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Creative music therapy (CMT) has been shown to promote the development of brain function and structure in preterm infants. We aimed to investigate the effect of CMT on cerebral oxygenation and perfusion to examine how the brain reacts to CMT. Absolute levels of cerebrovascular oxygen saturation (StO 2 ) were measured in clinically stable preterm-born neonates (n = 20, gestational age: ≥30 weeks and < 37 weeks) using two near-infrared spectroscopy (NIRS)-based tissue oximeters over the right prefrontal cortex and left auditory cortex. We applied the systemic physiology augmented functional NIRS approach. Each CMT session lasted 55 min and involved 9 intervals, including two 10-minute intervals during which the music therapist hummed and held the neonate. We found that CMT-induced changes in cerebrovascular StO 2 , perfusion and systemic physiology (i) could be classified into two groups (group 1: increase in StO 2 during the first singing interval, group 2: decrease in StO 2 ), (ii) differed in female neonates compared to male neonates, and (iii) correlated with individual blood haematocrit levels. Our exploratory study (i) demonstrates the impact of CMT on the neonate's physiology and (ii) highlights the need to analyze functional NIRS measurements in neonates separately according to their response pattern to avoid erroneous conclusions, e.g. when only the group average of the signal change is determined., Competing Interests: Declarations Competing interests F.H., T.K., T.R., T.R., B.C.H.V., E.O., H.Z, H.U.B., U.W. and D.B. declare no conflict of interest. D.O. and S.K. are affiliated with and MW is co-founder and president of the board of OxyPrem AG (a University of Zurich spin-off that produces an improved version of the near-infrared spectroscopy oximeters employed in the study). S.K., D.O., and M.W. had no influence on how the data were analyzed by F.S. F. S. provided scientific consulting for companies producing fNIRS devices (NIRx GmbH, Berlin, Germany; Kernel, Culver City, Los Angeles, USA)., (© 2024. The Author(s).)

Background: Infants born prematurely are at risk of developing retinopathy of prematurity, which is associated with abnormalities in retinal function as measured using electroretinography. The aim of this study was to record non-invasive flicker electroretinograms (ERGs) in preterm infants and compare function of moderate and very or extremely preterm infants., Methods: In this non-randomized, cross-sectional study, 40 moderate preterm (gestational age (GA) 34 0/7 to 36 6/7 weeks, Group A) and 40 very or extremely preterm infants (GA ≤ 31 weeks, Group B) were recruited for flicker ERG recording through closed eyelids using the RETeval® device and skin electrodes. Group A was tested within the first week of life and Group B between 34th and 37th week postmenstrual age. Flicker stimuli were presented at 28.3 Hz with stimulus levels of 3, 6, 12, 30 and 50 cd•s/m 2 . Primary endpoints were peak time (ms) and amplitude (µV)., Results: Flicker ERGs were recordable in most infants with the highest proportion of reproducible ERGs at 30 cd•s/m 2 . Amplitudes increased with stronger flicker stimulation, while peak times did not differ significantly between stimulus levels nor groups. Amplitudes were significantly greater in Group B at the strongest stimulus level (Mann-Whitney-U-Test=198.00, Z = 4.097, p = <0.001)., Conclusions: Feasibility of collecting flicker ERG data in most preterm infants was confirmed. We found no evidence of reduced retinal responses to flicker stimuli associated with extreme prematurity. Higher amplitudes in very and extremely preterm infants could indicate acceleration of retinal development following birth, triggered by visual stimulation., (© 2024. The Author(s).)

Background: Physiological changes during the insertion of a rescue nasopharyngeal tube (NPT) after birth are unclear., Methods: Observational study of very preterm infants in the delivery room. Data were extracted at predefined timepoints starting with first facemask placement after birth until 5 min after insertion of NPT. End-expiratory lung impedance (EELI), heart rate (HR) and SpO 2 /FiO 2 -ratio were analysed over time. Changes during the same time span of NIPPV via facemask and NIPPV via NPT were compared., Results: Overall, 1154 inflations in 15 infants were analysed. After NPT insertion, EELI increased significantly [0.33 AU/kg (0.19-0.57), p < 0.001]. Compared with the mask period, changes in EELI were not significantly larger during the NPT period [median difference (IQR) = 0.14 AU/kg (-0.14-0.53); p = 0.12]. Insertion of the NPT was associated with significant improvement in HR [52 (33-96); p = 0.001] and SpO 2 /FiO 2 -ratio [161 (69-169); p < 0.001] not observed during the mask period., Conclusions: In very preterm infants non-responsive to initial facemask ventilation after birth, insertion of an NPT resulted in a considerable increase in EELI. This additional gain in lung volume was associated with an immediate improvement in clinical parameters. The use of a NPT may prevent intubation in selected non-responsive infants., Impact: After birth, a nasopharyngeal tube may be considered as a rescue airway in newborn infants non-responsive to initial positive pressure ventilation via facemask. Although it is widely used among clinicians, its effect on lung volumes and physiological parameters remains unclear. Insertion of a rescue NPT resulted in a considerable increase in lung volume but this was not significantly larger than during facemask ventilation. However, insertion of a rescue NPT was associated with a significant and clinically important improvement in heart rate and oxygenation. This study highlights the importance of individual strategies in preterm resuscitation and introduces the NPT as a valid option., (© 2024. The Author(s).)

