UPDATE - 2022 Italian guidelines on the management of bronchiolitis in infants.

Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children. This document aims to update the consensus document published in 2014 to provide guidance on the current best practices for managing bronchiolitis in infants. The document addresses care in both hospitals and primary care. The diagnosis of bronchiolitis is based on the clinical history and physical examination. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Evidence suggests no benefit with the use of salbutamol, glucocorticosteroids and antibiotics with potential risk of harm. Because of the lack of effective treatment, the reduction of morbidity must rely on preventive measures. De-implementation of non-evidence-based interventions is a major goal, and educational interventions for clinicians should be carried out to promote high-value care of infants with bronchiolitis. Well-prepared implementation strategies to standardize care and improve the quality of care are needed to promote adherence to guidelines and discourage non-evidence-based attitudes. In parallel, parents' education will help reduce patient pressure and contribute to inappropriate prescriptions. Infants with pre-existing risk factors (i.e., prematurity, bronchopulmonary dysplasia, congenital heart diseases, immunodeficiency, neuromuscular diseases, cystic fibrosis, Down syndrome) present a significant risk of severe bronchiolitis and should be carefully assessed. This revised document, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of acute bronchiolitis.

Neonatal Lung Ultrasound and Surfactant Administration: A Pragmatic, Multicenter Study.

BACKGROUND: Previous research shows that a lung ultrasound score (LUS) can anticipate CPAP failure in neonatal respiratory distress syndrome. RESEARCH QUESTION: Can LUS also predict the need for surfactant replacement? STUDY DESIGN AND METHODS: Multicenter, pragmatic study of preterm neonates who underwent lung ultrasound at birth and those given surfactant by masked physicians, who also were scanned within 24 h from administration. Clinical data and respiratory support variables were recorded. Accuracy of LUS, oxygen saturation to Fio2 ratio, Fio2, and Silverman score for surfactant administration were evaluated using receiver operating characteristic curves. The simultaneous prognostic values of LUS and oxygen saturation to Fio2 ratio for surfactant administration, adjusting for gestational age (GA), were analyzed through a logistic regression model. RESULTS: Two hundred forty infants were enrolled. One hundred eight received at least one dose of surfactant. LUS predicted the first surfactant administration with an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI, 0.81-0.91), cut off of 9, sensitivity of 0.79 (95% CI, 0.70-0.86), specificity of 0.83 (95% CI, 0.76-0.89), positive predictive value of 0.79 (95% CI, 0.71-0.87), negative predictive value of 0.82 (95% CI, 0.75-0.89), positive likelihood ratio of 4.65 (95% CI, 3.14-6.89), and negative likelihood ratio of 0.26 (95% CI, 0.18-0.37). No significant difference was shown among different GA groups: 25 to 27 weeks' GA (AUC, 0.91; 95% CI, 0.84-0.99), 28 to 30 weeks' GA (AUC, 0.81; 95% CI, 0.72-0.91), and 31 to 33 weeks' GA (AUC, 0.88; 95% CI, 0.79-0.95), respectively. LUS declined significantly within 24 h in infants receiving one surfactant dose. When comparing Fio2, oxygen saturation to Fio2 ratio, LUS, and Silverman scores as criteria for surfactant administration, only the latter showed a significantly poorer performance. The combination of oxygen saturation to Fio2 ratio and LUS showed the highest predictive power, with an AUC of 0.93 (95% CI, 0.89-0.97), regardless of the GA interval. INTERPRETATION: LUS is a reliable criterion to administer the first surfactant dose regardless of GA. Its association with oxygen saturation to Fio2 ratio significantly improves the prediction power for surfactant need.

Lung Ultrasound Score Progress in Neonatal Respiratory Distress Syndrome.

