Skin thickness in preterm neonates: relationship with skin bilirubin and predicted mortality.

This study investigates the relationship between the thickness of skin in preterm infants and its link with bilirubin and mortality, as this may help understanding the potential deleterious effects of phototherapy. Observational, prospective cohort study enrolling preterm neonates needing phototherapy and admitted to a neonatal intensive care unit. Transcutaneous bilirubin (TcB) and blood bilirubin were simultaneously measured before the onset of phototherapy, if any. The skin depth was measured by high-frequency point-of-care ultrasound. Mortality risk was estimated using the critical risk index for babies-II. Correlations and multivariate regressions (adjusting for several confounders) were applied to study the relationship between skin depth, TcB, and predicted mortality. One hundred fifty-nine neonates were studied. There was a positive and steady correlation between skin depth and TcB (r = 0.402 (95%CI: 0.206; 0.568), p < 0.001) and inverse correlation between skin depth and predicted mortality (r = -0.503 (95%CI: -0.61; -0.37), p < 0.001) as well as between TcB and predicted mortality (r = -0.303 (95%CI: -0.49; -0.09), p = 0.005). Multivariate analyses showed skin depth to be the strongest risk factors associated with both increasing TcB (ß = 198 (59;338), p < 0.001) and decreasing risk of death (ß = -24 (-46;2), p = 0.049). Blood bilirubin and gestational age were also associated with TcB and predicted mortality, respectively.   Conclusion: In NICU-admitted preterm infants, thicker skin is associated with higher TcB levels irrespective of gestational age. Greater skin depth is also associated with lower predicted mortality irrespective of blood bilirubin. What is Known: • In preterm infants, phototherapy may improve neuro-developmental outcomes but, particularly in the smallest and sickest ones, may increase mortality. • Mechanisms behind this effect are unclear but could involve the small thickness of preterm skin. This however has never been studied in relationship with bilirubin and mortality. What is New: • In NICU-admitted preterm infants, thicker skin is associated with higher levels of transcutaneous bilirubin, irrespective of gestational age and with lower predicted mortality, irrespective of blood bilirubin. • These data suggest that a thinner skin may contain less bilirubin to be photoisomerised and protect internal tissues less efficiently.

Early life surfactant protein-D levels in bronchoalveolar lavage fluids of extremely preterm neonates.

Surfactant protein-D (SP-D) is a hydrophilic protein with multiple crucial anti-inflammatory and immunological functions. It might play a role in the development and course of pulmonary infections, acute respiratory distress syndrome, and other respiratory disorders. Only few small neonatal studies have investigated SP-D: we aimed to investigate the links between this protein, measured in the first hours of life in extremely preterm neonates, and clinical outcomes, as well its relationship with pulmonary secretory phospholipase A2 (sPLA2). Bronchoalveolar lavage fluids were obtained within the first 3 h of life. SP-D and sPLA2 were measured with ELISA and radioactive method, respectively; epithelial lining fluid concentrations were estimated with urea ratio. Clinical data were prospectively collected. One hundred extremely preterm neonates were nonconsecutively studied. SP-D was significantly raised with increasing gestational age (24-26 wk: 68 [0-1,694], 27 or 28 wk: 286 [0-1,328], 29 or 30 wk: 1,401 [405-2,429] ng/mL, overall P = 0.03). SP-D was significantly higher in cases with clinical chorioamnionitis with fetal involvement (1,138 [68-3,336]) than in those without clinical chorioamnionitis with fetal involvement (0 [0-900] ng/mL, P < 0.001). SP-D was lower in infants with bronchopulmonary dysplasia (BPD) (251 [0-1,550 ng/mL]) compared with those without bronchopulmonary dysplasia (BPD) or who died before its diagnosis (977 [124-5,534 ng/mL], P = 0.05) and this was also significant upon multivariate analysis [odds ration (OR): 0.997 (0.994-0.999), P = 0.024], particularly in neonates between 27- and 28-wk gestation. SP-D significantly correlated with the duration of hospital stay (ρ = -0.283, P = 0.002), invasive ventilation (ρ = -0.544, P = 0.001), and total sPLA2 activity (ρ = 0.528, P = 0.008). These findings help understanding the role of SP-D early in life and support further investigation about the role of SP-D in developing BPD.NEW & NOTEWORTHY Surfactant protein-D increases with gestational age and is inversely associated with BPD development. These results have been obtained in the first hours of life of extremely preterm neonates with optimal perinatal care.

