Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon.

G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.

Real-Time Ultrasound Tip Location Reduces Malposition and Radiation Exposure during Umbilical Venous Catheter Placement in Neonates: A Retrospective, Observational Study.

INTRODUCTION: The umbilical venous catheter is a vital access device in neonatal intensive care units for preterm and critically ill infants. Correct positioning is crucial, as malpositioning can lead to severe complications. According to international guidelines, the position of the umbilical venous catheter tip must be assessed in real time; traditionally, the catheter is visualized with a thoracoabdominal X-ray, but one of the most effective and safest methods is therefore real-time ultrasound. METHODS: This study compares real-time ultrasound and traditional X-ray methods for assessing umbilical venous catheter tip location in 461 cases. The rate of tip malposition was analyzed retrospectively. The secondary aim was to assess indwelling time of umbilical venous catheters and reasons of removal. RESULTS: Real-time ultrasound tip location, found to be more reliable and efficient, demonstrated a significantly lower incidence of primary malpositioning compared to X-ray assessments (9.6 vs. 75.9%). The study also highlighted the association of real-time ultrasound with reduced catheter manipulation, fewer radiographs, and higher indwelling times of umbilical venous catheter. The multiple logistic regression showed a high probability of the central safe position of the umbilical venous catheter tip using real-time ultrasound tip location (odds ratio 29.5, 95% confidence interval: 17.4-49.4). CONCLUSION: The findings support the adoption of real-time ultrasound in clinical settings to enhance umbilical venous catheter placement accuracy and minimize associated risks. A minimal training investment is needed to attain the proficiency to visualize the umbilical venous catheters, offering a substantial advantage in terms of both cost-effectiveness for the procedure and enhanced patient safety.

The SIECC protocol: A novel insertion bundle to minimize the complications related to epicutaneo-cava catheters in neonates.

Epicutaneo-cava catheters are the most widely used central venous catheters in the neonate, but their insertion and management are potentially associated with several complications, both during placement (failure to proceed with the catheter, primary malposition, etc.) and during maintenance (infection, venous thrombosis, catheter dislocation, secondary malposition, etc.). Recent studies have identified methods and techniques that may be effective in minimizing the risk of most of these complications. This paper proposes a structured, sequential insertion bundle-nicknamed "the SIECC protocol" (SIECC = Safe Insertion of Epicutaneo-Cava Catheters)-which includes seven evidence-based strategies which have been proven to increase the safety, effectiveness, and cost-effectiveness of the procedure.

A novel neonatal protocol for Safe Insertion of Umbilical Venous Catheters (SIUVeC): Minimizing complications in placement and management.

Insertion of umbilical venous catheters is a common procedure in neonatal intensive care. Though sometimes lifesaving, this maneuver is potentially associated with early and late complications, some of which may be severe and even life threatening (catheter malposition, hepatic lesions, venous thrombosis, pericardial effusion, etc.). The recent literature suggests several operative strategies that, if adopted systematically, may significantly reduce the incidence of both early and late catheter related complications. This paper describes a standardized protocol (Safe Insertion Umbilical Venous Catheter = SIUVeC) which incorporates such novel strategies, with the goal of minimizing the complications related to this procedure.

Diaphragm atrophy during invasive mechanical ventilation is related to extubation failure in preterm infants: An ultrasound study.

BACKGROUND: Diaphragm dysfunction is associated with poor outcomes in critically ill patients. Ventilator-induced diaphragmatic dysfunction (VIDD), including diaphragm atrophy (DA), is poorly studied in newborns. We aimed to assess VIDD and its associations in newborns. METHODS: Single-center prospective study. Diaphragm thickness was measured at end-inspiration (TDI) and end-expiration (TDE) on the right midaxillary line. DA was defined as decrease in TDE ≥ 10%. Daily measurements were recorded in preterm newborns on invasive mechanical ventilation (IMV) for ≥2 days. Clinical characteristics of patients and extubation failure were recorded. Univariate analysis, logistic regression, and mixed models were performed to describe VIDD and associated factors. RESULTS: We studied 17 patients (median gestational age 270/7 weeks) and 22 IMV cycles (median duration 9 days). Median TDE decreased from 0.118 cm (interquartile range [IQR] 0.094-0.165) on the first IMV day to 0.104 cm (IQR 0.083-0.120) on the last IMV day (p = .092). DA occurred in 11 IMV cycles (50%) from 10 infants early during IMV (median: second IMV day). Mean airway pressure (MAP) and lung ultrasound score (LUS) on the first IMV day were significantly higher in patients who developed DA. DA was more frequent in patients with extubation failure than in those with extubation success within 7 days (83.3 vs. 33.3%, p = .038). CONCLUSIONS: DA, significantly associated with extubation failure, occurred in 58.8% of the study infants on IMV. Higher MAP and LUS at IMV start were associated with DA. Our results suggest a potential role of diaphragm ultrasound to assess DA and predict extubation failure in clinical practice.

