International Online Survey on the Management of Patent Ductus Arteriosus.

INTRODUCTION: There is uncertainty and lack of consensus regarding optimal management of patent ductus arteriosus (PDA). We aimed to determine current clinical practice in PDA management across a range of different regions internationally. MATERIALS AND METHODS: We surveyed PDA management practices in neonatal intensive care units using a pre-piloted web-based survey, which was distributed to perinatal societies in 31 countries. The survey was available online from March 2018 to March 2019. RESULTS: There were 812 responses. The majority of clinicians (54%) did not have institutional protocols for PDA treatment, and 42% reported variable management within their own unit. Among infants <28 weeks (or <1,000 g), most clinicians (60%) treat symptomatically. Respondents in Australasia were more likely to treat PDA pre-symptomatically (44% vs. 18% all countries [OR 4.1; 95% CI 2.6-6.5; p < 0.001]), and respondents from North America were more likely to treat symptomatic PDA (67% vs. 60% all countries [OR 2.0; 95% CI 1.5-2.6; p < 0.001]). In infants ≥28 weeks (or ≥1,000 g), most clinicians (54%) treat symptomatically. Respondents in North America were more likely to treat PDAs in this group of infants conservatively (47% vs. 38% all countries [OR 2.3; 95% CI 1.7-3.2; p < 0.001]), and respondents from Asia were more likely to treat the PDA pre-symptomatically (21% vs. 7% all countries [OR 5.5; 95% CI 3.2-9.8; p < 0.001]). DISCUSSION/CONCLUSION: There were marked international differences in clinical practice, highlighting ongoing uncertainty and a lack of consensus regarding PDA management. An international conglomeration to coordinate research that prioritises and addresses these areas of contention is indicated.

Trial of aerosolised surfactant for preterm infants with respiratory distress syndrome.

OBJECTIVE: To evaluate the safety of an aerosolised surfactant, SF-RI 1, administered via nasal continuous positive airway pressure (nCPAP) and a prototype breath synchronisation device (AeroFact), to preterm infants with respiratory distress syndrome (RDS). DESIGN: Multicentre, open-label, dose-escalation study with historical controls. SETTING: Newborn intensive care units at Mater Mothers' Hospital, Brisbane, and Royal Hospital for Women, Sydney, Australia. PATIENTS: Infants 26 weeks through 30 weeks gestation who required nCPAP 6-8 cmH2O and fraction of inspired oxygen (FiO2) <0.30 at <2 hours of age. INTERVENTIONS: In part 1, infants received a single dose of 216 mg/kg of aerosolised surfactant. In part 2, infants could receive up to four doses of aerosolised surfactant. Three historical control infants were matched for each enrolled infant. MAIN OUTCOME MEASURES: Treatment failure was defined as Respiratory Severity Score (FiO2×cmH2O nCPAP) >2.4, nCPAP >8 cmH2O, arterial carbon dioxide >65 mm Hg, pH <7.20 or three severe apnoeas within 6 hours during the first 72 hours of life. Other outcomes included tolerance of the AeroFact treatment and complications of prematurity. RESULTS: 10 infants were enrolled in part 1 and 21 in part 2 and were compared with 93 historical controls. No safety issues were identified. In part 2, 6 of 21 (29%) AeroFact-treated infants compared with 30 of 63 (48%) control infants met failure criteria. Kaplan-Meier analysis of patients in part 2 showed a trend towards decreased rate of study failure in the AeroFact-treated infants compared with historical controls (p=0.10). CONCLUSION: The AeroFact system can safely deliver aerosolised surfactant to preterm infants with RDS who are on nCPAP. TRIAL REGISTRATION NUMBER: ACTRN12617001458325.

Evaluation of neonatal cerebral perfusion using three-dimensional power Doppler ultrasound volumes.