Respiratory and haemodynamic effects of 6h-pronation in neonates recovering from respiratory distress syndrome, or affected by acute respiratory distress syndrome or evolving bronchopulmonary dysplasia: a prospective, physiological, crossover, controlled cohort study.

Background: Pronation ameliorates oxygenation in adults with acute respiratory distress syndrome (ARDS); the effect in neonates with ARDS or other types of respiratory failure is unknown. We aimed to verify if pronation has similar respiratory and haemodynamic effects in three common types of neonatal respiratory failure. Methods: Prospective, physiologic, crossover, quasi-randomised, controlled cohort study performed in a tertiary academic neonatal intensive care unit. We enrolled neonates with: 1) recovering respiratory distress syndrome (RDS, mild restrictive pattern); 2) neonatal ARDS (NARDS, severe restrictive pattern); or 3) evolving bronchopulmonary dysplasia (BPD), that is chronic pulmonary insufficiency of prematurity (mixed restrictive/obstructive pattern). Neonates with other lung disorders, malformations or haemodynamic impairment were excluded. Patients were started prone or supine and then shifted to the alternate position for 6h; measurements were performed after 30' of "wash out" from the positioning and at the end of 6h period. Primary outcomes were respiratory (PtcCO2, modified ventilatory index, PtcO2/FiO2, SpO2/FiO2, oxygenation index, ultrasound-assessed lung aeration) and haemodynamic (perfusion index, heart rate, arterial pressure, cardiac output) parameters. Findings: Between May 1st, 2019, and May 31st, 2021, 161 participants were enrolled in this study, and included in the final analysis. Pronation improved gas exchange and lung aeration (p always <0.01) and these effects were overturned in the alternate position, except for lung aeration in NARDS where the improvement persisted. The effects were greater in patients recovering from RDS than in those with evolving BPD than in those with NARDS, in this order (p always <0.01). Pronation produced a net recruitment as lung ultrasound score decreased in patients shifted from supine (16.9 (standard deviation: 5.8)) to prone (14.1 (standard deviation: 3.3), p < 0.01) and this reduction correlated with oxygenation improvement. Haemodynamic parameters remained within normal ranges. Interpretation: 6h-pronation can be used to improve gas exchange and lung aeration in neonates with recovering RDS, evolving BPD or NARDS without relevant haemodynamic effects. Funding: None.

Secretory phospholipase A2 expression and activity in preterm clinical chorioamnionitis with fetal involvement.

Secretory phospholipase A2 (sPLA2) regulates the first step of inflammatory cascade and is involved in several pathological processes. sPLA2 also plays a role in preterm labor and parturition, since they are triggered by inflammatory mediators such as prostaglandins. Interestingly, chorioamnionitis (i.e., the presence of intrauterine inflammation) is also often associated with preterm birth. We aimed to verify if chorioamnionitis with fetal involvement modifies sPLA2 activity and expression profile in mothers and neonates delivered prematurely. We collected maternal plasma and amniotic fluid, as well as bronchoalveolar lavage fluid from preterm neonates born to mothers with or without clinical chorioamnionitis with fetal involvement. We measured concentrations of sPLA2 subtype-IIA and -IB, total enzyme activity, and proteins. Urea ratio was used to obtain epithelial lining fluid concentrations. Enzyme activity measured in maternal plasma (P < 0.001) and amniotic fluid (P < 0.001) was higher in chorioamnionitis cases than in controls. This was mainly due to the increased production of sPLA2-IIA, as the subtype -IB was present in a smaller amount and was similar between the two groups; sPLA2-IIA was increased in epithelial lining fluid (P = 0.045) or increased, although without statistical significance, in maternal plasma (P = 0.06) and amniotic fluid (P = 0.08) of chorioamnionitis cases. Cytokines that are known to increase sPLA2-IIA expression (TNF-α and IL-1ß) or whose expression was increased by sPLA2-IIA (IL-8) were higher in histologically confirmed chorioamnionitis [TNF-α (P = 0.028), IL-1ß (P < 0.001), and IL-8 (P = 0.038)]. These data represent the basis for future studies on sPLA2-IIA inhibition to prevent deleterious consequences of chorioamnionitis and preterm birth.