BACKGROUND AND OBJECTIVES: The utility of a lung ultrasound score (LUS) has been described in the early phases of neonatal respiratory distress syndrome (RDS). We investigated lung ultrasound as a tool to monitor respiratory status in preterm neonates throughout the course of RDS. METHODS: Preterm neonates, stratified in 3 gestational age cohorts (25-27, 28-30, and 31-33 weeks), underwent lung ultrasound at weekly intervals from birth. Clinical data, respiratory support variables, and major complications (sepsis, patent ductus arteriosus, pneumothorax, and persistent pulmonary hypertension of the neonate) were also recorded. RESULTS: We enrolled 240 infants in total. The 3 gestational age intervals had significantly different LUS patterns. There was a significant correlation between LUS and the ratio of oxygen saturation to inspired oxygen throughout the admission, increasing with gestational age (b = -0.002 [P < .001] at 25-27 weeks; b = -0.006 [P < .001] at 28-30 weeks; b = -0.012 [P < .001] at 31-33 weeks). Infants with complications had a higher LUS already at birth (12 interquartile range 13-8 vs 8 interquartile range 12-4 control group; P = .001). In infants 25 to 30 weeks' gestation, the LUS at 7 days of life predicted bronchopulmonary dysplasia with an area under the curve of 0.82 (95% confidence interval 0.71 to 93). CONCLUSIONS: In preterm neonates affected by RDS, the LUS trajectory is gestational age dependent, significantly correlates with the oxygenation status, and predicts bronchopulmonary dysplasia. In this population, LUS is a useful, bedside, noninvasive tool to monitor the respiratory status.

The babyPose dataset.

The database here described contains data relevant to preterm infants' movement acquired in neonatal intensive care units (NICUs). The data consists of 16 depth videos recorded during the actual clinical practice. Each video consists of 1000 frames (i.e., 100s). The dataset was acquired at the NICU of the Salesi Hospital, Ancona (Italy). Each frame was annotated with the limb-joint location. Twelve joints were annotated, i.e., left and right shoul- der, elbow, wrist, hip, knee and ankle. The database is freely accessible at http://doi.org/10.5281/zenodo.3891404. This dataset represents a unique resource for artificial intelligence researchers that want to develop algorithms to provide healthcare professionals working in NICUs with decision support. Hence, the babyPose dataset is the first annotated dataset of depth images relevant to preterm infants' movement analysis.

Dataset from spirometer and sEMG wireless sensor for diaphragmatic respiratory activity monitoring.

We introduce a dataset to provide insights into the relationship between the diaphragm surface electromyographic (sEMG) signal and the respiratory air flow. The data presented had been originally collected for a research project jointly developed by the Department of Information Engineering and the Department of Industrial Enginering and Mathematical Sciences, Polytechnic University of Marche, Ancona, Italy. This article describes data recorded from 8 subjects, and includes 8 air flow and 8 surface electromyographic (sEMG) signals for diaphragmatic respiratory activity monitoring, measured with a sampling frequency of 2 kHz.

False positive screen test for mucopolysaccharidoses in healthy female newborns.

BACKGROUND: In total, 930 urine samples obtained on 2nd and 3rd day from birth have been analyzed for the early diagnosis of Mucopolysaccharidoses. METHODS: Dimethylmethylene blue (DMB) assay and one-dimensional electrophoresis were performed in all urine samples. Agarose gel electrophoresis, before and after treatment with chondroitinase ABC and heparinases, was used for a comprehensive characterization. RESULTS: Out of 930 urine samples 7 showed anomalous electrophoretic pattern; 5 of them had high GAG levels by DMB test. Atypical samples (n = 7) were analyzed by agarose gel electrophoresis. After enzymatic digestion, some slow bands were still visible. A second urine sample of the above 7 newborns was analyzed at the age of 1 month, demonstrating both a normal pattern and normal GAG levels. Additional urine and vaginal mucus samples from 10 term neonates with vaginal bleeding showed the same electrophoretic pattern observed in the 7 false positive samples. CONCLUSIONS: The altered electrophoretic pattern may be due to the presence of glycoproteins and not to specific GAGs, due to high levels of maternal hormones exposure during pregnancy. To our knowledge, this is the first time maternal estrogen hormones are proposed as a likely cause of false-positive urinary glycosaminoglycan screen test in healthy newborns.

