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AIM: Apnoea of prematurity requires prompt intervention to prevent long-term adverse outcomes, but specific recommendations about the stimulation approach are lacking. Our study investigated the modalities of tactile stimulation for apnoea of prematurity in different settings. METHODS: In this multi-country observational prospective study, nurses and physicians of the neonatal intensive care units were asked to perform a tactile stimulation on a preterm neonatal manikin simulating an apnoea. Features of the stimulation (body location and hand movements) and source of learning (training course or clinical practice) were collected. RESULTS: Overall, 112 healthcare providers from five hospitals participated in the study. During the stimulation, the most frequent location were feet (72%) and back (61%), while the most frequent techniques were rubbing (64%) and massaging (43%). Stimulation modalities different among participants according to their hospitals and their source of learning of the stimulation procedures. CONCLUSION: There was a large heterogeneity in stimulation approaches adopted by healthcare providers to counteract apnoea in a simulated preterm infant. This finding may be partially explained by the lack of specific guidelines and was influenced by the source of learning for tactile stimulation.

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BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

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BACKGROUND: Patients who experience cardiorespiratory events usually have to be moved to specialized centers to perform cardiorespiratory studies. To avoid the transfer of these patients to specialized centers, a network has been created based on an interchange system, where the recordings were uploaded in unspecialized centers (spokes) and downloaded by the Sleep Disorders Breathing (SDB) Center (hub) to be analyzed. METHODS: The inter-hospital network was established in November 2008. Initially only 3 non-tertiary hospitals in the Tuscany Region joined the network. Currently, 12 Tuscany hospitals are included. RESULTS: From November 2008 to December 2020, 625 recordings were collected belonging to 422 infants. No recurrent life-threatening episode or infant death occurred in the study population and none of the infants needed to be readmitted or be moved to a tertiary center, except infants who underwent home monitoring. The discharge diagnoses belong to the following categories: apnoea, respiratory problem of the newborn, syncope, gastroesophageal reflux, altered consciousness, transient loss of consciousness and cyanosis. CONCLUSIONS: This study shows that the inter-hospital network is an efficient system that allows accurate and safe management of infants at risk for apnoea, bradycardia, and hypoxemia to remain in unspecialized centers, avoiding unnecessary transfers of patients and over - hospitalizations.

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AIM: To understand the variations in practice for caffeine use among neonatal units in the United Kingdom. METHODS: An online survey was sent to every neonatal unit in the United Kingdom. RESULTS: We received a response from 92 neonatal units (47%) with the proportion of response from special care, Local neonatal units, neonatal intensive care units and neonatal surgical units were 23%, 34%, 23% and 21% respectively. All the units reported the use of caffeine, and 40 units (46%) initiated caffeine within 24 h of birth. Fifty-nine units (64%) reported routine use of caffeine for pre-term infants <32 weeks. Seventy-one units (77%) reported that they continue caffeine for infants needing mechanical ventilation. Thirty-one units (34%) discontinued caffeine at 34 weeks post-menstrual age, irrespective of the respiratory support. Ten units (11%) reported discontinuation of caffeine only after weaning off all respiratory support, and 40% of units had a variable practice of discontinuing caffeine depending on the individual baby. Seventy-nine units (86%) reported they would regularly optimise caffeine dose based on weight checks. CONCLUSION: Our survey showed some variation in practice with regards to the timing of caffeine initiation, gestational age cut-off for routine caffeine prescription and discontinuation.

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Infants who are born prematurely are at significant risk of apnoea. In addition to the short-term consequences such as hypoxia, apnoea of prematurity has been associated with long-term morbidity, including poor neurodevelopmental outcomes. Clinical trials have illustrated the importance of methylxanthine drugs, in particular caffeine, in reducing the risk of long term adverse neurodevelopmental outcomes. However, the extent to which apnoea is causative of this secondary neurodevelopmental delay or is just associated in a background of other sequelae of prematurity remains unclear. In this review, we first discuss the pathophysiology of apnoea of prematurity, previous studies investigating the relationship between apnoea and neurodevelopmental delay, and treatment of apnoea with caffeine therapy. We propose a need for better methods of measuring apnoea, along with improved understanding of the neonatal brain's response to consequent hypoxia. Only then can we start to disentangle the effects of apnoea on neurodevelopment in preterm infants. Moreover, by better identifying those infants who are at risk of apnoea, and neurodevelopmental delay, we can work toward a risk stratification system for these infants that is clinically actionable, for example, with doses of caffeine tailored to the individual. Optimising treatment of apnoea for individual infants will improve neonatal care and long-term outcomes for this population.