A Parallel Tracking of Salivary and Gut Microbiota Profiles Can Reveal Maturation and Interplay of Early Life Microbial Communities in Healthy Infants.

In this study, the onset and shaping of the salivary and gut microbiota in healthy newborns during the first period of life has been followed, evaluating the impact of salivary microbiota on the development of early fecal microbial communities. The microbiota of 80 salivary and 82 fecal samples that were collected from healthy newborns in the first six months of life, was investigated by 16S rRNA amplicon profiling. The microbial relationship within and between the saliva and gut ecosystems was determined by correlation heatmaps and co-occurrence networks. Streptococcus and Staphylococcus appeared as early commensals in the salivary microbiota, dominating this ecosystem through the time, while Fusobacterium, Prevotella, Porphyromonas, Granulicatella, and Veillonella were late colonizers. Enterobacteriaceae, Staphylococcus and Streptococcus were gut pioneers, followed by the anaerobic Bifidobacterium, Veillonella, Eggerthella, and Bacteroides. Streptococcus, Staphylococcus, and Veillonella were shared by the gut and saliva ecosystems. The saliva and gut microbiota seem to evolve independently, driven by local adaptation strategies, except for the oral Streptococcus and Veillonella that are involved in gut microbiota development as seeding species. This study offers a piece of knowledge on how the oral microbiota may affect the gut microbiota in healthy newborns, shedding light onto new microbial targets for the development of therapies for early life intestinal dysbiosis.

Late congenital diaphragmatic hernia: is a significant challenge? A case series and review from literature.

BACKGROUND: Late-presenting congenital diaphragmatic hernia (L-CDH) diagnosis is a challenge for its clinical various presentation. In literature radiologic misdiagnosis is up to 62%. The aim of this study is analyze clinical findings about our cases series in a particular setting of Pediatric Emergency Department (PED) and review of literature. METHODS: We retrospectively analyzed the medical records of children older than 1 month, operated for L-CDH from November 2009 to December 2019 presented to PED, with a total of 20 children (5 Morgagni and 15 Bochdaleck). RESULTS: The median age at diagnosis was 1,48 years. 50% patients had a history of previouses symtptoms with a mean duration of 243,75 days. In 30 % of cases associated anomalies were presented, mainly cardiovascular. 25% of patients had undergone to chest X-ray in past history with misdiagnosis of pneumonia, microganulia and broncovascular thickening. Misdiagnosis are manly among left sided Bochdaleck hernia. Respiratory distress alone or associated with vomiting is commonest acute symptom refered to PED. Respiratory symptoms were more common in younger children, while gastrointestinal ones in older children (not statistically differences p=0,8769). Post-operative recurrence were frequent only in cases of right sided CDH and comparing with left ones, there is a difference statistically significant (p=0.0476). CONCLUSIONS: L-CDH should be suspected in cases of unexplained acute respiratory distress and vomiting, particulary when children are affected to associate cardiovascular malformation. In cases of patients with long previouses symptoms and various accesses to PED is important to emphasize history of respiratory distress, dysphagia and failure to thrive and should be considered a chest X-ray.

Extrapulmonary Surfactant Therapy: Review of Available Data and Research/Development Issues.

Since the discovery of surfactant, a large amount of knowledge has been accumulated about its biology and pharmacology. Surfactant is the cornerstone of neonatal respiratory critical care, but its proteins and phospholipids are produced in various tissues and organs, with possible roles only partially similar to that played in the alveoli. As surfactant research is focused mainly on its respiratory applications, knowledge about the possible role of surfactant in extrapulmonary disorders has never been summarized. Here we aim to comprehensively review the data about surfactant biology and pharmacology in organs other than the lung, especially focusing in the more promising surfactant extrapulmonary roles. We also review any preclinical or clinical data available about the therapeutic use of surfactant in these contexts. We offer a summary of knowledge and research/development milestones, as possible useful guidance for researchers of multidisciplinary background.

