Smell and taste of milk during tube feeding of preterm infants: neurodevelopmental follow-up of the randomized TASTE trial, study protocol.

BACKGROUND: The Taste And Smell To Enhance nutrition (TASTE) trial investigated the effects of smell and taste of milk with tube feeding compared to routine care on the growth of preterm infants. There was no difference between groups in growth (weight, head circumference, length) z-scores at discharge from the hospital. Infants in the intervention group had higher head circumference and length z-scores at 36 weeks postmenstrual age, both secondary outcomes. The objective of this follow-up study is to assess 2-year neurodevelopmental and growth outcomes after exposure of preterm infants to the smell and taste of milk with tube feeding compared to routine care. METHODS: This is a neurodevelopmental follow-up study of a two-center, placebo-controlled randomized trial. Infants born before 29 weeks postmenstrual age and/or with a birth weight of less than 1250 g were randomized to smell and taste of milk with each tube feed or routine care. The current follow-up assessed the 2-year neurodevelopmental and growth outcomes of participants of the TASTE trial discharged from the hospital (n = 334). The primary outcome is survival free of any major neurodevelopmental impairment comprising any moderate/severe cerebral palsy (Gross Motor Function Classification System score II-V), Bayley Scales of Infant and Toddler Development, Third/Fourth Edition (Bayley-III/Bayley-4) motor, cognitive, or language scores < -2SD, blindness, or deafness at 2 years of age. Other outcomes include death, breastfeeding within the first year, and respiratory support, oral feeding, and anthropometric parameters at 2 years of age. The Human Research Ethics Committees of Mater Misericordiae Limited and the Royal Women's Hospital approved the TASTE trial including the neurodevelopmental follow-up described in this protocol. DISCUSSION: For patients and their families, the neurodevelopmental outcomes of preterm infants are of utmost importance. Consequently, they should be investigated following any interventional study performed during the newborn period. Furthermore, improved weight gain and head growth in the hospital are associated with better long-term neurodevelopmental outcomes. Smelling and tasting of milk is an uncomplicated and cost-effective intervention that may improve the growth and neurodevelopmental outcomes of preterm infants. Potential limitations affecting this follow-up study, caused by the COVID-19 pandemic, are anticipated and discussed in this protocol. TRIAL REGISTRATION: Name of the registry: Australian and New Zealand Clinical Trials Registry; Registration number: ACTRN12617000583347 ; Registration date: 26 April 2017.

Higher versus lower nasal continuous positive airway pressure for extubation of extremely preterm infants in Australia (ÉCLAT): a multicentre, randomised, superiority trial.

