Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates. RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%. CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Current management of surgical neonates: is it optimal or do we need to improve? A national survey of the Italian Society of Neonatology.

PURPOSE: Few guidelines exist for the perioperative management (PM) of neonates with surgical conditions (SC). This study examined the current neonatal PM in Italy. METHODS: We invited 51 neonatal intensive care units with pediatric surgery in their institution to participate in a web-based survey. The themes included (1) the involvement of the neonatologist during the PM; (2) the spread of bedside surgery (BS); (3) the critical issues concerning the neonatal PM in operating rooms (OR) and the actions aimed at improving the PM. RESULTS: Response rate was 82.4%. The neonatologist is involved during the intraoperative management in 42.9% of the responding centers (RC) and only when the surgery is performed at the patient's bedside in 50.0% of RCs. BS is reserved for extremely preterm (62.5%) or clinically unstable (57.5%) infants, and the main barrier to its implementation is the surgical-anesthesiology team's preference to perform surgery in a standard OR (77.5%). Care protocols for specific SC are available only in 42.9% of RCs. CONCLUSION: Some critical issues emerged from this survey: the neonatologist involvement in PM, the spread of BS, and the availability of specific care protocols need to be implemented to optimize the care of this fragile category of patients.

Weaning from mechanical ventilation and assessment of extubation readiness.

Tremendous advancements in neonatal respiratory care have contributed to the improved survival of extremely preterm infants (gestational age ≤ 28 weeks). While mechanical ventilation is often considered one of the most important breakthroughs in neonatology, it is also associated with numerous short and long-term complications. For those reasons, clinical research has focused on strategies to avoid or reduce exposure to mechanical ventilation. Nonetheless, in the extreme preterm population, 70-100% of infants born 22-28 weeks of gestation are exposed to mechanical ventilation, with nearly 50% being ventilated for ≥ 3 weeks. As contemporary practices have shifted towards selectively reserving mechanical ventilation for those patients, mechanical ventilation weaning and extubation remain a priority yet offer a heightened challenge for clinicians. In this review, we will summarize the evidence for different strategies to expedite weaning and assess extubation readiness in preterm infants, with a particular focus on extremely preterm infants.

Evolution of mechanical ventilation of the newborn infant.

Artificial ventilation of the newborn infant is the foundation of neonatology. Early practitioners included pediatricians, anesthesiologists, cardiologists, respiratory therapists, and engineers. The discovery of surfactant, followed by the death of Patrick Kennedy, jump-started the new area, with investment and research rapidly expanding. The ever more complex design of mechanical ventilators necessitated a more thorough understanding of newborn pulmonary physiology in order to provide support with minimal associated injury. This piece briefly reviews and highlights this history.

Guidelines and Recommendations for Targeted Neonatal Echocardiography and Cardiac Point-of-Care Ultrasound in the Neonatal Intensive Care Unit: An Update from the American Society of Echocardiography.

Targeted neonatal echocardiography (TNE) involves the use of comprehensive echocardiography to appraise cardiovascular physiology and neonatal hemodynamics to enhance diagnostic and therapeutic precision in the neonatal intensive care unit. Since the last publication of guidelines for TNE in 2011, the field has matured through the development of formalized neonatal hemodynamics fellowships, clinical programs, and the expansion of scientific knowledge to further enhance clinical care. The most common indications for TNE include adjudication of hemodynamic significance of a patent ductus arteriosus, evaluation of acute and chronic pulmonary hypertension, evaluation of right and left ventricular systolic and/or diastolic function, and screening for pericardial effusions and/or malpositioned central catheters. Neonatal cardiac point-of-care ultrasound (cPOCUS) is a limited cardiovascular evaluation which may include line tip evaluation, identification of pericardial effusion and differentiation of hypovolemia from severe impairment in myocardial contractility in the hemodynamically unstable neonate. This document is the product of an American Society of Echocardiography task force composed of representatives from neonatology-hemodynamics, pediatric cardiology, pediatric cardiac sonography, and neonatology-cPOCUS. This document provides (1) guidance on the purpose and rationale for both TNE and cPOCUS, (2) an overview of the components of a standard TNE and cPOCUS evaluation, (3) disease and/or clinical scenario-based indications for TNE, (4) training and competency-based evaluative requirements for both TNE and cPOCUS, and (5) components of quality assurance. The writing group would like to acknowledge the contributions of Dr. Regan Giesinger who sadly passed during the final revisions phase of these guidelines. Her contributions to the field of neonatal hemodynamics were immense.

[Motor skills as the basis of sensorimotor development, an essential dimension according to André Bullinger]. / La motricité comme base du développement sensorimoteur, une dimension essentielle selon André Bullinger.