Rationale: The respiratory mechanisms of a successful transition of preterm infants after birth are largely unknown. Objectives: To describe intrapulmonary gas flows during different breathing patterns directly after birth. Methods: Analysis of electrical impedance tomography data from a previous randomized trial in preterm infants at 26-32 weeks gestational age. Electrical impedance tomography data for individual breaths were extracted, and lung volumes as well as ventilation distribution were calculated for end of inspiration, end of expiratory braking and/or holding maneuver, and end of expiration. Measurements and Main Results: Overall, 10,348 breaths from 33 infants were analyzed. We identified three distinct breath types within the first 10 minutes after birth: tidal breathing (44% of all breaths; sinusoidal breathing without expiratory disruption), braking (50%; expiratory brake with a short duration), and holding (6%; expiratory brake with a long duration). Only after holding breaths did end-expiratory lung volume increase: Median (interquartile range [IQR]) = 2.0 AU/kg (0.6 to 4.3), 0.0 (-1.0 to 1.1), and 0.0 (-1.1 to 0.4), respectively; P  < 0.001]. This was mediated by intrathoracic air redistribution to the left and non-gravity-dependent parts of the lung through pendelluft gas flows during braking and/or holding maneuvers. Conclusions: Respiratory transition in preterm infants is characterized by unique breathing patterns. Holding breaths contribute to early lung aeration after birth in preterm infants. This is facilitated by air redistribution during braking / holding maneuvers through pendelluft flow, which may prevent lung liquid reflux in this highly adaptive situation. This study deciphers mechanisms for a successful fetal-to-neonatal transition and increases our pathophysiological understanding of this unique moment in life. Clinical trial registered with www.clinicaltrials.gov (NCT04315636).

Objectives: To assess the clinical efficacy, safety, and potential physiological mechanisms of highflow therapy with superimposed high frequency oscillations ("osciflow")., Study Design: In this prospective, randomized, single center crossover trial, 30 preterm infants were randomized to receive osciflow or highflow therapy first, each for 180 min. During osciflow, an oscillatory amplitude of 20 mbar and a frequency of 6 Hz were set. The flow rate was 4 L/min during both interventions. Primary outcome was the paired difference in the combined number of desaturations (SpO 2  < 80%) and bradycardia (heart rate <80 beats per min) between interventions. Safety outcomes included nasal trauma, pneumothorax and treatment failure, and a pain score was assessed. In 20 infants, electrical impedance tomography (EIT) recordings were performed to evaluate oscillatory (V Osc ) and tidal volumes (V T ) at the lung level., Results: Infants with a mean (SD) postnatal age of 33.1 ± 1.2 weeks were included. The median (IQR) number of episodes of desaturation and bradycardia was 19.5 (6-49) during osciflow and 26 (6-44) during highflow therapy (paired difference -2; IQR -10 to 9; p = .37). There were no differences in safety outcomes and pain scores. During osciflow, EIT recordings showed a signal at 6 Hz, which was not detectable during highflow. Corresponding mean (SD) V Osc /V T ratio was 9% (±5%)., Conclusions: In preterm infants, osciflow did not reduce the number of desaturations and bradycardia compared with highflow therapy. Although V Osc were transmitted to the lung during osciflow, their magnitude was small. Osciflow was safe and well tolerated., (© 2023 Wiley Periodicals LLC.)