Human Milk Oligosaccharides: 2'-Fucosyllactose (2'-FL) and Lacto-N-Neotetraose (LNnT) in Infant Formula.

The authors reviewed the published evidence on the presence of oligosaccharides in human milk (HMO) and their benefits in in vitro and in vivo studies. The still limited data of trials evaluating the effect of mainly 2'-fucosyllactose (2'-FL) on the addition of some of HMOs to infant formula were also reviewed. PubMed was searched from January 1990 to April 2018. The amount of HMOs in mother's milk is a dynamic process as it changes over time. Many factors, such as duration of lactation, environmental, and genetic factors, influence the amount of HMOs. HMOs may support immune function development and provide protection against infectious diseases directly through the interaction of the gut epithelial cells or indirectly through the modulation of the gut microbiota, including the stimulation of the bifidobacteria. The limited clinical data suggest that the addition of HMOs to infant formula seems to be safe and well tolerated, inducing a normal growth and suggesting a trend towards health benefits. HMOs are one of the major differences between cow's milk and human milk, and available evidence indicates that these components do have a health promoting benefit. The addition of one or two of these components to infant formula is safe, and brings infant formula closer to human milk. More prospective, randomized trials in infants are need to evaluate the clinical benefit of supplementing infant formula with HMOs.

Estimating the contribution of surfactant replacement therapy to the alveolar pool: An in vivo study based on 13 C natural abundance in rabbits.

Variation of the isotopic abundance of selected nutrients and molecules has been used for pharmacological and kinetics studies under the premise that the administered molecule has a different isotopic enrichment from the isotopic background of the recipient subject. The aim of this study is to test the feasibility of assessing the contribution of exogenous surfactant phospholipids to the endogenous alveolar pool in vivo after exogenous surfactant replacement therapy in rabbits. The study consisted in measuring the consistency of 13 C/12 C ratio of disaturated-phosphatidylcholine palmitate (DSPC-PA) in 7 lots of poractant alfa, produced over a year, and among bronchoalveolar lavages of 20 rabbits fed with a standard chow. A pilot study was performed in a rabbit model of lavage-induced surfactant deficiency: 7 control rabbits and 4 treated with exogenous surfactant. The contribution of exogenous surfactant to the alveolar pool was assessed after intra-tracheal administration of 200 mg/kg of poractant alfa. The 13 C content of DSPC-PA was measured by isotope ratio mass spectrometry. The mean DSPC-PA 13 C/12 C ratio of the 7 lots of poractant alfa was -18.8‰ with a SD of 0.1‰ (range: -18.9‰; -18.6‰). The mean 13 C/12 C ratio of surfactant DSPC recovered from the lung lavage of 20 rabbits was -28.8 ± 1.2‰ (range: -31.7‰; -25.7‰). The contribution of exogenous surfactant to the total alveolar surfactant could be calculated in the treated rabbits, and it ranged from 83.9% to 89.6%. This pilot study describes a novel method to measure the contribution of the exogenous surfactant to the alveolar pool. This method is based on the natural variation of 13 C, and therefore it does not require the use of chemically synthetized tracers. This method could be useful in human research and especially in surfactant replacement studies in preterm infants.

Phytosterol Esterification is Markedly Decreased in Preterm Infants Receiving Routine Parenteral Nutrition.