BACKGROUND: Extremely preterm infants often require invasive mechanical ventilation, and clinicians aim to extubate these infants as soon as possible. However, extubation failure occurs in up to 60% of extremely preterm infants and is associated with increased mortality and morbidity. Nasal continuous positive airway pressure (nCPAP) is the most common post-extubation respiratory support, but there is no consensus on the optimal nCPAP level to safely avoid extubation failure in extremely preterm infants. We aimed to determine if higher nCPAP levels compared with standard nCPAP levels would decrease rates of extubation failure in extremely preterm infants within 7 days of their first extubation. METHODS: In this multicentre, randomised, open-label controlled trial done at three tertiary perinatal centres in Australia, we assigned extremely preterm infants to extubation to either higher nCPAP (10 cmH2O) or standard nCPAP (7 cmH2O). Infants were eligible if they were born at less than 28 weeks' gestation, were receiving mechanical ventilation via an endotracheal tube, and were being extubated for the first time to nCPAP. Eligible infants must have received previous treatment with exogenous surfactant and caffeine. Infants were ineligible if they were planned to be extubated to a mode of respiratory support other than nCPAP, if they had a known major congenital anomaly that might affect breathing, or if ongoing intensive care was not being provided. Parents or guardians provided prospective, written, informed consent. Infants were maintained within an assigned nCPAP range for a minimum of 24 h after extubation (higher nCPAP group 9-11 cmH2O and standard nCPAP group 6-8 cmH2O). Randomisation was stratified by both gestation (22-25 completed weeks or 26-27 completed weeks) and recruiting centre. The primary outcome was extubation failure within 7 days and analysis was by intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12618001638224. FINDINGS: Between March 3, 2019, and July 31, 2022, 483 infants were born at less than 28 weeks and admitted to the recruiting centres. 92 infants were not eligible, 172 were not approached, 65 families declined to participate, and 15 consented but were not randomly assigned. 139 infants were enrolled and randomly assigned, 70 to the higher nCPAP group and 69 to the standard nCPAP group. One infant in the higher nCPAP group was excluded from the analysis because consent was withdrawn after randomisation. 104 (75%) of 138 mothers were White. The mean gestation was 25·7 weeks (SD 1·3) and the mean birthweight was 777 grams (201). 70 (51%) of 138 infants were female. Extubation failure occurred in 24 (35%) of 69 infants in the higher nCPAP group and in 39 (57%) of 69 infants in the standard nCPAP group (risk difference -21·7%, 95% CI -38·5% to -3·7%). There were no significant differences in rates of adverse events between groups during the primary outcome period. Three patients died (two in the higher nCPAP group and one in the standard nCPAP group), pneumothorax occurred in one patient from each group, spontaneous intestinal perforation in three patients (two in the higher nCPAP group and one in the standard nCPAP group) and there were no events of pulmonary interstitial emphysema. INTERPRETATION: Extubation of extremely preterm infants to higher nCPAP significantly reduced extubation failure compared with extubation to standard nCPAP, without increasing rates of adverse effects. Future larger trials are essential to confirm these findings in terms of both efficacy and safety. FUNDING: National Health and Medical Research Council Centre for Research Excellence in Newborn Medicine, number 1153176.

Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants.

Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1ß and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.

Decreasing delivery room intubations: A quality improvement project.

AIM: The delivery room intubation rate for babies born less than 32 weeks postmenstrual age (PMA) at the Mater Mothers' Hospital in 2017 was 51%. Delivery room intubation of preterm infants may be associated with an increased risk of developing bronchopulmonary dysplasia. This quality improvement project aimed to decrease the rate of delivery room intubation for infants born less than 32 weeks PMA. METHODS: A quality improvement process using the evidence-based practice for improving quality framework and Plan-Do-Study-Act cycles was undertaken from October 2018 to December 2019. Commencing bubble continuous positive airway pressure for initial resuscitation in the delivery room was the principal change idea. RESULTS: The delivery room intubation rate for infants born less than 32 weeks PMA before the commencement of this project was 48% (cohort 1, n = 221). There was a significant decrease in the rate to 37.2% while the project was being conducted (cohort 2, n = 277) and a further significant reduction to 28.2% after introducing bubble continuous positive airway pressure in the delivery room (cohort 3, n = 202). There was a significant improvement in admission temperatures and a significant decrease in mortality rate between cohort 1 and cohort 2 but not between cohort 2 and cohort 3. There was no change in the rate of discharge home on oxygen between cohorts. CONCLUSIONS: This quality improvement project led to a significantly decreased delivery room intubation rate in infants born less than 32 weeks PMA. There was no evidence of any adverse outcomes with this approach.

Effects on Growth of Smell and Taste of Milk During Tube Feeding of Preterm Infants: A Randomized Clinical Trial.