Gut Mucosal and Fecal Microbiota Profiling Combined to Intestinal Immune System in Neonates Affected by Intestinal Ischemic Injuries.

Background and Purpose: Early life microbiota plays a crucial role in human health by acting as a barrier from pathogens' invasion and maintaining the intestinal immune homoeostasis. Altered fecal microbiota (FM) ecology was reported in newborns affected by intestinal ischemia. Our purpose was to describe, in these patients, the FM, the mucosal microbiota (MM) and the mucosal immunity. Methods: Fourteen newborns underwent intestinal resection because of intestinal ischemia. FM and MM were determined through targeted-metagenomics, diversity assignment and Kruskal-Wallis analyses of Operational taxonomic units (OTUs). The mucosal immune cells were analyzed through cytofluorimetry. Results and Conclusion: Based on the severity intestinal injueris we identified two groups: extensive (EII) and focal intestinal ischemia (FII). FM and MM varied in EII and FII groups, showing in the EII group the predominance of Proteobacteria and Enterobacteriaceae and the reduction of Bacteroidetes and Verrucomicrobia for both microbiota. The MM was characterized by a statistically significant reduction of Bacteroides, Lachnospiraceae and Ruminococcaceae and by a higher diversity in the EII compared to FII group. FM showed a prevalence of Proteobacteria, while the Shannon index was lower in the EII compared to FII group. An overall increment in B- and T-lymphocytes and Natural killer (NK) T-like cells was found for EII mucosal samples associated to an increment of TNF-α and INF-γ expressing cells, compared to FII group. FM and MM carry specific signatures of intestinal ischemic lesions. Further research may be crucial to address the role of specific taxa in EII, expecially with reference to inflammation grade and ischemia extension.

Porcine versus bovine surfactant therapy for RDS in preterm neonates: pragmatic meta-analysis and review of physiopathological plausibility of the effects on extra-pulmonary outcomes.

BACKGROUND: While porcine seems to be superior to bovine surfactants in terms of respiratory outcomes, it is unclear if a surfactant can improve extra-pulmonary outcomes in preterm neonates with respiratory distress syndrome and if there is any physiopathological/biological mechanism linking surfactant therapy to these outcomes. We aim to fill these knowledge gaps. METHODS: Systematic and pragmatic review coupled with meta-analysis of randomized controlled trials of bovine or porcine surfactants administered to treat RDS in preterm neonates; common extra-pulmonary neonatal intensive care outcomes were considered. As additional analysis, animal or human translational studies about mechanisms linking surfactant replacement to extra-pulmonary neonatal outcomes were also systematically reviewed. RESULTS: Porcine surfactant is associated with lower incidence of patent ductus arteriosus (OR:0.655; 95%CI:0.460-0.931); p = 0.018; 12 trials; 1472 patients); prenatal steroids (coeff.:-0.009, 95%CI:-0.03-0.009, p = 0.323) and gestational age (coeff.:0.079, 95%CI:-0.18-0.34, p = 0.554) did not influence this effect size. No significant differences were found between porcine and bovine surfactants on neonatal intensive care unit length of stay (mean difference (days):-2.977; 95%CI:-6.659-0.705; p = 0.113; 8 trials; 855 patients), intra-ventricular hemorrhage of any grade (OR:0.860; 95%CI:0.648-1.139); p = 0.293; 15 trials; 1703 patients), severe intra-ventricular hemorrhage (OR:0.852; 95%CI:0.624-1.163); p = 0.313; 15 trials; 1672 patients), necrotizing entero-colitis (OR:1.190; 95%CI:0.785-1.803); p = 0.412; 9 trials; 1097 patients) and retinopathy of prematurity (OR:0.801; 95%CI:0.480-1.337); p = 0.396; 10 trials; 962 patients). CONCLUSIONS: Physiopathological mechanisms explaining the effect of surfactant have been found for patent ductus arteriosus only, while they are lacking for all other endpoints. Porcine surfactant is associated with lower incidence of PDA than bovine surfactants. As there are no differences in terms of other extra-pulmonary outcomes and no physiopathological plausibility, these endpoints should not be used in future trials. REGISTRATION: PROSPERO n.CRD42018100906.