Bile Acids Pneumonia: A Respiratory Distress Syndrome in Early-Term Neonates.

Intrahepatic cholestasis of pregnancy (ICP) complicates among 0.2-2% of pregnancies and has been associated with adverse perinatal outcomes, including sudden stillbirth, meconium strained fluid, preterm birth, perinatal asphyxia, and transient tachypnea of the newborn. The diagnosis of "bile acids pneumonia" was previously proposed and a causative role of bile acids (BA) was supposed with a possible mechanism of action including surfactant dysfunction, inflammation, and chemical pneumonia. In the last few years, the role of lung ultrasound (LUS) in the diagnosis and management of neonatal respiratory distress syndrome has grown, and LUS scores have been introduced in the literature, as an effective predictor of the need for surfactant treatment among neonates with respiratory distress syndrome. We present four cases of infants born from pregnancies complicated by ICP, who developed respiratory distress syndrome early after birth. Lung ultrasound showed the same pattern for all infants, corresponding to a homogeneous alveolar-interstitial syndrome characterized by a diffuse coalescing B-line pattern (white lung). All infants evaluated require non-invasive respiratory support and in three cases surfactant administration, despite the near-term gestational age, with rapid improvement of respiratory disease and a good clinical outcome.

The Role of Ultrasound in Epicutaneo-Caval Catheter Insertion in Neonates: Systematic Review, Meta-Analysis and Future Perspectives.

Chest and abdominal X-rays after the insertion of an epicutaneo-caval catheter in infants are the standard method of checking the tip location in many neonatal intensive care units. The role of ultrasound in the tip location of the epicutaneo-caval catheter in neonates has been the subject of many recent studies. This systematic review investigates the accuracy of epicutaneo-caval catheter tip location by comparing ultrasound and conventional radiology. We performed a systematic literature search in multiple databases. The selection of studies yielded nineteen articles. The systematic review and meta-analysis were performed according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis). The analyses showed that ultrasound is a better imaging technique for epicutaneo-caval catheter tip location in the neonatal intensive care unit than conventional radiology. By improving operator training and selecting a standardized echography protocol, ultrasound could become the gold standard for visualizing the epicutaneo-caval catheter tip in the neonatal intensive care unit. This would have some important benefits: (1) increased accuracy in tip location (2); a more rapid use of the central venous access (3); and a significant reduction in radiation exposure.

Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.

Optical detection of infiltration during peripheral intravenous infusion in neonates.

BACKGROUND: Infiltration and extravasation are common complications during peripheral intravenous infusion in the neonatal intensive care unit, and diagnosis is usually clinical, by inspection and palpation. Delay in diagnosis due to poor surveillance or misinterpretation of clinical signs may carry serious damage to the tissues of the neonate. Recently, a novel technology based on optical detection of infiltration has become available. METHODS: We have studied two groups of term and preterm infants receiving non-vesicant intravenous infusions by the peripheral route (24G short peripheral cannulas), and we evaluated the incidence of infiltration. In the first group, we have compared the clinical detection of infiltration versus the detection obtained by a novel optical device, blinding the alarms of the device. In the second group, the comparison was carried out without blinding the alarms. RESULTS: Of the neonates included in this study, 60% were female, 86% had a gestational age <37 weeks (34 ± 2.5 weeks) and a mean birth weight of 2.08 ± 0.4 g. Total recorded monitoring time was 1318 h and average monitoring time for each short peripheral cannula was 26.4 h. The incidence of infiltration was 80%, most of them having a Millam score <2. The novel device showed an overall sensitivity of 88.9% in detecting infiltration. Specificity was 84.4%, as evaluated assuming as standard the clinical diagnosis. Interestingly, in cases of documented infiltration, the event was diagnosed by the optical device approximately 6 h before the clinical diagnosis. CONCLUSIONS: Continuous monitoring of the insertion site, as automatically ensured by this novel optical device, may play a complementary role in early detection of infiltration, even if the percentage of false positives and false negatives suggests that periodic clinical assessment by expert nurses cannot be omitted.