Importance: Smell and taste of food increase food anticipation, activate gut motility, and stimulate digestion and metabolism. Despite poor growth of many preterm infants in neonatal intensive care units, the smell and taste of milk with tube feeding are not generally considered a regular component of care. Objective: To determine the effect of smell and taste of milk with tube feeding on weight z scores at discharge from the hospital. Design, Setting, and Participants: A randomized, controlled, nonblinded, superiority trial was conducted at 2 perinatal centers between May 9, 2017, and February 1, 2020. Eligible infants (n = 659) were born at less than 29 weeks' postmenstrual age (PMA) and/or with a birth weight of less than 1250 g. Interventions: Infants were randomly assigned to receive either the smell and taste of milk with each tube feeding or routine care without the provision of smell and taste of milk. Main Outcomes and Measures: The primary outcome was weight z score at discharge from any hospital. Secondary outcomes included anthropometric measures at predefined time points, time to full enteral feeds, and other health outcomes associated with prematurity. Results: Of the 658 infants, a total of 396 infants were randomized; some parents had not been approached for consent (n = 144) or declined participation (n = 117), and 1 infant with consent was not randomized. Of the 396 infants, 196 were assigned to the treatment group (51% male; mean [SD] PMA at birth, 27.5 [2.2] weeks) and 200 were assigned to the control group (52% male; mean [SD] PMA at birth, 27.6 (2.3) weeks). Mean weight z scores at discharge were -0.87 (95% CI, -1.02 to -0.72) for the treatment group and -0.97 (95% CI, -1.11 to -0.83) for the control group (P = .40). The mean difference in z scores between the treatment and control groups at 36 weeks' PMA was 0.21 (95% CI, 0.01 to 0.4; P = .04) for head circumference and 0.26 (95% CI, 0.05 to 0.51; P = .04) for length. There were no clinically notable differences between the study groups for any other anthropometric, feeding, or health outcomes. Conclusions and Relevance: In this randomized clinical trial, regular smell and taste of milk included with tube feeding did not improve weight at discharge in preterm infants. Secondary outcomes suggest exposure to smell and taste may improve head circumference and length at 36 weeks' PMA, but not at discharge. Regular exposure to the smell and taste of milk is a simple and inexpensive intervention with potential benefits and no apparent adverse effects. Trial Registration: anzctr.org.au Identifier: ACTRN12617000583347.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

The effect of smell and taste of milk during tube feeding of preterm infants (the Taste trial): a protocol for a randomised controlled trial.

INTRODUCTION: Smell and taste of milk are not generally considered when tube feeding preterm infants. Preterm infants have rapid growth, particularly of the brain, and high caloric needs. Enteral feeding is often poorly tolerated which may lead to growth failure and long-term neurodevelopmental impairment. Smell and taste are strong stimulators of digestion and metabolism. We hypothesise that regular smell and taste during tube feeding will improve weight z-scores of very preterm infants at discharge from hospital. METHODS AND ANALYSIS: Taste is a randomised, unblinded two-centre trial. Infants born at <29 weeks' gestation and/or <1250 g at birth and admitted to a participating neonatal intensive care unit are eligible. Randomisation occurs before infants receive two hourly feeds for 24 hours. Infants are randomised to either smell and taste of milk with each tube feed or tube feeding without the provision of smell and taste. The primary outcome is weight z-score at discharge. Secondary outcomes include: days to full enteral feeds, duration of parenteral nutrition, rate of late-onset sepsis, post menstrual age at removal of nasogastric tube and at discharge from hospital, anthropometric data and neurodevelopmental outcomes at 2 years of corrected age. ETHICS AND DISSEMINATION: Human Research Ethics Committees of Mater Misericordiae (trial reference number: HREC/16/MHS/112) and the Royal Women's Hospital (trial reference number: 17/21) last approved the trial protocol (version 4.2; Date: 18 December 2018) and recruitment commenced in May 2017 and November 2017, respectively. The trial results will be published in a peer-reviewed journal and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12617000583347.

Neonatal Cardiovascular Function after Antenatal Sildenafil for Severe, Early-Onset Intrauterine Growth Restriction: A Substudy of the STRIDER-NZAus Randomized Placebo-Controlled Trial.

We evaluated the effect of antenatal sildenafil on neonatal cardiovascular function in a subgroup of 27 infants of mothers participating in the STRIDER-NZAus randomized controlled trial. In this small study, we found no association between antenatal sildenafil and neonatal cardiac dysfunction including no pulmonary hypertension in exposed or unexposed infants.

Smell and taste in the preterm infant.