Objective: The effect of prophylactic surfactant nebulisation (SN) is unclear. We aimed to determine whether prophylactic SN improves early lung aeration., Design: Parallel, randomised clinical trial, conducted between March 2021 and January 2022., Setting: Delivery room (DR) of a tertiary neonatal centre in Zurich, Switzerland., Patients: Preterm infants between 26 0/7 and 31 6/7 weeks gestation INTERVENTIONS: Infants were randomised to receive positive distending pressure alone or positive distending pressure and additional SN (200 mg/kg; poractant alfa) using a customised vibrating membrane nebuliser. SN commenced with the first application of a face mask immediately after birth., Main Outcome Measures: Primary outcome was the difference in end-expiratory lung impedance from birth to 30 min after birth (∆EELI 30min ). EELI correlates well with functional residual capacity. Secondary outcomes included physiological and clinical outcomes., Results: Data from 35 infants were collected, and primary outcome data were analysed from 32 infants (n=16/group). Primary outcome was not different between intervention and control group (median (IQR): 25 (7-62) vs 10 (0-26) AU/kg, p=0.21). ∆EELI was slightly higher in the intervention group at 6 and 12 hours after birth, particularly in the central areas of the lung. There were no differences in cardiorespiratory and clinical parameters. Two adverse events were noted in the intervention group., Conclusions: Prophylactic SN in the DR did not significantly affect ∆EELI 30min and showed only minimal effects on lung physiology. Prophylactic SN in the DR was feasible. There were no differences in clinical outcomes., Trial Registration Number: NCT04315636., Competing Interests: Competing interests: The nebulisers were provided free of charge by PARI Pharma and the EIT monitor and belts were provided by SenTec AG., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: High-grade intraventricular hemorrhage (IVH) in very preterm infants is a known risk factor for adverse neurodevelopmental outcome. Prognosis is less clear for low-grade (grades I/II) IVH however, with conflicting study results in recent years., Objective: To evaluate the impact of low-grade IVH on neurodevelopmental outcome at 2 years corrected age in preterm infants born below 32 weeks gestation at the University hospital of Zurich between 2009 and 2014., Methods: Among 843 live-born preterm infants born during the observation period, 509 were included in our study. Exclusion criteria were death, high-grade IVH, cystic periventricular leukomalacia and congenital malformations. Infants were grouped into those with or without low-grade IVH according to cranial ultrasound. Neurodevelopmental impairment (NDI) was defined as cognitive or motor developmental score > 2 standard deviations below the mean and/or CP grades 2-5 and/or moderate/severe vision loss and/or hearing problem corrected with hearing aids. Multivariate linear regression was used to assess effect of low-grade IVH on endpoints while adjusting for other risk factors., Results: 87 preterm infants had low-grade IVH (42 grade I, 45 grade II) on cranial ultrasound. These were compared to 422 preterm infants without IVH. Follow-up rate was 82.4 %. Preterm infants with low-grade IVH had higher rates of NDI (21.8 vs 13.3 %, p = 0.047). Infants with IVH grade II had significantly higher rates for CP (8.9 % vs 3.6 %, p = 0.003), visual impairment (20.5 % vs 8.3 %, p = 0.009) and NDI (33.3 % vs 13.3 %, p < 0.001)., Conclusion: In our study, low-grade IVH - and especially IVH grade II - is associated with adverse neurodevelopmental outcome at 2 years of corrected age., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Mechanisms of non-invasive high-frequency oscillatory ventilation (nHFOV) in preterm infants are unclear. We aimed to compare lung volume changes during apnoeas in preterm infants on nHFOV and nasal continuous positive airway pressure (nCPAP)., Methods: Analysis of electrical impedance tomography (EIT) data from a randomised crossover trial comparing nHFOV with nCPAP in preterm infants at 26-34 weeks postmenstrual age. EIT data were screened by two reviewers to identify apnoeas ≥10 s. End-expiratory lung impedance (EELI) and tidal volumes (V T ) were calculated before and after apnoeas. Oxygen saturation (SpO 2 ) and heart rate (HR) were extracted for 60 s after apnoeas., Results: In 30 preterm infants, 213 apnoeas were identified. During apnoeas, oscillatory volumes were detectable during nHFOV. EELI decreased significantly during apnoeas (∆EELI nCPAP: -8.0 (-11.9 to -4.1) AU/kg, p<0.001; ∆EELI nHFOV: -3.4 (-6.5 to -0.3), p=0.03) but recovered over the first five breaths after apnoeas. Compared with before apnoeas, V T was increased for the first breath after apnoeas during nCPAP (∆V T : 7.5 (3.1 to 11.2) AU/kg, p=0.001). Falls in SpO 2 and HR after apnoeas were greater during nCPAP than nHFOV (mean difference (95% CI): SpO 2 : 3.6% (2.7 to 4.6), p<0.001; HR: 15.9 bpm (13.4 to 18.5), p<0.001)., Conclusion: Apnoeas were characterised by a significant decrease in EELI which was regained over the first breaths after apnoeas, partly mediated by a larger V T . Apnoeas were followed by a considerable drop in SpO 2 and HR, particularly during nCPAP, leading to longer episodes of hypoxemia during nCPAP. Transmitted oscillations during nHFOV may explain these benefits., Trial Registration Number: ACTRN12616001516471., Competing Interests: Competing interests: VDG and CMR declare that they received an EIT monitor free of charge for a different research project by SenTec AG. All other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Our objective was to evaluate the temporal trend of systemic postnatal steroid (PNS) receipt in infants of 24-28 weeks' gestational age, identify characteristics associated with PNS receipt, and correlate PNS receipt with the incidence of bronchopulmonary dysplasia (BPD) and BPD/death from an international cohort included in the iNeo network., Methods: We conducted a retrospective study using data from 2010 to 2018 from seven international networks participating in iNeo (Canada, Finland, Israel, Japan, Spain, Sweden, and Switzerland). Neonates of 24 and 28 weeks' gestational age who survived 7 days and who received PNS were included. We assessed temporal trend of rates of systemic PNS receipt and BPD/death., Results: A total of 47,401 neonates were included. The mean (SD) gestational age was 26.4 (1.3) weeks and birth weight was 915 (238) g. The PNS receipt rate was 21% (12-28% across networks) and increased over the years (18% in 2010 to 26% in 2018; p &lt; 0.01). The BPD rate was 39% (28-44% across networks) and remained unchanged over the years (35.2% in 2010 to 35.0% in 2018). Lower gestation, male sex, small for gestational age status, and presence of persistent ductus arteriosus (PDA) were associated with higher rates of PNS receipt, BPD, and BPD/death., Conclusion: The use of PNS in extremely preterm neonates increased, but there was no correlation between increased use and the BPD rate. Research is needed to determine the optimal timing, dose, and indication for PNS use in preterm neonates., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: We sought to determine the effect of stimulation during positive pressure ventilation (PPV) on the number of spontaneous breaths, exhaled tidal volume (VTe), mask leak and obstruction., Design: Secondary analysis of a prospective, randomised trial comparing two face masks., Setting: Single-centre delivery room study., Patients: Newborn infants ≥34 weeks' gestation at birth., Methods: Resuscitations were video recorded. Tactile stimulations during PPV were noted and the timing, duration and surface area of applied stimulus were recorded. Respiratory flow waveforms were evaluated to determine the number of spontaneous breaths, VTe, leak and obstruction. Variables were recorded throughout each tactile stimulation episode and compared with those recorded in the same time period immediately before stimulation., Results: Twenty of 40 infants received tactile stimulation during PPV and we recorded 57 stimulations during PPV. During stimulation, the number of spontaneous breaths increased (median difference (IQR): 1 breath (0-3); p adj <0.001) and VTe increased (0.5 mL/kg (-0.5 to 1.7), p adj =0.028), whereas mask leak (0% (-20 to 1), p adj =0.12) and percentage of obstructed inflations (0% (0-0), p adj =0.14) did not change, compared with the period immediately prior to stimulation. Increased duration of stimulation (p adj <0.001) and surface area of applied stimulus (p adj =0.026) were associated with a larger increase in spontaneous breaths in response to tactile stimulation., Conclusions: Tactile stimulation during PPV was associated with an increase in the number of spontaneous breaths compared with immediately before stimulation without a change in mask leak and obstruction. These data inform the discussion on continuing stimulation during PPV in term infants., Trial Registration Number: Australian and New Zealand Clinical Trial Registry (ACTRN12616000768493)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To measure changes in end-expiratory lung impedance (EELI) as a marker of functional residual capacity (FRC) during the entire extubation procedure of very preterm infants., Methods: Prospective observational study in preterm infants born at 26-32 weeks gestation being extubated to non-invasive respiratory support. Changes in EELI and cardiorespiratory parameters (heart rate, oxygen saturation) were recorded at pre-specified events during the extubation procedure compared to baseline (before first handling of the infant)., Results: Overall, 2912 breaths were analysed in 12 infants. There was a global change in EELI during the extubation procedure (p = 0.029). EELI was lowest at the time of extubation [median (IQR) difference to baseline: -0.30 AU/kg (-0.46; -0.14), corresponding to an FRC loss of 10.2 ml/kg (4.8; 15.9), p adj  = 0.004]. The biggest EELI loss occurred during adhesive tape removal [median change (IQR): -0.18 AU/kg (-0.22; -0.07), p adj  = 0.004]. EELI changes were highly correlated with changes in the SpO 2 /FiO 2 ratio (r = 0.48, p < 0.001). Forty per cent of FRC was re-recruited at the tenth breath after the initiation of non-invasive ventilation (p < 0.001)., Conclusions: The extubation procedure is associated with significant changes in FRC. This study provides novel information for determining the optimal way of extubating a preterm infant., Impact: This study is the first to examine the development of lung volumes during the entire extubation procedure including the impact of associated events. The extubation procedure significantly affects functional residual capacity with a loss of approximately 10 ml/kg at the time of extubation. Removal of adhesive tape is the major contributing factor to FRC loss during the extubation procedure. Functional residual capacity is regained within the first breaths after initiation of non-invasive ventilation and is further increased after turning the infant into the prone position., (© 2021. The Author(s).)