AIM: Despite improvement in preterm survival, neurological morbidity remains high. 3D fractional moving blood volume (3D-FMBV) quantifies neonatal cerebral perfusion by calculating a standardised measure of the amount of moving blood in a region of interest and correlates with tissue perfusion in animal studies. However, its feasibility and reproducibility are yet to be assessed in newborn infants. METHODS: Fractional moving blood volume analysis was performed on three-dimensional power Doppler ultrasound (PD-US) volumes from a cohort of preterm infants recruited in 2015 from the Royal Hospital for Women Neonatal Intensive Care Unit. The volumes were acquired by two sonographers and analysed by two different observers. The 3D-FMBV algorithm was applied to calculate an estimate for perfusion. Reproducibility and agreement were assessed using intra-class correlation coefficients (ICC) and Bland-Altman plots. RESULTS: All 3D PD-US volumes were analysed successfully. Intra-observer reliability was excellent with an ICC of 0.907 (95% CI 0.751-0.968) and 0.906 (95% CI 0.741-0.967) for two independent observers respectively. The inter-observer reliability of the entire technique was good with an ICC of 0.752 (CI: 0.404-0.909). CONCLUSION: We have successfully shown the feasibility and reliability of applying the 3D-FMBV technique to the neonatal brain in a healthy preterm population.

Survival prediction modelling in extreme prematurity: are days important?

OBJECTIVE: To demonstrate that days are important in extreme prematurity when creating survival prediction models based on gestation. STUDY DESIGN: Prospectively collected data were analysed for all admitted infants born 23 + 0 to 27 + 6 weeks gestation in the Australian and New Zealand Neonatal Network from 2009 to 2016. The effect of days on observed survival rates was assessed using a non-parametric test for trend. Prediction models created based on gestational age in completed weeks only or weeks plus days were compared. RESULT: Seven thousand eight hundred and thirty-six extreme preterm infants were studied. Observed survival increased with days for 23, 24, 25, and 27 weeks gestational age (P = 0.01; P < 0.001; P = 0.003; P = 0.003) but not for 26 weeks (P = 0.19). A survival prediction model based on weeks and days performed better than completed weeks only (AUC 0.722 vs 0.712; P < 0.001). CONCLUSION: In extreme prematurity, survival estimate accuracy improves when survival prediction models include days in addition to weeks.

When should intensive care be provided for the extremely preterm infants born at the margin of viability? A survey of Australasian parents and clinicians.

AIM: This study aimed to explore clinician and parent opinions of risk limits on resuscitation and intensive care (IC) for extremely premature infants born at the margin of viability. METHODS: Two anonymous on-line surveys were conducted from August 2016 to January 2017. Survey participants were: (i) clinicians affiliated with neonatal intensive care units in Australia; and (ii) parents or individuals who expressed interest in premature babies through the Facebook page of Miracle Babies Foundation. RESULTS: A total of 961 responses were received. Among 204 clinicians, 52% were neonatologists, 22% obstetricians, 20% neonatal intensive care unit nurses and 4% were midwives. Among 757 parents, 98% had a premature baby. Only 75% of clinicians responded to the risk limits questions. Median mortality risk above which they would not recommend resuscitation/IC was 70% (interquartile range (IQR) 50-80%); major disability risk in survivors 60% (IQR 50-75%); and composite risk of mortality and major disability 70% (IQR 50-80%). All parents answered the risk limit questions. The median mortality risk for not planning resuscitation was 90% (IQR 60-90%); major disability risk in survivors 50% (IQR 30-90%); and composite risk 90% (IQR 50-90%). Most clinicians (82%) stated that decisions should be guided by parent opinions if there are uncertainties. Parents had varying perception of previous counselling, and 57% stated that both their viewpoint and doctor's predicted risk influenced their decision-making. CONCLUSIONS: Clinicians and parents had different views on mortality and major disability risks when deciding on resuscitation/neonatal IC treatment. When there was uncertainty, both agreed on working together.

The Effect of Continuous Positive Airway Pressure on Cerebral and Splanchnic Oxygenation in Preterm Infants.