Olfaction and gustation are critical for the enjoyment of food but also have important metabolic roles, initiating the cephalic phase response that sets in train secretion of hormones important for metabolism and digestion before any food is actually ingested. Smell and taste receptors are functional in the fetus and there is evidence for antenatal learning of odours. Despite enteral nutrition and metabolism being major issues in the care of very preterm infants, often little consideration is given to the potential role of smell and taste in supporting these processes, or in the role they may have in encoding hypothalamic circuitry in a way that promotes healthy metabolism in the post­neonatal period. This review will discuss the evidence for the role of smell and taste in the newborn infant.

Smell and Taste to Improve Nutrition in Very Preterm Infants: A Randomized Controlled Pilot Trial.

BACKGROUND: The perception of smell and taste, though present early in development, is not routinely considered in the care of preterm infants. Smell and taste are known to increase gut motility, insulin secretion, and the release of appetite, digestive and metabolic hormones. OBJECTIVE: We aimed to investigate the effect of regular smell and taste on the time from birth to full enteral feeds, and the feasibility of the study protocol in very preterm infants. METHODS: In a randomized controlled trial, infants <29 weeks' postmenstrual age (PA) were assigned to receive either the smell and taste of milk before each feed or to have no exposure to the smell and taste of milk (control). RESULTS: Infants in the treatment group (n = 28) and control group (n = 23) were born at a mean (SD) PA of 26.7 (1.5) and 27.2 (1.4) weeks, respectively. They reached full enteral feeds at a median (IQR) of 13.5 (10.0-19.0) and 15.5 (11.0-22.0) days, respectively. Survival analysis showed an adjusted hazard ratio of 1.63 (95% confidence interval 0.91-2.91; p = 0.10) for the effect on the time to establish full enteral feeds. Repeated-measures analysis indicated significant group differences in weight z scores at 36 weeks' PA and at discharge in favor of the intervention (p < 0.05). CONCLUSION: These data indicate that the smell and taste of milk may improve milk tolerance and weight in preterm infants. The role of regular smell and taste in promoting enteral nutrition and growth in preterm infants merits a larger trial powered to detect important outcomes.

Hemodynamic effects of nasal continuous positive airway pressure in preterm infants with evolving chronic lung disease, a crossover randomized trial.

Previous studies suggest that high airway pressure may compromise cardiac output. We investigated the effect of 3 nasal continuous positive airway pressure levels on cardiac output in preterm infants with evolving chronic lung disease. We found that brief changes in continuous positive airway pressure did not affect cardiac output.

The effects of nasal continuous positive airway pressure on cardiac function in premature infants with minimal lung disease: a crossover randomized trial.

OBJECTIVE: To assess the effects of different nasal continuous positive airway pressure (nCPAP) pressures on cardiac performance in preterm infants with minimal lung disease, we conducted a randomized, blinded crossover study. STUDY DESIGN: We studied infants between 28 and 34 weeks' corrected gestational age, treated with nCPAP of 5 cm H2O, in air. Infants with significant cardiac shunts were excluded. Infants were randomly assigned to nCPAP levels of 4, 6, and 8 cm H2O for 15 minutes each. Right and left ventricular outputs and left pulmonary artery and superior vena cava flows were measured 15 minutes after each change. RESULTS: Thirty-four infants born at a mean gestational age of 29 weeks with a birth weight of 1.3 kg were studied. There were no significant differences in right and left ventricular outputs and left pulmonary artery and superior vena cava flows at different levels of nCPAP. CONCLUSION: We investigated the effect of increasing nCPAP levels on cardiac output. We conclude that nCPAP levels between 4 and 8 cm H2O did not have an effect on cardiac output in stable preterm infants with minimal lung disease.

Echocardiographic assessment of left ventricular outflow tract diameter in preterm infants.