Rationale: There is increasing evidence for a clinical benefit of noninvasive high-frequency oscillatory ventilation (nHFOV) in preterm infants. However, it is still unknown whether the generated oscillations are effectively transmitted to the alveoli. Objectives: To assess magnitude and regional distribution of oscillatory volumes (V Osc ) at the lung level. Methods: In 30 prone preterm infants enrolled in a randomized crossover trial comparing nHFOV with nasal continuous positive airway pressure, electrical impedance tomography recordings were performed. During nHFOV, the smallest amplitude to achieve visible chest wall vibration was used, and the frequency was set at 8 hertz. Measurements and Main Results: Thirty consecutive breaths during artifact-free tidal ventilation were extracted for each of the 228 electrical impedance tomography recordings. After application of corresponding frequency filters, Vt and V Osc were calculated. There was a signal at 8 and 16 Hz during nHFOV, which was not detectable during nasal continuous positive airway pressure, corresponding to the set oscillatory frequency and its second harmonic. During nHFOV, the mean (SD) V Osc /Vt ratio was 0.20 (0.13). Oscillations were more likely to be transmitted to the non-gravity-dependent (mean difference [95% confidence interval], 0.041 [0.025-0.058]; P  < 0.001) and right-sided lung (mean difference [95% confidence interval], 0.040 [0.019-0.061]; P  < 0.001) when compared with spontaneous Vt. Conclusions: In preterm infants, V Osc during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non-gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.