Effect of Different Probes and Expertise on the Interpretation Reliability of Point-of-Care Lung Ultrasound.

BACKGROUND: The effect of different probes and operator experience on the reliability of lung ultrasound (LU) interpretation has not been investigated. We studied the effect of probes and operator experience on the interpretation reliability of LU in critically ill neonates. METHODS: This was a prospective, blind, cohort study enrolling patients with basic patterns ("B," "severe B," consolidation). Patients were scanned with microlinear (15 MHz; L15), phased-array sectorial (6-12 MHz; S7), and microconvex (8 MHz; C8) probes, in random order. Static images were acquired in high resolution, anonymized, and included in a pictorial database in random sequences. Seventeen clinicians with different LU experience were asked to blindly assess the pictorial database. Interrater agreement and interpretation reliability were analyzed. Subanalyses according to expertise and probe, and multivariate linear regression (including an "expertise × probe" interaction factor), were also performed. RESULTS: The agreement tends to be lower and more heterogeneous for residents (intraclass correlation coefficient [ICC], 0.82 [95% CI, 0.74-0.9], P < .001; I2, 67%, P = .04) and for fellows (ICC, 0.93 [95% CI, 0.9-0.97], P < .001; I2, 69%, P = .04), especially when using nonlinear probes, compared with senior physicians (ICC, 0.95 [95% CI, 0.93-0.96], P < .001; I2, 0%, P = .433). Area under the curve (AUC) values were high for all probes (L15, 0.96 [95% CI, 0.93-0.99]; C8, 0.91 [95% CI, 0.85-0.98]; S7, 0.86 [95% CI, 0.82-0.91]) and physicians (senior physicians, 0.95 [95% CI, 0.83-0.99]; fellows, 0.95 [95% CI, 0.75-0.99]; residents, 0.86 [95% CI, 0.5-0.99]). Worse reliability and higher heterogeneity were found when the evaluation was performed by residents (AUC, 0.9 [95% CI, 0.85-0.94], P < .01; I2, 93.6%, P < .001) than by fellows (AUC, 0.99 [95% CI, 0.9-0.999], P < .001; I2, 34.3%, P = .09) and/or by senior physicians (AUC, 0.99 [95% CI, 0.9-0.999], P < .001; I2, 18%, P = .236). The "expertise × probe" interaction factor was associated with lower ICC (standardized regression coefficient ß, -0.69; P < .0001; adjusted R2, 0.99) and AUC (standardized regression coefficient ß, -0.76; P < .0001; adjusted R2, 0.98). CONCLUSIONS: LU interpretation in neonates shows good interrater agreement and reliability, irrespective of the probe and rater expertise. The use of nonlinear probes by novice operators is associated with the lowest agreement and reliability.

Life-Threatening Extreme Methemoglobinemia during Standard Dose Nitric Oxide Therapy.

We report the first case of life-threatening extreme neonatal-acquired methemoglobinemia that occurred during inhaled nitric oxide (iNO) at the standard 20 ppm dose in a neonate with early onset sepsis and suprasystemic pulmonary hypertension. Life-threatening methemoglobinemia has been efficaciously treated with methylene blue and ascorbic acid, while stopping iNO and starting iloprost and sildenafil. The patient was subjected to various tests (including gene sequencing and hemoglobin electrophoresis) and did not have any known genetic cause or predisposition for methemoglobinemia. Neuroimaging and the 2-year clinical follow-up were completely normal.

Otogenic lateral sinus thrombosis in children: proposal of an experience-based treatment flowchart.