The future of neonatal lung ultrasound: Validation of an artificial intelligence model for interpreting lung scans. A multicentre prospective diagnostic study.

BACKGROUND: Artificial intelligence (AI) is a promising field in the neonatal field. We focused on lung ultrasound (LU), a useful tool for the neonatologist. Our aim was to train a neural network to create a model able to interpret LU. METHODS: Our multicentric, prospective study included newborns with gestational age (GA) ≥ 33 + 0 weeks with early tachypnea/dyspnea/oxygen requirements. For each baby, three LU were performed: within 3 h of life (T0), at 4-6 h of life (T1), and in the absence of respiratory support (T2). Each scan was processed to extract the region of interest used to train a neural network to classify it according to the LU score (LUS). We assessed sensitivity, specificity, positive and negative predictive value of the AI model's scores in predicting the need for respiratory assistance with nasal continuous positive airway pressure and for surfactant, compared to an already studied and established LUS. RESULTS: We enrolled 62 newborns (GA = 36 ± 2 weeks). In the prediction of the need for CPAP, we found a cutoff of 6 (at T0) and 5 (at T1) for both the neonatal lung ultrasound score (nLUS) and AI score (AUROC 0.88 for T0 AI model, 0.80 for T1 AI model). For the outcome "need for surfactant therapy", results in terms of area under receiver operator characteristic (AUROC) are 0.84 for T0 AI model and 0.89 for T1 AI model. In the prediction of surfactant therapy, we found a cutoff of 9 for both scores at T0, at T1 the nLUS cutoff was 6, while the AI's one was 5. Classification accuracy was good both at the image and class levels. CONCLUSIONS: This is, to our knowledge, the first attempt to use an AI model to interpret early neonatal LUS and can be extremely useful for neonatologists in the clinical setting.

Ultrasound-guided diagnostic pericardiocentesis in preterm infants: a case report.

Pericardial effusion (PE) in pediatric population can be asymptomatic or a life-threatening event. Reports on neonates or preterm infants are scarce and generally related to pericardiocentesis of large amounts of PE in emergency situations.We describe a diagnostic pericardiocentesis in a preterm infant with small and loculated pericardial effusion and suspected cardiac mass. We used an ultrasound-guided long-axis in-plane pericardiocentesis technique, with a needle-cannula. The operator obtained a subxiphoid pericardial effusion view with a high frequency linear probe and entered the skin below the tip of the xiphoid process with a 20-gauge closed IV needle-cannula (ViaValve®). The needle was identified in its entirety as it courses through soft tissue up to pericardial sac. The main advantages of this approach are a continuous viewing and angulation of the needle through all planes of the tissue and the use of a small, practical, closed IV needle-cannula with blood control septum to prevent fluid exposure while disconnecting the syringe. This novel approach is easy and safe in neonatal population, for diagnostic or emergency drainages and can be performed at bedside in a neonatal intensive care unit.

Securement of Umbilical Venous Catheter Using Cyanoacrylate Glue: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the role of cyanoacrylate glue in reducing dislodgement of umbilical venous catheters (UVCs). STUDY DESIGN: This was a single-center, randomized, controlled, nonblinded trial. All infants requiring an UVC according to our local policy were included in the study. Infants with a UVC with a centrally located tip as verified by real-time ultrasound examination were eligible for the study. Primary outcome was the safety and efficacy of securement by cyanoacrylate glue plus cord-anchored suture (SG group) vs securement by suture alone (S group), as measured by reduction in dislodgment of the external tract of the catheter. Secondary outcomes were tip migration, catheter-related bloodstream infection, and catheter-related thrombosis. RESULTS: In the first 48 hours after UVC insertion, dislodgement was significantly higher in the S group than in the SG group (23.1% vs 1.5%; P < .001). The overall dislodgement rate was 24.6% in the S group vs 7.7% in the SG group (P = .016). No differences were found in catheter-related bloodstream infection and catheter-related thrombosis. The incidence of tip migration was similar in both groups (S group 12.2% vs SG group 11.7%). CONCLUSIONS: In our single-center study, cyanoacrylate glue was safe and effective for securement of UVCs, and particularly effective in decreasing early catheter dislodgments. TRIAL REGISTRATION: UMIN-CTR Clinical Trial; Registration number: R000045844.

Combination of ketamine and fentanyl (KetaFent) for safe insertion of ultrasound-guided central venous catheters in infants.