Premature birth is stressful for infants and parents and can adversely affect the parent-infant dyad. This mixed-methods pilot study evaluates whether creative music therapy (CMT) can alleviate anxiety, stress, and depressive symptoms in parents and support the bonding process with their infant. Sixteen parent couples were included. Ten couples were randomly allocated to the music therapy group (MTG) and six to the control group (CG). All couples completed psychological questionnaires measuring anxiety and depressive symptoms as well as an implicit measure of parent-infant attachment at two weeks postpartum (T1), at approximate neonatal intensive care unit (NICU) hospitalization halftime (T2), and two weeks after the infant had been discharged (T3). At T1 and T2, the parents additionally completed a questionnaire assessing the degree of stress they experienced at the NICU. Qualitative data were collected through a semi-structured, problem-centered interview with MTG parents at T3. The results of the quantitative analyses revealed reductions in anxiety levels from T1 to T2 ( p = 0.002) as well as decreases in depressive symptoms from T2 to T3 ( p = 0.022). No such changes were apparent in the CG. In fact, parental stress increased from T1 to T2 ( p = 0.016). Significant increases in attachment across time were also observed within the MTG, but not in the CG. The qualitative inquiry confirmed that CMT can support the parent-infant relationship. Being in musical interaction evoked feelings of joy and relaxation in the parents and encouraged them to interact more profoundly with their infant. The results call for a more extensive powered follow-up study to further investigate CMT's potential for parental well-being and parent-infant bonding.