Introduction: Left ventricular output (LVO) measurement is an important part of the echocardiographic assessment of cardiac function in preterm infants. The accurate measurement of left ventricular outflow tract diameter (LVOD) is key to the calculation of LVO. Given the lack of an appropriate gold standard, we used right ventricular output (RVO) as the comparator and sought to identify the most accurate method of determining LVO in preterm infants. Methods: We studied stable preterm infants without significant cardiac shunts. LVOD was measured at the aortic valve, the aortic sinus and at the sinotubular junction. LVOs were calculated and the precision and accuracy of each was determined relative to the RVO using the Bland-Altman method. Results: 52 infants were included in this analysis. The mean difference between RVO and LVO was largest when LVOD was measured at the aortic valve and aortic sinus, +106 and -115 ml/kg/min, respectively, and smallest when measured at the sinotubular junction, 9 ml/kg/min. Limits of agreement between RVO and LVO were narrowest when LVOD was measured at the STJ. Conclusion: LVOD measurement at the sinotubular junction provides more precise and accurate measurement of LVO, in comparison to RVO, than measurement at the aortic valve or the aortic sinus.

Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons.

The effects of intravenous (i.v.) anaesthetics on nicotinic acetylcholine receptor (nAChR)-induced transients in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and membrane currents were investigated in neonatal rat intracardiac neurons. In fura-2-loaded neurons, nAChR activation evoked a transient increase in [Ca(2+)](I), which was inhibited reversibly and selectively by clinically relevant concentrations of thiopental. The half-maximal concentration for thiopental inhibition of nAChR-induced [Ca(2+)](i) transients was 28 microM, close to the estimated clinical EC(50) (clinically relevant (half-maximal) effective concentration) of thiopental. In fura-2-loaded neurons, voltage clamped at -60 mV to eliminate any contribution of voltage-gated Ca(2+) channels, thiopental (25 microM) simultaneously inhibited nAChR-induced increases in [Ca(2+)](i) and peak current amplitudes. Thiopental inhibited nAChR-induced peak current amplitudes in dialysed whole-cell recordings by approximately 40% at -120, -80 and -40 mV holding potential, indicating that the inhibition is voltage independent. The barbiturate, pentobarbital and the dissociative anaesthetic, ketamine, used at clinical EC(50) were also shown to inhibit nAChR-induced increases in [Ca(2+)](i) by approximately 40%. Thiopental (25 muM) did not inhibit caffeine-, muscarine- or ATP-evoked increases in [Ca(2+)](i), indicating that inhibition of Ca(2+) release from internal stores via either ryanodine receptor or inositol-1,4,5-trisphosphate receptor channels is unlikely. Depolarization-activated Ca(2+) channel currents were unaffected in the presence of thiopental (25 microM), pentobarbital (50 microM) and ketamine (10 microM). In conclusion, i.v. anaesthetics inhibit nAChR-induced currents and [Ca(2+)](i) transients in intracardiac neurons by binding to nAChRs and thereby may contribute to changes in heart rate and cardiac output under clinical conditions.

Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons.

The origin of intracellular Ca2+ concentration ([Ca2+]i) transients stimulated by nicotinic (nAChR) and muscarinic (mAChR) receptor activation was investigated in fura-2-loaded neonatal rat intracardiac neurons. ACh evoked [Ca2+]i increases that were reduced to approximately 60% of control in the presence of either atropine (1 microM) or mecamylamine (3 microM) and to <20% in the presence of both antagonists. Removal of external Ca2+ reduced ACh-induced responses to 58% of control, which was unchanged in the presence of mecamylamine but reduced to 5% of control by atropine. The nAChR-induced [Ca2+]i response was reduced to 50% by 10 microM ryanodine, whereas the mAChR-induced response was unaffected by ryanodine, suggesting that Ca2+ release from ryanodine-sensitive Ca2+ stores may only contribute to the nAChR-induced [Ca2+]i responses. Perforated-patch whole cell recording at -60 mV shows that the rise in [Ca2+]i is concomitant with slow outward currents on mAChR activation and with rapid inward currents after nAChR activation. In conclusion, different signaling pathways mediate the rise in [Ca2+]i and membrane currents evoked by ACh binding to nicotinic and muscarinic receptors in rat intracardiac neurons.