Several studies reported the association between total plasma phytosterol concentrations and the parenteral nutrition-associated cholestasis (PNAC). To date, no data are available on phytosterol esterification in animals and in humans during parenteral nutrition (PN). We measured free and esterified sterols (cholesterol, campesterol, stigmasterol, and sitosterol) plasma concentrations during PN in 16 preterm infants (500-1249 g of birth weight; Preterm-PN), in 11 term infants (Term-PN) and in 12 adults (Adult-PN). Gas chromatography-mass spectrometry was used for measurements. Plasma concentrations of free cholesterol (Free-CHO), free phytosterols (Free-PHY) and esterified phytosterols (Ester-PHY) were not different among the three PN groups. Esterified cholesterol (Ester-CHO) was statistically lower in Preterm-PN than Adult-PN. Preterm-PN had significantly higher Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios than Adult-PN (Free-CHO/Ester-CHO: 1.1 ± 0.7 vs. 0.6 ± 0.2; Free-PHY/Ester-PHY: 4.1 ± 2.6 vs. 1.3 ± 0.8; *P < 0.05). Free-CHO/Ester-CHO and Free-PHY/Ester-PHY ratios of Term-PN (Free-CHO/Ester-CHO: 1.1 ± 0.4; Free-PHY/Ester-PHY: 2.9 ± 1.7) were not different from either Preterm-PN or from Adult-PN. Plasma Free-CHO/Ester-CHO and Free-PHY/Ester-PHY were unchanged after 24 h on fat-free PN both in Preterm-PN and in Adult-PN. Free-PHY/Ester-PHY did not correlate with phytosterol intake in Preterm-PN. Free-PHY/Ester-PHY of Preterm-PN was positively correlated with the Free-CHO/Ester-CHO and negatively correlated with gestational age and birth weight. In conclusion, PHY were esterified to a lesser extent than CHO in all study groups; the esterification was markedly decreased in Preterm-PN compared to Adult-PN. The clinical consequences of these findings warrant further investigations.

Amino Acid Intake in Preterm Infants.

A large proportion of extremely low-birth-weight infants requires parenteral nutrition for variable lengths of time. Amino acids are the key ingredients of parenteral nutrition. The goal of appropriate amino acid administration is to promote anabolism and normal cellular development in order to limit the incidence of postnatal growth restriction, which is associated with neurodevelopmental delays. The benefits of early amino acid commencement soon after birth are compelling, especially on nitrogen balance, while long-term outcome studies are lacking. Amino acid administration at 2.5 g/kg per day has been shown to be superior to lower intakes; however, the benefits of intakes above 2.5 g/kg per day remain controversial.

Does Whole-Body Hypothermia in Neonates with Hypoxic-Ischemic Encephalopathy Affect Surfactant Disaturated-Phosphatidylcholine Kinetics?

BACKGROUND: It is unknown whether Whole-Body Hypothermia (WBH) affects pulmonary function. In vitro studies, at relatively low temperatures, suggest that hypothermia may induce significant changes to the surfactant composition. The effect of WBH on surfactant kinetics in newborn infants is unknown. We studied in vivo kinetics of disaturated-phosphatidylcholine (DSPC) in asphyxiated newborns during WBH and in normothermic controls (NTC) with no or mild asphyxia. Both groups presented no clinically apparent lung disease. METHODS: Twenty-seven term or near term newborns requiring mechanical ventilation were studied (GA 38.6±2.2 wks). Fifteen during WBH and twelve NTC. All infants received an intra-tracheal dose of 13C labelled DSPC and tracheal aspirate were performed. DSPC amount, DSPC half-life (HL) and pool size (PS) were calculated. RESULTS: DSPC amount in tracheal aspirates was 0.42 [0.22-0.54] and 0.36 [0.10-0.58] mg/ml in WBH and NTC respectively (p = 0.578). DSPC HL was 24.9 [15.7-52.5] and 25.3 [15.8-59.3] h (p = 0.733) and DSPC PS was 53.2 [29.4-91.6] and 40.2 [29.8-64.6] mg/kg (p = 0.598) in WBH and NTC respectively. CONCLUSIONS: WBH does not alter DSPC HL and PS in newborn infants with no clinical apparent lung disease.

Are Infants with Bronchopulmonary Dysplasia Prone to Gastroesophageal Reflux? A Prospective Observational Study with Esophageal pH-Impedance Monitoring.

