Lung ultrasound score parallels trends in systemic haemodynamics after PDA ligation: a case series.

B-lines in lung ultrasound (LU) are non-specific but highly informative sign of interstitial pulmonary oedema (iPE). Sustained exposure to a high-volume left-to-right patent ductus arteriosus (PDA) shunt is associated with iPE. Cardiorespiratory deterioration, named post-ligation cardiac syndrome (PLCS), may follow surgical ligation between 6 and 12 h post-operatively. We conducted a pilot longitudinal evaluation of peri-procedural LU score change. Infants < 32-week gestational age or < 1500-g birthweight undergoing PDA ligation, where pre-, 1 h and 6-12 h LU were performed, were included. Two independent raters evaluated LU score (LUS). Neonatologist performed echocardiography (NPE) was performed concurrently to appraise changes in left ventricular output (LVO). Milrinone was initiated if LVO was < 200 mL/kg/min 1 h after surgery, to prevent PLCS. The primary outcome was peri-procedural LUS change. Secondary outcomes included PLCS. Five infants were included (birthweight 787(88) g; gestational age 25.6(0.7) weeks). Postnatal age and weight at the intervention were 41(14) days and 1175(295) g. All infants, but one, received milrinone prophylaxis. None of the patients developed PLCS or required rescue HFOV. Post-interventional LUS were lower compared to pre-operative LUS (p = 0.041 vs 1 h, p = 0.042 vs 6-12 h). A concurrent fall post-operative LVO was noted (p < 0.05 vs pre-operative). CONCLUSION: A sustained fall in LUS after PDA ligation was identified, which most likely reflects reduction in pulmonary blood flow and interstitial edema. Changes in LUS paralleled changes in LVO, suggesting physiologic linkage. These data suggest that LU may be a useful tool to guide monitoring the biologic nature of pulmonary disease after PDA ligation. WHAT IS KNOWN: • Sustained exposure to a high-volume left-to-right patent ductus arteriosus (PDA) shunt is associated with interstitial pulmonary oedema. • In the most immature patients, cardiorespiratory deterioration, named post-ligation cardiac syndrome, presents 6-12 h post-operatively. WHAT IS NEW: • An early and sustained fall in lung ultrasound score (LUS) after PDA ligation most likely reflects reduction in pulmonary blood flow and interstitial oedema. LUS changes parallel changes in left ventricular output, suggesting linkage. • LU is a promising adjunctive tool in the post-operative management of PDA ligation.

Pulmonary hypertension in a neonatologist-performed echocardiographic follow-up of bronchopulmonary dysplasia.

Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation, including pulmonary hypertension (PH). PH may complicate bronchopulmonary dysplasia (BPD) course. Aims of this retrospective study were to assess the feasibility of NPE follow-up of infants with BPD and to describe the course of PH of infants with moderate/severe BPD. Preterm infants <32 gestational weeks or birthweight ≤1500 g with moderate/severe BPD underwent NPE follow-up, from 36 weeks postmenstrual age up to 8 months postnatal age. Twenty-three preemies were included (birth weight 840 (213) g, gestational age 26.8 (2.3) weeks); 12/23 developed mild PH, 2/12 after discharge. PH resolved at 8.9 (3.9) months. Clinical and echocardiographic variables did not differ between infants with and without PH, except pulmonary artery acceleration time (PAAT) and PAAT/right ventricle ejection time (RVET) ratio (PAAT: 36 weeks, 68.9 (11.9) vs 52.0 (19.1), p = 0.0443; 6 months: 83.9 (38.9) vs 74.8 (16.9), p = 0.0372). No deaths or admissions for PH were reported. Neonatologist's Image Quality Assessment score attributed by the cardiologist assumed as gold standard was adequate or optimal (9.5/14 total score); inter-rater agreement was excellent (ICC 0.974).Conclusions: NPE follow-up seems to be feasible and safe in both intensive care and outpatient clinic. Mild PH is frequently detected in moderate/severe BPD, with good prognosis. What is Known: • Preterm infants with bronchopulmonary dysplasia (BPD) may develop pulmonary hypertension (PH) and have a late diagnosis. • Neonatologist-performed echocardiography (NPE) is an established tool for bedside hemodynamic evaluation of the neonate. What is New: • To our knowledge this is the first study of NPE follow-up of moderate/severe BPD, describing the course of mild PH from diagnosis to its resolution. • NPE follow-up of BPD seems to be safe and practicable, in both intensive care and outpatient clinic, as long as neonatologists maintain a sound collaboration with pediatric cardiologists.