Centrally inserted central catheters (CICCs) are placed by ultrasound guided puncture of the internal jugular or brachio-cephalic vein. It is crucial to achieve a good level of sedation and analgesia in order to keep the babies still thus reducing the risk of procedural failure. The aim of this study is to evaluate the efficacy of the combination of ketamine and fentanyl during the CICC placement procedure. We retrospectively collected data from 72 infants who underwent CICC insertion after sedation with KetaFent protocol. The primary outcome was to assess the success of the procedure defined as CICC placement. Secondary outcome was intubation during the procedure in non-ventilated infants (noninvasive ventilation or spontaneous respiration), need for repeat doses of study medications to complete the procedure, time to complete the procedure, the level of analgesia assessed using vital parameters. The procedure was completed in 100% of cases. There were no cases of hypotension during and at the end of the procedure. No intubation was performed on non-ventilated infants. The combination of ketamine and fentanyl for sedation and analgesia in infants requiring insertion of a CICC is 100% successful. It is associated with a low risk of side effect like apnea and intubation. Insertion of a central venous catheter is a painful procedure for infants. Adequate sedation is mandatory to keep the baby still thus reducing the risk of procedural failure.

Cord blood presepsin as a predictor of early-onset neonatal sepsis in term and preterm newborns.

BACKGROUND: To date, no studies on presepsin values in cord blood of term infants with risk factors for early-onset sepsis (EOS) are available, whereas only one study reported presepsin values in cord blood of preterm infants at risk. In this study, we investigated the presepsin values in cord blood of term and preterm infants with documented risk factors for EOS. METHODS: In this single-center prospective pilot study, we enrolled neonates presenting with documented risk factors for EOS. P-SEP levels were assessed in a blood sample collected from the clamped umbilical cord after the delivery in 93 neonates, using a point-of-care device. The primary outcome of our study was to evaluate the role of cord blood P-SEP in predicting clinical EOS in term and preterm infants. RESULTS: During the study period, we enrolled 93 neonates with risk factors for EOS with a gestational age ranging between 24.6 and 41.6 weeks (median 38.0). The median P-SEP value in all infants was 491 pg/ml (IQR 377 - 729). Median cord P-SEP values were significantly higher in infants with clinical sepsis (909 pg/ml, IQR 586 - 1307) rather than in infants without (467 pg/ml, IQR 369 - 635) (p = 0.010). We found a statistically significant correlation between cord P-SEP value at birth and the later diagnosis of clinical sepsis (Kendall's τ coefficient 0.222, p = 0.002). We identified the maximum Youden's Index (best cut-off point) at 579 pg/ml, corresponding to a sensitivity of 87.5% and a specificity of 71.8% in predicting clinical sepsis. CONCLUSIONS: Maximum Youden's index was 579 pg/ml for clinical EOS using cord P-SEP values. This could be the starting point to realize multicenter studies, confirming the feasibility of dosing P-SEP in cord blood of infants with risk factors of EOS to discriminate those who could develop clinical sepsis and spare the inappropriate use of antibiotics.

Lung Ultrasound in the Early Diagnosis and Management of the Mild Form of Meconium Aspiration Syndrome: A Case Report.

MAS is a common cause of neonatal respiratory distress in term and post-term neonates. Meconium staining of the amniotic fluid occurs in about 10-13% of normal pregnancies, and about 4% of these infants develop respiratory distress. In the past, MAS was diagnosed mainly on the basis of history, clinical symptoms, and chest radiography. Several authors have addressed the ultrasonographic assessment of the most common respiratory patterns in neonates. In particular, MAS is characterised by a heterogeneous alveolointerstitial syndrome, subpleural abnormalities with multiple lung consolidations, characterised by a hepatisation aspect. We present six cases of infants with a clinical history of meconium-stained fluid who presented with respiratory distress at birth. Lung ultrasound allowed the diagnosis of MAS in all the studied cases, despite the mild clinical picture. All children had the same ultrasound pattern with diffuse and coalescing B-lines, pleural line anomalies, air bronchograms, and subpleural consolidations with irregular shapes. These patterns were distributed in different areas of the lungs. These signs are specific enough to distinguish between MAS and other causes of neonatal respiratory distress, allowing the clinician to optimise therapeutic management.

A novel echocardiography method to assess upper body systemic blood flow in preterm infants and comparison with superior vena cava flow measurement.