PURPOSE: To describe the prevalent clinical, laboratory, and radiological features of otogenic lateral sinus thrombosis (OLST) in children; to identify clinical predictors of outcome; to propose a management algorithm derived from experience. METHODS: A retrospective review was conducted of the clinical records of patients with OLST, treated in a single tertiary care referral center for pediatric disease from 2006 to 2017. The inclusion criteria were pediatric age (0-16 years) and OLST diagnosis confirmed by a pre- and post-contrast CT or venography-MRI scan. Primary outcome measures were early (1-2 months) and late (6 months) sinus recanalization assessed by means of neuroimaging. RESULTS: Twenty-five patients (8 females and 17 males; mean age = 6 ± 3 years) were included. A genetic abnormality associated with thrombophilia was found in 24 (96%) patients. At diagnosis, anticoagulant treatment with low-molecular-weight heparin (LMWH) was started in all subjects, while surgical treatment (mastoidectomy and tympanostomy tube insertion) was performed in 16/25 (64%) patients. Follow-up neuroimaging showed lateral sinus recanalization in 12/25 (48%) patients after 1-2 months and in 17/25 (68%) after 6 months. At multivariate logistic regression analysis, no significant predictors of the early and late neuroradiological outcome were found. CONCLUSIONS: All children with OLST should be screened for thrombophilia to decide on treatment duration and to assess the need for future antithrombotic prophylaxis. Immediately after diagnosis, anticoagulant treatment with LMWH should be started according to the international guidelines. Instead, our experience suggests that surgical treatment should not be indicated in all patients, but decided on a case-to-case basis.

Sometimes it is better to wait: First Italian case of a newborn with transient abnormal myelopoiesis and a favorable prognosis.

Congenital leukemia is rare disease with an incidence of one to five cases per million births. Transient abnormal myelopoiesis (TAM), also called transient myeloproliferative disorder, is a pre-leukemia disorder that may occur in Down syndrome (DS) or non-DS infants. TAM may enter spontaneous remission; however, continual monitoring is required, as this disorder has been observed to develop into acute megakaryoblastic leukemia in 16-30% of cases. In the literature, 16 cases of TAM in non-DS infants have been reported. The case presented in the current study is, to the best of our knowledge, the first case of an Italian non-DS newborn presenting with clinical manifestations of acute leukemia at five days after birth, exhibiting a normal karyotype, trisomy 21 only in blast cells, and spontaneous remission. Chromosomal analyses on peripheral blood cells, bone marrow cells and dermal fibroblasts were conducted using a G-banding technique, and fluorescence in situ hybridization (FISH) was used to identify the critical regions of DS. Amplification of GATA binding protein 1 (GATA1) exon 2 genomic DNA was performed using polymerase chain reaction. Cytogenetic analysis of 50 peripheral blood cells and dermal fibroblasts from the patient revealed a normal karyotype: 46, XX. Conversely, cytogenetic analysis of the patient's bone marrow revealed an abnormal karyotype 47, XX+21. In order to investigate this result, FISH was performed, which identified the presence of three signals in 70% of the cells and two signals in 30% of bone marrow cells. GATA1 sequencing revealed the substitution of a single base (c.150delG) in exon 2. Seven months after the initial analysis, FISH and cytogenetic analyses of the stimulated/unstimulated peripheral blood cells and bone marrow cells were performed, revealing that each exhibited diploid signals, as observed in a normal karyotype.

Human milk and breastfeeding in surgical infants.

Human milk and breastfeeding represent the nutritional normative standards for term and preterm newborns. With the term "surgical infants" we refer to all newborns who undergo surgery during the first days of life and who are assisted in the neonatal intensive care unit during the postoperative period and then in the neonatal surgery unit. There are many obstacles to breastfeeding these newborns. The "barriers" include the unstable clinical conditions before and after surgery, the period of separation between the mother and child, and often the lack of attention to breastfeeding. Few studies have assessed if newborns with surgical diseases are breastfeed and if human milk is beneficial for their outcome. We believe that the best option is to offer them their own mother's milk through the promotion and support of breastfeeding. A specific program focused on the needs of these vulnerable children should be created. Furthermore the surgical and pediatric staff of the neonatal surgery unit should be informed and trained to increase such a program's feasibility.