Lung function between 8 and 15 years of age in very preterm infants with fetal growth restriction.

BACKGROUND: The impact of intrauterine growth restriction (IUGR) on lung function in very preterm children is largely unknown as current evidence is mainly based on studies in children born small for gestational age but not necessarily with IUGR. METHODS: Spirometry, transfer factor of the lung for carbon monoxide (TLco), and lung clearance index (LCI) were cross-sectionally evaluated at 8.0-15.0 years of age in children born <32 weeks of gestation with IUGR (n = 28) and without IUGR (n = 67). Controls born at term (n = 67) were also included. RESULTS: Very preterm children with IUGR had lower mean forced expired volume in the first second (FEV1) z-score than those with normal fetal growth (∆ -0.66, 95% confidence interval (CI) -1.12, -0.19), but not significant differences in LCI (∆ +0.24, 95% CI -0.09, 0.56) and TLco z-score (∆ -0.11, 95% CI -0.44, 0.23). The frequency of bronchopulmonary dysplasia (BPD) in the two groups was, respectively, 43% and 10% (P = 0.003). IUGR was negatively associated with FEV1 (B = -0.66; P = 0.004), but the association lost significance (P = 0.05) when adjusting for BPD. CONCLUSIONS: IUGR has an impact on conducting airways function of very preterm children at school age, with part of this effect being mediated by BPD. Ventilation inhomogeneity and diffusing capacity, instead, were not affected. IMPACT: IUGR does not necessarily imply a low birthweight for gestational age (and vice versa). While a low birthweight is associated with worse respiratory outcomes, the impact of IUGR on lung function in premature children is largely unknown. IUGR affects conducting airways function in school-age children born <32 weeks with IUGR, but not ventilation inhomogeneity and diffusing capacity. The impact of IUGR on FEV1 seems mainly related to the higher risk of BPD in this group.

Regional ventilation inhomogeneity in survivors of extremely preterm birth.

INTRODUCTION: Survivors of extreme prematurity may have disrupted lung development. We hypothesized that the multiple breath washout (MBW) index Scond, which is intended to reflect ventilation inhomogeneity from the conducting airways, could be a sensitive marker of respiratory impairment in this group. METHODS: Spirometry, TLco, and MBW were cross-sectionally evaluated at 8 to 14 years of age in children born at <28 weeks between 2004 and 2010 in Udine, Italy. Age-matched controls born at term were also included. Bronchopulmonary dysplasia (BPD) was defined as oxygen-dependence at 36 weeks postmenstrual age. The limits of normal were the 5th percentile of the reference population (Global Lung Initiative) for spirometry and TLco and the 95th percentile of controls for Lung Clearance Index, Scond, and Sacin from MBW. RESULTS: Results were obtained in 47 extremely preterm children (53% boys, mean ± standard deviation age 11.3 ± 2.0 years, 40% with BPD) and 60 controls (50% boys, 11.6 ± 1.9 years). There were significant differences between preterm children and controls in all lung function outcomes, except for Sacin. Among children born <28 weeks, Scond tended to be frequently abnormal than FEV1 z-score (29% vs 14%, P = .06). At multivariable linear regression, in the preterm group, current asthma was significantly associated with a higher Scond (B = 0.019, 95% confidence interval, 0.000-0.038), whereas BPD was not. CONCLUSION: Almost a third of extremely preterm children at school age showed Scond alterations that affected also children without BPD. Longitudinal studies should clarify the prognostic meaning of Scond abnormalities in this group.

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. METHODS: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. DISCUSSION: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. TRIAL REGISTRATION: NCT03162653, www.ClinicalTrials.gov , May 22, 2017.

In vivo measure of neonate brain optical properties and hemodynamic parameters by time-domain near-infrared spectroscopy.

By exploiting a multichannel portable instrument for time-domain near-infrared spectroscopy (TD-NIRS), we characterized healthy neonates' brains in term of optical properties and hemodynamic parameters. In particular, we assessed the absolute values of the absorption and reduced scattering coefficients at two wavelengths, together with oxy-, deoxy- and total hemoglobin concentrations, and the blood oxygen saturation of the neonates' brains. In this study, 33 healthy full-term neonates were tested, obtaining the following median values: 0.28 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; 5.8 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; 72% for [Formula: see text]. In general, the agreement of these values with the sparse existing literature appears not always consistent. These findings demonstrate the first measurements of optical properties of the healthy neonate brain using TD-NIRS and show the need for clarification of optical properties across methods and populations.

Brain regions and functional interactions supporting early word recognition in the face of input variability.