BACKGROUND: Despite the known clinical benefits of continuous positive airway pressure (CPAP) to support preterm infants breathing, there are limited studies that have examined its effect on regional oxygenation. OBJECTIVES: This study aimed to investigate how the application of CPAP affects cerebral and splanchnic tissue oxygenation in preterm infants. METHODS: A pilot observational study was conducted in infants using near-infrared spectroscopy while off CPAP and on CPAP. Regional cerebral and splanchnic saturations and variability (coefficient of variability; CV) were evaluated. RESULTS: Twenty-six infants (25-37 weeks gestational age at birth) were studied. The mean cerebral oxygenation did not differ with the application of CPAP (80 ± 4.2% without CPAP; 80 ± 1.9% with CPAP), but variability around the mean was less with CPAP (CV 5 vs. 2%, respectively). Mean cerebral fractional oxygen extraction (FOE) increased with CPAP from 0.13 ± 0.06 to 0.17 ± 0.04% (p = 0.002). Splanchnic oxygenation increased significantly from 66 ± 11.6 to 75 ± 9.1% with CPAP (p < 0.001) and also became more stable (CV 13 vs. 7%, respectively). Splanchnic FOE decreased with CPAP from 0.28 ± 0.13 to 0.22 ± 0.10% (p = 0.002). CONCLUSION: The application of CPAP did not affect mean cerebral oxygenation in this group of preterm and term infants; however, it led to a significant increase in splanchnic oxygenation. These findings highlight the important role that respiratory support may play in maintaining adequate and stable oxygen delivery to vital organs.

Four-Dimensional Ultrasound for Evaluating Newborn Cardiac Output: A Pilot Study of Healthy Infants.

BACKGROUND: There is currently no reliable non-invasive method of measuring cardiac output in neonatal intensive care. Spatiotemporal image correlation (STIC) is a novel four-dimensional (4D) ultrasound technique that was developed to assess the foetal heart, and it may be a useful way to assess neonatal haemodynamics. OBJECTIVE: This study aimed to evaluate the feasibility and reproducibility of determining neonatal cardiac output using STIC ultrasound in newborn infants. DESIGN: Infants were recruited opportunistically from a neonatal intensive care unit and then examined by 2 independent observers. STIC was used to obtain images of the heart. End-diastolic and end-systolic ventricular volumes were measured using virtual organ computer-aided analysis (VOCAL) and used to calculate cardiac output. Reproducibility was assessed with intraclass correlation coefficients (ICC) and agreement with Bland-Altman analysis. RESULTS: Twenty-four clinically stable infants of 34-43 weeks corrected gestational age were assessed. Both observers successfully acquired 4D STIC volumes in all infants. Left ventricular output showed good reproducibility, with an intra-observer ICC of 0.86 (0.69-0.94) and inter-observer ICC of 0.87 (0.70-0.95). Right ventricular output also showed good reproducibility, with an intra-observer ICC of 0.88 (0.70-95) and inter-observer ICC of 0.84 (0.63-0.93). CONCLUSIONS: Determining cardiac output using 4D STIC ultrasound is feasible and reproducible in well newborn infants. With further evaluation, this technique may provide valuable information about haemodynamic status in newborn infants requiring intensive care.

Neurodevelopmental outcomes of extremely preterm infants in New South Wales and the Australian Capital Territory.

AIM: This study aimed to provide updated information on gestation-specific neurodevelopmental outcomes of extremely to very preterm infants 23-28 weeks' gestation admitted to neonatal intensive care units (NICUs). METHODS: This was a population-based retrospective cohort study of infants born between 23+0 and 28+6 weeks' gestation and admitted to a network of NICUs between 2007 and 2012 in a well-defined geographic area of New South Wales (NSW) and the Australian Capital Territory (ACT). Primary outcome was moderate to severe neurodevelopmental impairment. RESULTS: Of 2287 infants admitted to NICUs, 1914 (83.7%) survived to discharge, and 1514 (79.8% = 1514/1897) were followed up. Moderate to severe neurodevelopmental impairment was 11% overall, and the incidence decreased with increasing gestational age (GA): 25, 23, 15, 13, 9 and 7% at 23, 24, 25, 26, 27 and 28 weeks, respectively. Male gender, major intraventricular haemorrhage, late-onset sepsis, chronic lung disease and post-natal corticosteroid therapy were found to be independently associated with increased risk of moderate to severe impairment. Compared with an incidence of 16% in the 1998-2004 cohort, there was a significant reduction in moderate to severe neurodevelopmental impairment in the current cohort (unadjusted odds ratio: 0.65, 95% confidence interval: 0.52-0.80). CONCLUSIONS: We report the latest neurodevelopmental outcomes of extremely to very preterm infants in NSW and the ACT. Neurodevelopmental outcome rates based on GA alone may not provide the true estimate as these outcomes can vary based on the presence or absence of other relevant perinatal factors.