OBJECTIVE: To perform an observational cohort study with esophageal pH-multichannel intraluminal impedance (pH-MII) monitoring in symptomatic preterm infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN: We prospectively studied 46 infants born ≤32 weeks gestational age: 12 infants with BPD and 34 infants without BPD. Each patient had symptoms consistent with gastroesophageal reflux and had 24-hour pH-MII, which were compared between BPD and non-BPD by univariate analysis and quantile regression analysis. RESULTS: Demographic and clinical characteristics were similar between infants with and without BPD, except for fluid administration (145 vs 163 mL/kg/d, P = .003), length of stay (92 vs 69 days, P = .019), and time to achieve complete oral feeding (76 vs 51 days, P = .013). The analysis of 1104 hours of pH-MII tracings demonstrated that infants with BPD compared with infants without BPD had increased numbers of pH-only events (median number 21 vs 9) and a higher symptom sensitivity index for pH-only events (9% vs 4.9%); the number and characteristics of acid, weakly acid, nonacid and gas gastroesophageal reflux events, acid exposure, esophageal clearance, and recorded symptoms did not significantly differ between the 2 groups. CONCLUSIONS: The increased number of (and sensitivity for) pH-only events among infants with BPD may be explained by several factors, including lower milk intake, impaired esophageal motility, and a peculiar autonomic nervous system response pattern.

Quality of newborn care: adherence to guidelines for parenteral nutrition in preterm infants in four European countries.

OBJECTIVE: The level of adherence to guidelines should be explored particularly in preterm infants for whom poor nutrition has major effects on outcomes in later life. The objective was to evaluate compliance to international guidelines for parenteral nutrition (PN) in preterm infants across neonatal intensive care units (NICUs) of four European countries. DESIGN: Clinical practice survey by means of a questionnaire addressing routine PN protocols, awareness and implementation of guidelines. SETTING: NICUs in the UK, Italy, Germany and France. PARTICIPANTS: One senior physician per unit; 199 units which represent 74% of the NICUs of the four countries. PRIMARY OUTCOME MEASURE: Adherence of unit protocol to international guidelines. SECONDARY OUTCOME MEASURE: Factors that influence adherence to guidelines. RESULTS: 80% of the respondents stated that they were aware of some PN clinical practice guidelines. For amino acid infusion (AA), 63% of the respondents aimed to initiate AA on D0, 38% aimed to administer an initial dose ≥1.5 g/kg/day and 91% aimed for a target dose of 3 or 4 g/kg/day, as recommended. For parenteral lipids, 90% of the respondents aimed to initiate parenteral lipids during the first 3 days of life, 39% aimed to use an initial dose ≥1.0 g/kg/day and 76% defined the target dose as 3-4 g/kg/day, as recommended. Significant variations in PN protocols were observed among countries, but the type of hospital or the number of admissions per year had only a marginal impact on the PN protocols. CONCLUSIONS: Most respondents indicated that their clinical practice was based on common guidelines. However, the initiation of PN is frequently not compliant with current recommendations, with the main differences being observed during the first days of life. Continuous education focusing on PN practice is needed, and greater efforts are required to disseminate and implement international guidelines.

Surfactant protein B amount and kinetics in newborn infants: an optimized procedure.

Surfactant protein B (SP-B) plays a key role in surfactant homeostasis affecting its biophysical properties and physiological function. Recently, a method to measure SP-B amount and kinetics from tracheal aspirates (TAs) became available. The main objective of this study was to improve the critical steps of the procedure to obtain a better SP-B sensitivity. We administered a 24 h continuous infusion of 1 mg/kg/h of 1(13)C-leucine to ten newborn infants. SP-B was isolated from serial TAs and its fractional synthesis rate, secretion time, peak time and half life were derived from (13)C enrichment curves obtained by gas chromatography mass spectrometry. SP-B amount in TAs was also assessed. During the extraction step, acidification and organic solvent ratio optimization doubled the recovery of SP-B from TAs, so did the elongation of the propylation time (from 20 min to 1 h) with enhanced leucine derivatization yield. Measurement of (13)C leucine enrichments, and therefore all SP-B kinetics parameters, were successfully calculated in all TAs samples due to the increase of SP-B yield. SP-B amount was 0.29 (0.16-0.41) % of total phospholipids with a minimum value of 0.08% belonging to one of the respiratory distress syndrome (RDS) patients. In conclusion, this new procedure enables accurate determination of SP-B kinetics even in the presence of low protein amount like in preterm RDS patients.