Aim: We surveyed care practices for critically ill very preterm infants admitted to neonatal intensive care units (NICUs) in the International Network for Evaluating Outcomes in Neonates (iNeo) to identify differences relevant to outcome comparisons., Methods: We conducted an online survey on care practices for critically ill very preterm infants and infants with severe intracranial haemorrhage (ICH). The survey was distributed in 2015 to representatives of 390 NICUs in 11 countries. Survey replies were compared with network incidence of death and severe ICH for infants born between 23 0/7 and 28 6/7  weeks of gestation from January 1, 2015, to December 31, 2015., Results: Most units in Israel, Japan and Tuscany, Italy, favoured withholding care when care was considered futile, whereas most units in other networks favoured redirection of care. For infants with bilateral grade 4 ICH, redirection of care was very frequently (≥90% of cases) offered in the majority of units in Australia and New Zealand and Switzerland, but rarely in other networks. Networks where redirection of care was frequently offered for severe ICH had lower rates of survivors with severe ICH., Conclusion: We identified marked inter-network differences in care approaches that need to be considered when comparing outcomes., (© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Creative music therapy for preterm infants and their parents (CMT) has emerged as a promising family-integrated early intervention involving communicative musicality to improve infant development, parental well-being, and bonding. It aims at relaxing and nurturing the infant as well as promoting safety and social interaction for the parent-infant dyad. A music therapist specially trained in CMT hums or sings in an infant-directed, improvised, lullaby style continually adjusting to the individual needs, expressions, and breathing pattern of the preterm infant. Based on the principles of family-integrated care, the family is incorporated individually in the therapeutic process, namely by delivering CMT during kangaroo care (KC) and by motivating and facilitating parental vocal interaction with their infant to strengthen the parent-infant bonding. CMT aims at relaxing, stimulating, and coregulating premature infants at a time when many other interventions are still risky and can overwhelm the vulnerable patient group. CMT may be advantageous not by educating and teaching parents, but rather by uncovering the intuitive capacities of parenting that are often overshadowed by the traumatic experience of preterm birth. However, CMT can only be provided when the infants are clinically stable. CMT with parental integration is feasible when parents are available and receptive to participate. This paper presents a detailed protocol on how to use CMT to empower preterm infants and their families.

Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Noninvasive high-frequency oscillatory ventilation compared with nasal continuous positive airway pressure significantly reduced the number of desaturations and bradycardia in preterm infants. However, noninvasive high-frequency oscillatory ventilation was associated with increased oxygen requirements and higher heart rates., Trial Registration: Australian and New Zealand Clinical Trial Registry: ACTRN12616001516471., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim was to determine the precision of a noninvasive near-infrared spectroscopy (NIRS)-based tissue oximeter (OxyPrem v1.3). Using a linear mixed-effects model, we quantified the variability for cerebral tissue oxygenation (StO2) measurements in 35 preterm neonates to be 2.64%, a value that meets the often-articulated clinicians' demand for a precise tissue oxygenation measurement. We showed that the variability of StO2 values measured was dominated by spontaneous systemic hemodynamic fluctuations during the measurement, meaning that precision of the instrument was actually even better. Based on simultaneous and continuous measurements of peripheral arterial oxygenation and cerebral StO2 with a second sensor, we were able to determine and quantify the physiological instability precisely. We presented different methods and analyses aiming at reducing this systematic physiological error of in vivo precision assessments. Using these methods, we estimated the precision of the OxyPrem tissue oximeter to be   ≤  1.85  %  . With our study, we deliver relevant information to establish highly precise cerebral oxygenation measurements with NIRS-based oximetry, facilitating the further development toward a substantially improved diagnosis and treatment of patients with respect to brain oxygenation., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

Background: Inhaled glucocorticoids may increase the risk of pneumonia in adults. Thus, respiratory infections may be a potential explanation for the non-significantly increased mortality seen in the glucocorticoid group in the largest randomized trial on inhaled glucocorticoids for preventing bronchopulmonary dysplasia in preterm infants published to date (NEuroSIS)., Objective: To evaluate the effect of inhaled budesonide on the risk of death due to respiratory infections in the NEuroSIS trial., Methods: We performed post hoc analyses of prospectively collected data from 856 preterm infants on presumed but not culture-proven sepsis and antimicrobial drug use. Additionally, pulmonary complications reported on adverse event forms, death certificates and autopsy reports were compared between study groups., Results: Treatment groups did not differ in the number of episodes with suspected sepsis (184/437 [42.1%] in the budesonide vs. 171/419 [40.8%] in the placebo group). Neither the number of patients receiving antimicrobial drugs nor the length of antimicrobial treatment differed between groups. Our analyses for pulmonary adverse events as well as for pulmonary complications reported on death certificates and autopsy reports did not suggest a negative impact of inhaled budesonide on these outcomes., Conclusion: The current analysis does not support the assumption that respiratory tract infections explain the increased mortality seen in the glucocorticoid group in the NEuroSIS trial., (© 2017 S. Karger AG, Basel.)