Patterns of use of near-infrared spectroscopy in neonatal intensive care units: international usage survey.

AIM: To assess uptake and applications of near-infrared spectroscopy (NIRS) by neonatal intensive care units (NICUs). METHODS: A pre-piloted online questionnaire was distributed in May 2015 to 12 perinatal societies in Asia, Europe, Australasia, North America and Middle East for dissemination to NICUs. Questions surveyed demographics, NIRS research/clinical applications, usage frequency, training approaches and target infant populations. RESULTS: In total, 255 responses from 235 NICUs were obtained. Of these, 85 (36%) owned a NIRS device. Australian and New Zealand NICUs were more likely to own NIRS technology than Asian (OR 1.12, 95% CI: 0.38-3.37) and North American (OR 2.63, 95% CI: 1.07-6.45) NICUs. A total of 69 (71%) used NIRS within clinical or mixed clinical-research settings, however routine reliance for management and prognostication was low (9% and 3%, respectively). Of those without NIRS technology, 96 (64%) had no acquisition intentions. The main limiting factors were controversial evidence on efficacy (59%) and financial considerations (50%). About 51% of respondents received in-house NIRS training and 32% had access to written guidelines. CONCLUSION: There is considerable geographical variation in NIRS usage in NICUs that is, on the whole, limited by consumer perception of lack of evidence for its clinical utility. This knowledge gap should be addressed by future research.

Magnetic noninvasive acupuncture for infant comfort (MAGNIFIC) - a single-blinded randomised controlled pilot trial.

AIM: To determine the safety and feasibility of auricular noninvasive magnetic acupuncture (MA) to decrease infant pain during heel pricks. METHODS: Infants requiring heel pricks for blood collection were randomised to either MA (n = 21) or placebo (P) (n = 19) after parental informed consent. MA or placebo stickers were placed on both ears according to the Battlefield Protocol by an unblinded investigator and left on for 3 days. Pain was assessed with the Premature Infant Pain Profile (PIPP) by blinded clinicians. RESULTS: Mean gestation (MA:34.1, P:34.4 weeks) and age of infants (MA:5.3, P:4.5 days) were similar as were mean (SD) pre (MA:1.7(1.4), P:2.1(1.9)) and post (MA:1.6(1.4), P: 2.1(1.7)) heel prick PIPP scores. PIPP scores were significantly lower in MA infants during heel pricks (MA:5.9(3.7), P: 8.3(4.7), p = 0.04). One-way ANCOVA modelling showed that MA was significantly associated with lower PIPP scores after controlling for analgesic use (p = 0.043). No differences in heart rate, oxygen saturation, analgesic use or adverse effects (e.g. local skin reactions) noted. CONCLUSION: This pilot study shows that auricular MA is feasible in neonates and may reduce PIPP scores during heel pricks. Further study is required to determine the impact of MA on other painful or stressful conditions and on neurodevelopment.

Cerebral oxygenation as measured by near-infrared spectroscopy in neonatal intensive care: correlation with arterial oxygenation.