Perception and cognition in infants have been traditionally investigated using habituation paradigms, assuming that babies' memories in laboratory contexts are best constructed after numerous repetitions of the very same stimulus in the absence of interference. A crucial, yet open, question regards how babies deal with stimuli experienced in a fashion similar to everyday learning situations-namely, in the presence of interfering stimuli. To address this question, we used functional near-infrared spectroscopy to test 40 healthy newborns on their ability to encode words presented in concomitance with other words. The results evidenced a habituation-like hemodynamic response during encoding in the left-frontal region, which was associated with a progressive decrement of the functional connections between this region and the left-temporal, right-temporal, and right-parietal regions. In a recognition test phase, a characteristic neural signature of recognition recruited first the right-frontal region and subsequently the right-parietal ones. Connections originating from the right-temporal regions to these areas emerged when newborns listened to the familiar word in the test phase. These findings suggest a neural specialization at birth characterized by the lateralization of memory functions: the interplay between temporal and left-frontal regions during encoding and between temporo-parietal and right-frontal regions during recognition of speech sounds. Most critically, the results show that newborns are capable of retaining the sound of specific words despite hearing other stimuli during encoding. Thus, habituation designs that include various items may be as effective for studying early memory as repeated presentation of a single word.

Predictive algorithms for early detection of retinopathy of prematurity.

PURPOSE: To evaluate sensitivity, specificity and the safest cut-offs of three predictive algorithms (WINROP, ROPScore and CHOP ROP) for retinopathy of prematurity (ROP). METHODS: A retrospective study was conducted in three centres from 2012 to 2014; 445 preterms with gestational age (GA) ≤ 30 weeks and/or birthweight (BW) ≤ 1500 g, and additional unstable cases, were included. No-ROP, mild and type 1 ROP were categorized. The algorithms were analysed for infants with all parameters (GA, BW, weight gain, oxygen therapy, blood transfusion) needed for calculation (399 babies). RESULTS: Retinopathy of prematurity (ROP) was identified in both eyes in 116 patients (26.1%), and 44 (9.9%) had type 1 ROP. Gestational age and BW were significantly lower in ROP group compared with no-ROP subjects (GA: 26.7 ± 2.2 and 30.2 ± 1.9, respectively, p < 0.0001; BW: 839.8 ± 287.0 and 1288.1 ± 321.5 g, respectively, p = 0.0016). Customized alarms of ROPScore and CHOP ROP correctly identified all infants having any ROP or type 1 ROP. WINROP missed 19 cases of ROP, including three type 1 ROP. ROPScore and CHOP ROP provided the best performances with an area under the receiver operating characteristic curve for the detection of severe ROP of 0.93 (95% CI, 0.90-0.96, and 95% CI, 0.89-0.96, respectively), and WINROP obtained 0.83 (95% CI, 0.77-0.87). Median time from alarm to treatment was 11.1, 5.1 and 9.1 weeks, for WINROP, ROPScore and CHOP ROP, respectively. CONCLUSION: ROPScore and CHOP ROP showed 100% sensitivity to identify sight-threatening ROP. Predictive algorithms are a reliable tool for early identification of infants requiring referral to an ophthalmologist, for reorganizing resources and reducing stressful procedures to preterm babies.

Lung Ultrasound Diagnostic Accuracy in Neonatal Pneumothorax.

Background. Pneumothorax (PTX) still remains a common cause of morbidity in critically ill and ventilated neonates. At the present time, lung ultrasound (LUS) is not included in the diagnostic work-up of PTX in newborns despite of excellent evidence of reliability in adults. The aim of this study was to compare LUS, chest X-ray (CXR), and chest transillumination (CTR) for PTX diagnosis in a group of neonates in which the presence of air in the pleural space was confirmed. Methods. In a 36-month period, 49 neonates with respiratory distress were enrolled in the study. Twenty-three had PTX requiring aspiration or chest drainage (birth weight 2120 ± 1640 grams; gestational age = 36 ± 5 weeks), and 26 were suffering from respiratory distress without PTX (birth weight 2120 ± 1640 grams; gestational age = 34 ± 5 weeks). Both groups had done LUS, CTR, and CXR. Results. LUS was consistent with PTX in all 23 patients requiring chest aspiration. In this group, CXR did not detect PTX in one patient while CTR did not detect it in 3 patients. Sensitivity and specificity in diagnosing PTX were therefore 1 for LUS, 0.96 and 1 for CXR, and 0.87 and 0.96 for CTR. Conclusions. Our results confirm that also in newborns LUS is at least as accurate as CXR in the diagnosis of PTX while CTR has a lower accuracy.