Context: Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy., Objective: To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants., Data Sources: PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources., Study Selection: Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD., Data Extraction: This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system., Results: Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks' postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I 2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I 2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I 2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days' postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I 2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events., Limitations: Long-term follow-up data are awaited from a recent large randomized controlled trial., Conclusions: Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited., (Copyright © 2016 by the American Academy of Pediatrics.)

Survival of extremely preterm infants has increased over recent years, but bronchopulmonary dysplasia (BPD) remains a major cause of morbidity. In the USA, BPD is the most common chronic respiratory disorder of infancy and affects the pulmonary and overall health of 10,000 preterm infants annually. Preclinical and clinical studies suggest a crucial role for lung inflammation and host immune response in the pathogenesis of BPD. Inflammation may result from, amongst others, chorioamnionitis, postnatal infection, ventilation, and the administration of oxygen. Infants with BPD have worse long-term outcomes than those without chronic lung disease. They are more than twice as likely to be readmitted to hospital in their first year of life and, having survived their primary hospitalizations, they are more likely to die than very preterm infants without chronic lung disease. Survivors with BPD have an increased risk of neurodevelopmental impairment and their respiratory function remains compromised well into adolescence. As the first generations of extremely low birth weight (ELBW) survivors have not yet reached retirement age, there are currently no reliable data addressing the association between BPD and pulmonary diseases of the elderly such as chronic obstructive pulmonary disease. Although BPD is quite common in ELBW infants, there are infants who do not develop BPD, which supports the argument that BPD is a preventable disease, emphasizing the need for high-quality safety and efficacy prevention studies. However, according to an Institute of Medicine statement regarding pediatric drug studies, the therapeutic area that has the fewest drugs indicated for neonates is BPD. As inflammation seems to be a primary mediator of injury in the pathogenesis of BPD, anti-inflammatory agents such as steroids have long been the focus of preventive research activities. However, systemic steroids, although reducing BPD, have frequently been linked to adverse neurodevelopmental outcomes and these considerations may have contributed to the recently reported widespread use of inhaled corticosteroids in neonatal units in North America and Europe. Inhaled corticosteroids were prescribed to 25% of infants born at <29 weeks of gestation with birth weights <1,500 g in neonatal units of 35 children's hospitals in the USA. According to a survey across all neonatal units in Germany, 46% administered inhaled corticosteroids to preterm infants either as prophylaxis or treatment for BPD [10]. Pediatricians and neonatologists should ask themselves whether the off-label use of inhaled corticosteroids in preterm infants is justifiable in view of the available evidence. The authors of the pertinent review from the Cochrane Collaboration, including 7 studies and 492 infants, conclude that there is currently no evidence to support the routine use of inhaled steroids for the prevention of BPD. Recently, the primary outcome results of the Neonatal European Study of Inhaled Steroids (NEUROSIS), including 863 very preterm infants (gestational age 23-27 weeks), have been presented at scientific conferences, but the full study report is not yet published. By contrast, intratracheal instillation of budesonide using surfactant as a vehicle has not yet become part of clinical practice. There are fewer studies addressing the risks and benefits of this mode of administration. In a randomized blinded pilot study in 116 very low birth weight infants who had severe radiographic respiratory distress syndrome and required mechanical ventilation shortly after birth, early intratracheal instillation of budesonide using surfactant as a vehicle resulted in significantly lower mean airway pressure on day 1 and day 3 and a significantly lower oxygen index and PCO2 during the first 3 days compared with infants in the control group who had received surfactant without corticosteroids. More infants were extubated in the treatment group than in the controls at 1 and 2 weeks and the combined outcome of death or chronic lung disease was significantly lower in the treatment group than in the control group (19 of 60 vs. 34 of 56). No clinically significant adverse effects were observed during the study and at the time of the follow-up assessment at 2-3 years of age. In the future, intratracheal instillation of budesonide using surfactant as a vehicle may play a role in the prevention of BPD in ELBW infants. However, before this therapy can be introduced into routine clinical care, remaining open questions need to be answered and appropriately powered studies need to be performed., (© 2015 S. Karger AG, Basel.)