Simultaneous measurement of phosphatidylglycerol and disaturated-phosphatidylcholine palmitate kinetics from alveolar surfactant. Study in infants with stable isotope tracer, coupled with isotope ratio mass spectrometry.

Disaturated-phosphatidylcholine (DSPC) and phosphatidylglycerol (PG) are respectively the first and the third most abundant phospholipid in human alveolar surfactant. Their concentration decreases in airway surfactant of adults and infants with respiratory distress syndrome and cystic fibrosis. In this study, we used mass spectrometry (IRMS) to investigate the turnover of DSPC and PG in tracheal aspirates (TA) obtained from infants with normal or diseased lungs. We studied eight infants requiring mechanical ventilation: two with no lung disease, four with diaphragmatic hernia, one with ATP-binding cassette sub-family A member 3 heterozygote mutation and one with sepsis. Patients received deuterated water for 48 h as metabolic precursors of palmitate-DSPC and palmitate-PG. Serial TAs were obtained every 6 h for five days or until extubation. DSPC and PG were isolated from TA by column and high-performance thin layer chromatography. Deuterium enrichments of palmitate-DSPC and PG residues were measured by IRMS coupled with a gas chromatographer. Median secretion time (ST), peak time (PT) and fractional synthesis rate (FSR) were 3.7 [0.9- 13.4] h, 71.0 [52.2 - 85.2] h and 6.6 [6.3 - 11.1] %/day for DSPC and 19.3 [6.4 - 22.8] h, 49.0 [33.0 - 52.5] h and 5.8 [4.8 - 10.9] %/day for PG. This study shows that it is feasible to use deuterium derived from body water to trace simultaneously airway surfactant DSPC and PG in humans. When compared within the same patient, DSPC and PG had similar fractional synthesis rates, but PG had a shorter PT, suggesting differences in the life cycle of these essential surfactant components.

Parenteral nutrition of preterm infants with a lipid emulsion containing 10% fish oil: effect on plasma lipids and long-chain polyunsaturated fatty acids.

OBJECTIVE: To compare plasma lipids in preterm infants given a new lipid emulsion containing 10% fish oil, 50% medium-chain triacylglycerols, and 40% soybean oil, compared with a standard preparation containing 50:50 medium-chain triacylglycerols: soybean oil. STUDY DESIGN: Preterm infants weighing <1250 g at birth (n=47) were randomly assigned to receive parenteral nutrition with a fish oil lipid (n=23) or soybean oil (n=24). Plasma lipid classes and plasma and red blood cell fatty acids were determined by gas chromatography in cord blood and on postnatal days 7 and 14. RESULTS: On day 7, the infants receiving fish oil lipid had significantly lower plasma phospholipids, cholesterol esters, and free cholesterol but similar triglyceride concentrations. They also had significantly higher phospholipid docosahexaenoic acid (2.77 ± 0.08 versus 2.46 ± 0.01 mol%, P<.01) and eicosapentaenoic acid (1.58 ± 0.01 versus 0.25 ± 0.01 mol%, P<.01) as well as lower arachidonic acid (10.64 ± 0.29 versus 11.93 ± 0.29 mol%, P<.01) compared with those receiving soybean oil. Similar differences were found in red blood cells. CONCLUSIONS: The fish oil lipid emulsion was well tolerated, and infants receiving fish oil had lower plasma lipids and improved fatty acids status. The effect of these changes on inflammation, growth, and neurodevelopment should be explored.