On the edge of language acquisition: inherent constraints on encoding multisyllabic sequences in the neonate brain.

To understand language, humans must encode information from rapid, sequential streams of syllables - tracking their order and organizing them into words, phrases, and sentences. We used Near-Infrared Spectroscopy (NIRS) to determine whether human neonates are born with the capacity to track the positions of syllables in multisyllabic sequences. After familiarization with a six-syllable sequence, the neonate brain responded to the change (as shown by an increase in oxy-hemoglobin) when the two edge syllables switched positions but not when two middle syllables switched positions (Experiment 1), indicating that they encoded the syllables at the edges of sequences better than those in the middle. Moreover, when a 25 ms pause was inserted between the middle syllables as a segmentation cue, neonates' brains were sensitive to the change (Experiment 2), indicating that subtle cues in speech can signal a boundary, with enhanced encoding of the syllables located at the edges of that boundary. These findings suggest that neonates' brains can encode information from multisyllabic sequences and that this encoding is constrained. Moreover, subtle segmentation cues in a sequence of syllables provide a mechanism with which to accurately encode positional information from longer sequences. Tracking the order of syllables is necessary to understand language and our results suggest that the foundations for this encoding are present at birth.

A 16q deletion involving FOXF1 enhancer is associated to pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary capillary hemangiomatosis (PCH) is an uncommon pulmonary disorder, with variable clinical features depending on which lung structure is affected, and it is usually linked to pulmonary arterial hypertension. Congenital PCH has been very rarely described and, so far, the only causative gene identified is EIF2AK4, which encodes for a translation initiation factor. However, not all PCH cases might carry a mutation in this gene. CASE PRESENTATION: We report the clinical and cytogenetic characterization of a patient (male, newborn, first child of healthy non-consanguineous parents) died after three days of life with severe neonatal pulmonary hypertension, due to diffuse capillary hemangiomatosis diagnosed post mortem. Conventional karyotyping, Microarray-Based Comparative Genomic Hydridization (CGHa) and quantitative PCR were performed. CGHa revealed a heterozygous chromosome 16q23.3q24.1 interstitial deletion, spanning about 2.6 Mb and involving a FOXF1 gene enhancer. Quantitative PCR showed that the proband's deletion was de novo. Microsatellite analysis demonstrate that the deletion occurred in the maternal chromosome 16. CONCLUSION: FOXF1 loss of function mutation have been so far identified in alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), a lung disease different from PCH. Our data suggest the hypothesis that disruption of the FOXF1 gene enhancer could be a genetic determinant of PCH. Moreover, our findings support the idea that FOXF1 is a paternally imprinted gene.

Neonatal Lung Sonography: Interobserver Agreement Between Physician Interpreters With Varying Levels of Experience.

OBJECTIVES: To assess the reliability of lung sonography in neonates between physician interpreters with different degrees of experience. METHODS: We retrospectively reviewed lung sonograms from neonates admitted to a neonatal intensive care unit with respiratory distress in the first 24 hours of life. The first scans were selected; only patients with available video clips documenting both hemithoraxes were included. The clips were independently examined by 4 different experienced observers blinded to clinical data. The interpreting physicians made a codified sonographic diagnosis, and the Cohen κ coefficient was used to measure the reliability between a proven experienced main interpreter and expert (κ1), intermediate (κ2), and beginner (κ3) control interpreters. We also calculated the specific agreement on respiratory distress syndrome and transient tachypnea of the neonate. RESULTS: Four hundred sixty-five clips were taken from 114 neonates examined over a 16-month period. The patients' median gestational age (range) was 34 weeks (25-41 weeks), and the median birth weight (range) was 2085 g (608-4134 g). Eighty-eight percent of examinations were performed within 24 hours after birth. The overall κ coefficients (95% confidence intervals) were κ1 = 0.94 (0.88-1.00); κ2 = 0.72 (0.61-0.83); and κ3 = 0.81 (0.71-0.90). For respiratory distress syndrome, κ1 = 0.94 (0.87-1.00); κ2 = 0.90 (0.81-0.99); and κ3 = 0.87 (0.78-0.97). For transient tachypnea of the neonate, κ1 = 0.95 (0.89-1.00); κ2 = 0.76 (0.64-0.88); and κ3 = 0.81 (0.70-0.91). CONCLUSIONS: In neonates with early respiratory distress, lung sonography has high interobserver agreement even between interpreters with varying levels of experience.

Lung ultrasound accuracy in respiratory distress syndrome and transient tachypnea of the newborn.

