). We hypothesise that nHF is non-inferior to nasal continuous positive airway pressure (CPAP) as primary support for newborn infants with respiratory distress, in the population cared for in non-tertiary SCNs. METHODS AND ANALYSIS: The HUNTER trial is an unblinded Australian multicentre, randomised, non-inferiority trial. Infants are eligible if born at a gestational age ≥31 weeks with birth weight ≥1200 g and admitted to a participating non-tertiary SCN, are <24 hours old at randomisation and require non-invasive respiratory support or supplemental oxygen for >1 hour. Infants are randomised to treatment with either nHF or CPAP. The primary outcome is treatment failure within 72 hours of randomisation, as determined by objective oxygenation, apnoea or blood gas criteria or by a clinical decision that urgent intubation and mechanical ventilation, or transfer to a tertiary NICU, is required. Secondary outcomes include incidence of pneumothorax requiring drainage, duration of respiratory support, supplemental oxygen and hospitalisation, costs associated with hospital care, cost-effectiveness, parental stress and satisfaction and nursing workload. ETHICS AND DISSEMINATION: Multisite ethical approval for the study has been granted by The Royal Children's Hospital, Melbourne, Australia (Trial Reference No. 34222), and by each participating site. The trial is currently recruiting in eight centres in Victoria and New South Wales, Australia, with one previous site no longer recruiting. The trial results will be published in a peer-reviewed journal and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001203640; pre-results.

Videomicroscopy as a tool for investigation of the microcirculation in the newborn.

The perinatal period remains a time of significant risk of death or disability. Increasing evidence suggests that this depends on microcirculatory behavior. Sidestream dark-field orthogonal polarized light videomicroscopy (OPS) has emerged as a useful assessment of adult microcirculation but the values derived are not delineated for the newborn. We aimed to define these parameters in well term newborn infants. Demographic details were collected prospectively on 42 healthy term neonates (n = 20 females, n = 22 males). OPS videomicroscopy (Microscan) was used to view ear conch skin microcirculation at 6, 24, and 72 h of age. Stored video was analyzed by a masked observer using proprietary software. There were no significant differences between the sexes for any structural parameters at any time point. There was a significant increase over time in small vessel perfusion in female infants only (P = 0.009). A number of 6- and 72-h measurements were significantly correlated, but differed from the 24-h values. These observations confirm the utility of the ear conch for neonatal microvascular videomicroscopy. They provide a baseline for studies into the use of OPS videomicroscopy in infants. The changes observed are comparable with previous studies of term infants using these and other microvascular techniques. It is recommended that studies for examining the mature neonatal microvascular structure be delayed until 72 h of life, but studies of the physiology of cardiovascular transition should include the 24-h time point after delivery.

Inotropes do not increase cardiac output or cerebral blood flow in preterm piglets.

BACKGROUND: The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. METHODS: Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions. RESULTS: At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope. CONCLUSION: In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn.

Influence of sympathetic activity in the control of peripheral microvascular tone in preterm infants.

BACKGROUND: Microvascular dysregulation following preterm birth is associated with increased illness severity and hypotension, particularly in males. Sympathetic nervous vascular regulation is evident in females. We hypothesized that sympathetic dysfunction in male preterm infants may contribute to a failure of peripheral microvascular vasoconstriction. METHODS: Microvascular blood flow of infants 24-43 wk gestational age was assessed at 6, 24, and 72 h of age by laser Doppler. Blood flow Fourier transformed frequency distribution spectra (low frequency/high frequency ratio) were used to assess the influence of sympathetic tone on microvascular regulation. Total sympathetic output was assessed as urinary normetanephrine. RESULTS: Microvascular sympathetic activity at 24 h postnatal age decreased in early preterm males, but not females. Peripheral sympathetic activity increased with advancing postnatal age in females, but decreased in males. In early preterm infants, total normetanephrine outputs increase significantly with postnatal age, in both sexes. CONCLUSION: Sympathetic activation following preterm birth is sexually dimorphic, with preterm males having reduced sympathetic tone and reduced upregulation of sympathetic tone following birth. There is evidence of a disconnect between central sympathetic activity and local peripheral microcirculatory sympathetic drive. This may relate to autonomic nervous immaturity and highlights the need to understand how preterm birth may affect autonomic function.

Identification of Eight Different Isoforms of the Glucocorticoid Receptor in Guinea Pig Placenta: Relationship to Preterm Delivery, Sex and Betamethasone Exposure.

The placental glucocorticoid receptor (GR) is central to glucocorticoid signalling and for mediating steroid effects on pathways associated with fetal growth and lung maturation but the GR has not been examined in the guinea pig placenta even though this animal is regularly used as a model of preterm birth and excess glucocorticoid exposure. Guinea pig dams received subcutaneous injections of either vehicle or betamethasone at 24 and 12 hours prior to preterm or term caesarean-section delivery. At delivery pup and organ weights were recorded. Placentae were dissected, weighed and analysed using Western blot to examine GR isoform expression in nuclear and cytoplasmic extracts. A comparative examination of the guinea pig GR gene identified it is capable of producing seven of the eight translational GR isoforms which include GRα-A, C1, C2, C3, D1, D2, and D3. GRα-B is not produced in the Guinea Pig. Total GR antibody identified 10 specific bands from term (n = 29) and preterm pregnancies (n = 27). Known isoforms included GRγ, GRα A, GRß, GRP, GRA and GRα D1-3. There were sex and gestational age differences in placental GR isoform expression. Placental GRα A was detected in the cytoplasm of all groups but was significantly increased in the cytoplasm and nucleus of preterm males and females exposed to betamethasone and untreated term males (KW-ANOVA, P = 0.0001, P = 0.001). Cytoplasmic expression of GRß was increased in female preterm placentae and preterm and term male placentae exposed to betamethasone (P = 0.01). Nuclear expression of GRß was increased in all placentae exposed to betamethasone (P = 0.0001). GRα D2 and GRα D3 were increased in male preterm placentae when exposed to betamethasone (P = 0.01, P = 0.02). The current data suggests the sex-specific placental response to maternal betamethasone may be dependent on the expression of a combination of GR isoforms.