AIM: To assess correlation between cerebral oxygenation (rScO2 ), as measured by near-infrared spectroscopy (NIRS), and arterial oxygenation (PaO2 ), as measured by arterial blood gases, in preterm neonates. METHODS: Preterm neonates <37 weeks gestation with an indwelling arterial vascular catheter were recruited between April and August 2015 from the neonatal intensive care unit of the Royal Hospital for Women, Randwick NSW, Australia. The NIRS sensor was placed on the frontolateral aspect of the head prior to arterial gas sampling. NIRS, blood gas and clinical observation data were analysed using mixed linear modelling. RESULTS: Twenty-two neonates between 24 and 31 weeks gestation (mean 27.6 weeks) were recruited, and 75 readings obtained. No significant correlation was identified between cerebral oxygenation (rScO2 ) and arterial oxygenation (PaO2 ) (p = 0.37). There was also no significant correlation between rScO2 and clinically relevant parameters of SaO2 (p = 0.06), SpO2 (p = 0.44) and PaCO2 (p = 0.79). CONCLUSION: This study did not demonstrate any correlation between NIRS values and arterial oxygenation in clinically stable preterm infants. These results highlight some of the difficulties in clinical interpretation of NIRS values in neonatal intensive care, and further evaluation is needed to determine the applicability of NIRS to management of preterm infants.

Prediction of outcomes of extremely low gestational age newborns in Australia and New Zealand.

OBJECTIVE: To determine the accuracy of the National Institute of Child Health and Human Development (NICHD) calculator in predicting death and neurodevelopmental impairment in Australian and New Zealand infants. DESIGN: Population-based cohort study. SETTING: Australia and New Zealand. PATIENTS: Preterm infants 22-25 completed weeks gestation. INTERVENTIONS: Comparison of NICHD calculator predicted rates of death and death or neurodevelopmental impairment, with actual rates recorded in the Australian and New Zealand Neonatal Network cohort. MAIN OUTCOME MEASURES: Infant death and death or neurodevelopmental impairment rates. RESULTS: A total of 714 infants were included in the study. Of these infants, 100 (14.0%) were <24 weeks, 389 (54.5%) male, 529 (74.1%) were singletons, 42 (5.9%) had intrauterine growth restriction, 563 (78.9%) received antenatal steroids and 625 (87.5 %) were born in a tertiary hospital. There were 288 deaths (40.3%), 75 infants (10.5%) with neurodevelopment impairment and 363 (50.8%) with death or neurodevelopmental impairment. The area under the curve (AUC) for prediction of death and the composite death or neurodevelopmental impairment by the NICHD calculator in our population was 0.65(95% CI 0.61 to 0.69) and 0.65 (95% CI 0.61 to 0.69), respectively. When stratified and compared with gestational age outcomes, the AUC did not change substantially for the outcomes investigated. The calculator was less accurate with outcome predictions at the extreme categories of predicted outcomes-underestimation of outcomes for those predicted to have the lowest risk (<20%) and overestimation for those in the highest risk category (>80%). CONCLUSION: In our recent cohort of extremely preterm infants, the NICHD model does not accurately predict outcomes and is marginally better than gestational age based outcomes.

Reference Ranges for Neonatal Basal Ganglia Perfusion as Measured by Fractional Moving Blood Volume.

BACKGROUND: Regional changes in cerebral blood flow and perfusion are implicated in the pathogenesis of adverse neurological events that lead to death and severe disability in the newborn infant. The basal ganglia, in particular, are extremely sensitive to acute hypoxia in the perinatal period, but normal perfusion to this area is unknown. OBJECTIVES: To establish a reference range for regional basal ganglia perfusion using fractional moving blood volume (FMBV) as an index. METHODS: Head ultrasounds were performed on neonates from 25 to 41 weeks' gestation. Power Doppler images were obtained from a pre-specified coronal plane. FMBV was calculated offline after selecting the basal ganglia as a region of interest. The average of five calculations was considered to be representative of the regional perfusion for each neonate. The data were analysed, and a neonatal reference range was defined. RESULTS: 124 neonates were included in the study, and all had analysable data. The mean FMBV was 28.8% (±9.6) with a reference range defined as 10-48%. The mean FMBV for neonates <32 weeks', 32-35 weeks' and >35 weeks' gestation were 29.4% (±7.8), 29.2% (±11.0) and 27.4% (±9.7), respectively. Analysis of variance showed no significant difference between neonates based on gestation. CONCLUSIONS: We have successfully used the index FMBV to define a reference range for perfusion in the basal ganglia. These data can be used as a reference for subsequent studies that evaluate basal ganglia perfusion in pathological conditions.