BACKGROUND: Lung ultrasound (LUS) is a promising technique for the diagnosis of neonatal respiratory diseases. Preliminary data has shown a good sensitivity and specificity of LUS in the diagnosis of respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN). OBJECTIVE: The aim of this study was to calculate the sensitivity, specificity, and negative (NPV) and positive predictive value (PPV) of LUS for RDS and TTN, using an external reader blinded to the clinical condition. DESIGN AND METHODS: Neonates with respiratory distress had a LUS within 1 h of admission. Images were uploaded and sent to the external reader, who made the ultrasound diagnosis according to the appearance of the images. The final clinical diagnosis was made according to all the available data, except LUS data. Sensitivity, specificity, PPV, and NPV were calculated considering the final clinical diagnosis as the gold standard. RESULTS: Fifty-nine neonates were studied (mean gestational age: 33 ± 4 weeks, mean birth weight: 2,145 ± 757 g). Twenty-three infants had a final diagnosis of RDS and 30 of TTN. LUS showed a sensitivity of 95.6% and specificity of 94.4%, with a PPV of 91.6% and a NPV of 97.1% for RDS, and a sensitivity of 93.3% and specificity of 96.5% with a PPV of 96.5% and a NPV of 93.4% for TTN. CONCLUSIONS: LUS showed high sensitivity and specificity in diagnosing RDS and TTN.

Language universals at birth.

The evolution of human languages is driven both by primitive biases present in the human sensorimotor systems and by cultural transmission among speakers. However, whether the design of the language faculty is further shaped by linguistic biological biases remains controversial. To address this question, we used near-infrared spectroscopy to examine whether the brain activity of neonates is sensitive to a putatively universal phonological constraint. Across languages, syllables like blif are preferred to both lbif and bdif. Newborn infants (2-5 d old) listening to these three types of syllables displayed distinct hemodynamic responses in temporal-perisylvian areas of their left hemisphere. Moreover, the oxyhemoglobin concentration changes elicited by a syllable type mirrored both the degree of its preference across languages and behavioral linguistic preferences documented experimentally in adulthood. These findings suggest that humans possess early, experience-independent, linguistic biases concerning syllable structure that shape language perception and acquisition.

Lung ultrasound: its role in neonatology and pediatrics.

BACKGROUND: Lung ultrasound (LUS) has become more and more popular in the first decade of the 21(st) century, both in neonatal and in pediatric age groups. Several papers addressed the usefulness of this procedure mainly because of its possibility to be utilised at the bedside, without risk of irradiation along with simple and immediate interpretations of the images. AIMS: The purpose of this paper is to update the knowledge on LUS related to the most common neonatal respiratory diseases and some pediatric acute lung diseases. STUDY DESIGN: We describe the technique of LUS execution, the normal LUS appearance and the LUS findings in the most common neonatal and pediatric acute diseases. SUBJECTS: LUS findings related to neonates of different gestational age as well as of pediatric patients from infancy to childhood are shown. OUTCOME MEASURES: Issues on the evolution and effect of treatment related to LUS findings of neonatal and pediatric respiratory diseases are discussed. RESULTS: LUS depicted peculiar and reproducible patterns in all the lung diseases described. CONCLUSIONS: The use of LUS in the clinical field seems to be a reasonable and easy-to-use practice that can be considered an extension of the clinical exam. As a consequence of this feature, LUS, to fully express its potential, must be performed by the clinician in charge of the patient.

Surfactant administration for neonatal respiratory distress does not improve lung interstitial fluid clearance: echographic and experimental evidence.

OBJECTIVE: Recent ultrasonographic studies suggest that the administration of surfactant to preterm infants with respiratory distress syndrome (RDS) does not affect lung water clearance. The purpose of the study was also to look at clearance of lung water in preterm rabbits receiving surfactant. METHODS: Lung ultrasound was performed in 73 neonates at different gestational ages (range 23-34 weeks) with radiological and clinical signs of RDS, before and after surfactant administration. In premature rabbits (28-29 days' gestational age), either receiving or not receiving surfactant, we followed the time course of lung water balance considering the wet weight/dry weight ratio, the morphology and compliance of alveoli and pulmonary interstitial pressure. RESULTS: In all RDS infants lung ultrasound images consistently showed a generalized increase in extravascular lung fluid which remained unchanged after surfactant administration and did not affect the rate of fluid clearance. Surfactant administration in premature rabbits did not improve the time course of lung fluid clearance. CONCLUSIONS: Data from ultrasound in preterm babies are confirmed by animal experiments.