To evaluate feasibility, reproducibility, and prognostic value of a new echocardiographic method to assess systemic arterial blood flow directed to the upper part of the body (UBAF, upper body arterial flow) alternative to superior vena cava flow (SVCF) measurement. We performed echocardiographic evaluations in 106 infants in the first 2 days of life to obtain SVCF, left ventricle output (LVO), UBAF, and standard parameters of patent ductus arteriosus (PDA) significance. UBAF was calculated by subtracting from LVO the aortic arch blood flow measured immediately distally to the origin of the left subclavian artery. Main outcome measures: UBAF and SVCF agreement was assessed by Bland-Altman analysis in terms of bias, limits of agreement and repeatability index. The Intraclass Correlation Coefficient was used to measure the strength of inter-rater agreement. The agreement between UBAF and SVCF was high. The Concordance Correlation Coefficient (CCC) was 0.7434. (CCC 0.7434, 95% C.I. [0.656, 0.8111]). There was a good absolute agreement between the two raters ICC = 0.747; p value < 0.0001; 95%CI [0.601; 0.845]. Adjusting for confounding factors (BW, GA, PDA) included in the model, there was a statistically significant relationship between UBAF and SVCF. CONCLUSION: UBAF showed a strong agreement with the SCVF with a better reproducibility. Our data support UBAF as a potentially useful marker of cerebral perfusion in the evaluation of preterm infants. WHAT IS KNOWN: • Low SVC (superior vena cava) flow in the neonatal period has been associated with periventricular haemorrhage and unfavourable long-term neurodevelopmental outcome. • Ultrasound measurement of flow in SVC shows relatively high inter-operator variability. WHAT IS NEW: • Our study highlights how much overlap there is between upper-body arterial flow (UBAF) measurement and SCV flow measurement. UBAF is easier to perform and has a strong correlation with better reproducibility. • UBAF may replace measurement of cava flow as a method for haemodynamic monitoring of unstable preterm and asphyxiated infants.

Real-Time Ultrasound Tip Location Reduces Malposition and Radiation Exposure during Epicutaneo-Caval Catheter Placement in Neonates.

OBJECTIVE: Epicutaneo-caval catheters (ECCs) are essential for the care of sick infants who require long-term medical and nutritional management. The aim of this study was to investigate the use of real-time ultrasound as an alternative to X-rays to reduce the incidence of primary malpositions during catheter insertion. STUDY DESIGN: Data on ECCs were retrospectively collected in a tertiary neonatal intensive care unit. Catheter were analyzed considering the tip location technique (standard chest-abdominal radiograph vs real-time ultrasound) RESULTS: A total of 248 ECCs were analyzed. Of these, 118 catheters had primary malposition (47.6%). The tip of 165 catheters was assessed using standard chest-abdominal X-rays and 107 (64.8%) were found to be in an inappropriate location. In the group of 83 catheters that were placed using real-time ultrasound for tip location, only 11 catheters (13.2%) had primary malposition. The rate of malposition among the two groups showed a statistically significant difference (p < 0.001). Hypothetically, 300 chest X-rays could have been saved if real-time ultrasound had been used to locate the tip, reducing radiation exposure to infants. CONCLUSION: The use of a real-time ultrasound may be beneficial in reducing primary catheter malpositions compared with conventional radiography. In addition, secondary malpositions and catheter-related complications can be monitored over time. KEY POINTS: · Conventional radiology cannot be considered the "gold standard" for ECC tip location.. · Ultrasound is more accurate and reduces insertion time reducing the rate of primary malposition.. · Ultrasound can be performed in real time and it is the best technique for ECC tip location in infants..

Normal values for superior vena cava flow in preterm neonates using a new echocardiographic approach.

OBJECTIVE: Recently, a novel approach to imaging Superior Vena Cava (SVC) flow has been presented, showing better repeatability and better agreement with MRI-derived SVC flow measures. The objective was to establish normal values of SVC flow with the novel approach in the first 48 h of life. STUDY DESIGN: This was a prospective, observational study. All infants with gestational age (GA) less than 31 weeks were eligible. Echocardiographic evaluation was performed at 5, 12, 24, 48 h of postnatal life. A subgroup of uncomplicated infants was studied to define a normal range for SVC flow. RESULTS: Forty-five infants were enrolled. We estimated normative values in a subgroup of 31 uncomplicated infants. The median SVC flow significantly increases from 83 ml/kg/min at 5 h of life to 153 ml/kg/min at 48 h (p < .001). CONCLUSION: Using the novel approach we derived normal values of SVC flow in a cohort of uncomplicated preterm population at high risk for developing IVH.