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AIM: Neonatal intensive care unit (NICU) nurses provide tactile stimulation to terminate apnoea in preterm infants, but guidelines recommending specific methods are lacking. In this study, we evaluated current methods of tactile stimulation performed by NICU nurses. METHODS: Nurses were asked to demonstrate and explain their methods of tactile stimulation on a manikin, using an apnoea scenario. All nurses demonstrated their methods three times in succession, with the manikin positioned either prone, supine or lateral. Finally, the nurses were asked how they decided on the methods of tactile stimulation used. The stimulation methods were logged in chronological order by describing both the technique and the location. The nurses' explanations were transcribed and categorised. RESULTS: In total, 47 nurses demonstrated their methods of stimulation on the manikin. Overall, 57 different combinations of technique and location were identified. While most nurses (40/47, 85%) indicated they learned how to stimulate during their training, 15/40 (38%) of them had adjusted their methods over time. The remaining 7/47 (15%) stated that their stimulation methods were self-developed. CONCLUSION: Tactile stimulation performed by NICU nurses to terminate apnoea was highly variable in both technique and location, and these methods were based on either prior training or intuition.

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AIMS: The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach. METHODS: Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnoea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modelling of caffeine in Chinese preterm newborn on a population-wide scale was conducted using NONMEM. RESULTS: A 1-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70 and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L. CONCLUSION: A population PK model of caffeine was developed in Chinese newborns. Body weight-implemented allometric scaling, postmenstrual age and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants.

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Apnoea, a pause in respiration, is almost ubiquitous in preterm infants born before completing 30 weeks gestation. Apnoea often begets hypoxemia and/or bradycardia, and has the potential to result in adverse neurodevelopmental consequences. Our current inability to predict apnoeic events in preterm infants requires apnoea to first be detected by monitoring device/s in order to trigger an intervention by bedside (medical or nursing) staff. Such a reactive management approach is laborious, and makes the consequences of apnoeic events inevitable. Recent technological advances and improved signal processing have allowed the possibility of developing prediction models for apnoeic events in preterm infants. However, the development of such models has numerous challenges and is only starting to show potential. This paper identifies requisite components and current gaps in developing prediction models for apnoeic events, and reviews previous studies on predicting apnoeic events in preterm infants.

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Hyperreflexia of the peripheral chemoreceptors is a potential contributor of apnoeas of prematurity (AoP). Recently, it was shown that elevated P2X3 receptor expression was associated with elevated carotid body afferent sensitivity. Therefore, we tested whether P2X3 receptor antagonism would reduce AoP known to occur in newborn rats. Unrestrained whole-body plethysmography was used to record breathing and from this the frequency of apnoeas at baseline and following administration of either a P2X3 receptor antagonist - AF-454 (5 mg/kg or 10 mg/kg s.c.) or vehicle was derived. In a separate group, we tested the effects of AF-454 (10 mg/kg) on the hypoxic ventilatory response (10 % FiO2). Ten but not 5 mg/kg AF-454 reduced the frequency of AoP and improved breathing regularity significantly compared to vehicle. Neither AF-454 (both 5 and 10 mg/kg) nor vehicle affected baseline respiration. However, P2X3 receptor antagonism (10 mg/kg) powerfully blunted hypoxic ventilatory response to 10 % FiO2. These data suggest that P2X3 receptors contribute to AoP and the hypoxic ventilatory response in newborn rats but play no role in the drive to breathe at rest.

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NEW FINDINGS: What is the topic of this review? We review the influence of prematurity on the cardiorespiratory system and examine the common sequel of alterations in oxygen tension, and immune activation in preterm infants. What advances does it highlight? The review highlights neonatal animal models of intermittent hypoxia, hyperoxia and infection that contribute to our understanding of the effect of stress on neurodevelopment and cardiorespiratory homeostasis. We also focus on some of the important physiological pathways that have a modulatory role on the cardiorespiratory system in early life. ABSTRACT: Preterm birth is one of the leading causes of neonatal mortality. Babies that survive early-life stress associated with immaturity have significant prevailing short- and long-term morbidities. Oxygen dysregulation in the first few days and weeks after birth is a primary concern as the cardiorespiratory system slowly adjusts to extrauterine life. Infants exposed to rapid alterations in oxygen tension, including exposures to hypoxia and hyperoxia, have altered redox balance and active immune signalling, leading to altered stress responses that impinge on neurodevelopment and cardiorespiratory homeostasis. In this review, we explore the clinical challenges posed by preterm birth, followed by an examination of the literature on animal models of oxygen dysregulation and immune activation in the context of early-life stress.