Caffeine, a methylxanthine and nonspecific inhibitor of adenosine receptors, is an example of a drug that has been in use for more than 40 years. It is one of the most commonly prescribed drugs in neonatal medicine. However, until 2006, it had only a few relatively small and short-term studies supporting its use. It is thanks to the efforts of Barbara Schmidt and the Caffeine for Apnea of Prematurity (CAP) Trial Group that we now have high-quality and reliable data not only on short-term but also long-term outcomes of caffeine use for apnea of prematurity. CAP was an international, multicenter, placebo-controlled randomized trial designed to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnea of prematurity is managed without methylxanthines in infants at a high risk of apneic attacks. CAP was kept simple and pragmatic in order to allow for maximum generalizability and applicability. Infants with birth weights of 500-1,250 g were enrolled during the first 10 days of life if their clinicians considered them to be candidates for methylxanthine therapy. The most frequent indication for therapy reported in CAP was treatment of documented apnea, followed by the facilitation of the removal of an endotracheal tube. Only about 20% of the neonatologists in the trial started caffeine for the prevention of apnea and the findings of CAP cannot automatically be extrapolated to an exclusive prophylactic indication. However, recent data suggest that the administration of prophylactic methylxanthine by neonatologists is now common practice.

Background and Objectives: (1) To investigate the relationship of salivary and plasma cortisol levels in preterm infants with a focus on the usability of salivary cortisol in diagnostic work-up of infants at risk of adrenal insufficiency. (2) To perform a systematic review addressing this question., Methods: Clinical study: We conducted a prospective observational single-center study in preterm infants. We analyzed plasma and saliva cortisol concentrations by enzyme immunoassay. Correlation analysis was used to determine the relation between salivary and plasma cortisol levels and the agreement of the measurement methods was analyzed according to Bland-Altman. Systematic review: A systematic literature search (PubMed and Embase) on the relationship of salivary and plasma cortisol levels in neonates was performed in November 2012., Results: Clinical study: We enrolled 58 preterm infants (median (interquartile range) gestational age at birth was 31.4 (28.1-32.7) weeks, birth weight 1,340 (974-1,745) g, respectively). Correlation analyses revealed a relationship of plasma cortisol and salivary cortisol levels. Rank correlation coefficient was 0.6. Estimating plasma cortisol levels based on measured salivary cortisol levels showed poor agreement of the two methods for determining plasma cortisol levels (direct and via salivary cortisol). Sensitivity and specificity of salivary cortisol for the detection of adrenal insufficiency were 0.66 and 0.62, respectively. Systematic review: Six studies in preterm infants and term neonates depicting the correlation of salivary and plasma cortisol were identified with a range of saliva-plasma correlation coefficients from 0.44 to 0.83., Conclusions: Substitution of plasma cortisol by salivary cortisol determination cannot be recommended in preterm infants because of unsatisfactory agreement between methods.

Background: Necrotizing enterocolitis (NEC) is the most common serious acquired disease of the gastrointestinal tract in preterm infants. Probiotic bacteria are live microbial supplements that colonize the gastrointestinal tract and potentially provide benefit to the host., Objective: To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and other morbidities in preterm infants., Methods: A meta-analysis was performed in accordance with the Cochrane Neonatal Review Group methods. Preterm infants <37 weeks' gestational age and/or <2,500 g birth weight were included. Literature searches were made of MEDLINE, EMBASE, Cochrane Library Controlled Trials Register (CENTRAL), and abstracts of annual meetings of the Society for Pediatric Research and the European Society of Pediatric Research., Results: Nine eligible trials randomizing 1,425 infants were included. Included trials were highly variable with regard to enrollment criteria, baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. In a meta-analysis, enteral probiotics supplementation significantly reduced the incidence of severe NEC [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75)]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition [weighted mean difference -1.9 (95% CI -4.6, 0.77)]. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. The included trials reported no systemic infection with the probiotics supplemental organism., Conclusion: Enteral supplementation of probiotics reduces the risk of severe NEC and mortality in preterm infants. A large randomized controlled trial is required to investigate the benefit and safety profile of probiotics supplementation in ELBW infants., (Copyright 2009 S. Karger AG, Basel.)

Objective: To determine in a systematic review, whether interventions for infant development that involve parents, improve neurodevelopment at 12 months corrected age or older., Study Design: Randomized trials were identified where an infant intervention was aimed to improve development and involved parents of preterms; and long-term neurodevelopment using standardized tests at 12 months (or longer) was reported., Result: Identified studies (n=25) used a variety of interventions including parent education, infant stimulation, home visits or individualized developmental care. Meta-analysis at 12 months (N=2198 infants) found significantly higher mental (N=2198) and physical (N=1319) performance scores favoring the intervention group. At 24 months, the mental (N=1490) performance scores were improved, but physical (N=1025) performance scores were not statistically significant. The improvement in neurodevelopmental outcome was not sustained at 36 months (N=961) and 5 years (N=1017)., Conclusion: Positive clinically meaningful effects (>5 points) are seen to an age of 36 months, but are no longer present at 5 years.