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AIM: We investigated the characteristics and effects of sleep stage, supplemental oxygen and caffeine on periodic breathing (PB) and apnoea of prematurity (AOP) in preterm infants. METHODS: This 2013-2015 study recruited 21 preterm infants on neonatal wards in the Helsinki and Uusimaa Hospital District, Finland, at a median corrected gestational age of 35.7 weeks and performed polysomnography at baseline, during supplemental oxygen and during caffeine treatment. RESULTS: All infants demonstrated PB, during a median of 11% of sleep time and 85% of PB occurred during non-rapid eye movement sleep (NREM). Apnoea episodes were brief during PB, but 66% were associated with oxygen desaturation. Supplemental oxygen substantially reduced PB time by 99% and caffeine by 91%. Oxygen desaturation decreased from 38 per hour at baseline to 8.5 with oxygen and 24 with caffeine (all p < 0.001). AOPs decreased from 1.4 per hour at baseline to 0.4 with oxygen (p = 0.03) and 0.3 with caffeine (p = 0.07). Most (84%) apnoea episodes over 15 seconds were mixed episodes during REM sleep. CONCLUSION: PB occurred predominantly during NREM sleep, caused intermittent hypoxia, and was suppressed by supplemental oxygen and caffeine. In contrast, long apnoea episodes representing AOP were only modestly decreased.

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Respiratory infections among infants constitute a major burden to health care systems in developed nations, yet the course and risk factors leading to these conditions are poorly understood. We examine the longitudinal patterns of respiratory infection hospitalisation (RIH) and how these patterns are influenced by neonatal pulmonary morbidities. We included all live births (n = 429 058) occurring in the Australian state of Queensland between January 2009 and December 2015. Data were structured so that each participant had a record (present/absent) of RIH for each month from birth to 12 months. Initially, latent class growth analysis was used to identify the trajectories of RIH adjusted for spatial-temporal factors; using the identified trajectories of RIH as outcomes, we built a multinomial logistic regression model to identify neonatal predictors of RIH trajectories. Our results indicated that a four-class solution was the best fit to the data, comprising a 'no-risk' trajectory, a 'low-risk' trajectory, an 'early-risk' trajectory and a 'chronic-risk' trajectory. Compared with the no-risk trajectory, membership in the other trajectories was predicted by a range of neonatal pulmonary morbidities, with transient tachypnoea of newborn showing a specific relationship with the early-risk group and sleep apnoea showing a specific and strong risk with the chronic-risk group. Our findings suggest the possibility of identifying neonates at risk of recurrent RIH and implementing effective intervention strategies prior to neonatal discharge.

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STUDY OBJECTIVES: Pulse-oximetry (SpO2 ) allows the identification of important clinical physiology. However, summary statistics such as mean values and desaturation incidence do not capture the complexity of the information contained within continuous recordings. The aim of this study was to develop an objective method to quantify important SpO2 characteristics; and assess its utility in healthy infant and preterm neonate cohorts. METHODS: An algorithm was developed to calculate the desaturation incidence, depth, and duration. These variables are presented using three plots: SpO2 cumulative-frequency relationship; desaturation-depth versus incidence; desaturation-duration versus incidence. This method was applied to two populations who underwent nocturnal pulse-oximetry: (1) thirty-four healthy term infants studied at 2-weeks, 3, 6, 12, and 24-months of age and (2) thirty-seven neonates born <26 weeks and studied at discharge from NICU (37-44 weeks post-conceptual age). RESULTS: The maturation in healthy infants was characterized by reduced desaturation index (27.2/h vs 3.3/h at 2-weeks and 24-months, P < 0.01), and increased percentage of desaturation events ≥6-s in duration (27.8% vs 43.2% at 2-weeks and 3-months, P < 0.01). Compared with term-infants, preterm infants had a greater desaturation incidence (54.8/h vs 27.2/h, P < 0.01), and these desaturations were deeper (52.9% vs 37.6% were ≥6% below baseline, P < 0.01). The incidence of longer desaturations (≥14-s) in preterm infants was correlated with healthcare utilization over the first 24-months (r = 0.63, P < 0.01). CONCLUSIONS: This tool allows the objective comparison of extended oximetry recordings between groups and for individuals; and serves as a basis for the development of reference ranges for populations.

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