In neonatology and pediatric intensive care units, as in pediatric units, development support care practiced according to the approach of psychologist André Bullinger takes into account sensorimotor and psychological aspects. Considering the quality and quantity of movements, from the antenatal period, allows for individualized and early care. Sensitive periods of sensorimotor development, during which brain plasticity is optimal, are decisive for psychomotor and cognitive development. Observation and evaluation of movements, as well as postural support to enable active motor skills, constitute essential elements of the developmental support provided to vulnerable children of all ages.

[Towards an ideal environment in neonatology]. / Vers un environnement idéal en néonatalogie.

The establishment of sensory systems occurs gradually along a transnatal continuum. During premature birth, hospitalization in neonatology, through its atypical sensory stimulations, can disrupt the development of the baby's still immature brain. To promote harmonious development in children, caregivers and parents must learn to take into account their sensory expectations in order to create the most suitable environment possible for their development.

Fluid and Parenteral Nutrition Practices in Extreme Preterm Neonates Among Neonatology Practitioners in India: A Web-based Survey.

An online survey pertinent to fluid and parenteral nutrition practices in extreme preterm neonates was undertaken with responses from 123 neonatology practitioners across India. The initial fluid rate of 80 mL/kg/day was preferred by 67% neonatologists for 750-1000 g neonates. Half of them increased the fluid rates when weight loss per day was >2%. Practices vary widely across settings and guideline tailor made to clinical conditions is needed.

Creation of a rating scale to teach Less Invasive Surfactant Administration (LISA) in simulation.

BACKGROUND: Simulation-based training is gaining increasing prominence in neonatology training. The Less Invasive Surfactant Administration (LISA) method is starting to be taught in simulation. The aim of this educational study was to develop and validate a rating scale for teaching the LISA method in simulation. METHODS: The Downing framework was used to create this performance-rating scale. A first version of the scale was submitted to 12 French and Belgian experts to obtain their opinions. Consensus was reached using a modified Delphi method. The performance of 40 pediatricians was then evaluated with this scale on a preterm neonate manikin simulating a neonatal respiratory distress syndrome. Each run was evaluated using the scale by two independent observers based on video recordings. RESULTS: The Cronbach alpha score of the rating scale was 0.72. The intraclass correlation coefficient (ICC) was 0.91 and the scores between raters were not significantly different. Finally, this rating scale correctly distinguished the experienced from the inexperienced learners (p < 0.01). CONCLUSIONS: This rating scale is one of the first rating scales for the evaluation and teaching of the LISA method in simulation. This tool has ample potential for use in clinical practice to evaluate the performance of surfactant administration in preterm neonates.

Practice of immersion in hot water to relieve pain in neonatology: an integrative review.

OBJECTIVES: to identify immersion use in hot water to relieve pain in newborns. METHODS: an integrative literature review, carried out in the PubMed, VHL, EMBASE, Scopus, CINAHL, Cochrane and SciELO databases, with investigations in English, Spanish, French or Portuguese, published between 2002 and 2022. The Health Sciences Descriptors (DeCS) and Medical Subject Headings (MeSH) were used to answer the following question: what are the uses of hot water immersion in relieving pain in newborns? RESULTS: nine studies were included, mainly Brazilian, experimental, with a predominance of strong and moderate levels of evidence. Hydrotherapy and bath use (immersion and bandaging) was observed, promising interventions in reducing pain scores, assessed using scales, physiological and endocrine parameters. CONCLUSIONS: hot water proved to be a promising non-pharmacological intervention in relieving pain in infants in different contexts.

Dangerous Things We Used to Do in Neonatology.

Neonatology has been a rapidly growing specialty, starting in the early 1900s with premature infants displayed in incubator shows, to today with complex disease processes treated in state-of-the-art neonatal intensive care units. Along the way evolving knowledge, medications, and technology provided opportunities to learn from mistakes and misguided treatments. The ability to learn from past mistakes improves our care now and illustrates the need for humility and vigilance in everything we do. This article explores errors made in the past as we look forward to the future.

Health care-associated infections in neonatology.

Health care-associated infections are common in neonatology, but there is no consensus on their definitions. This makes it difficult to compare their incidence or assess the effectiveness of prevention bundles. This is why we think it is very important to achieve a consensus on the definitions and diagnostic criteria for one of the most frequent causes of morbidity in hospitalised neonates. This document aims to standardise the definitions for the most frequent health care-associated infections, such as catheter-associated bloodstream infection, ventilator-associated pneumonia and surgical wound infection, as well as the approach to their diagnosis and treatment.

Transforming neonatal care with artificial intelligence: challenges, ethical consideration, and opportunities.

Artificial intelligence (AI) offers tremendous potential to transform neonatology through improved diagnostics, personalized treatments, and earlier prevention of complications. However, there are many challenges to address before AI is ready for clinical practice. This review defines key AI concepts and discusses ethical considerations and implicit biases associated with AI. Next we will review literature examples of AI already being explored in neonatology research and we will suggest future potentials for AI work. Examples discussed in this article include predicting outcomes such as sepsis, optimizing oxygen therapy, and image analysis to detect brain injury and retinopathy of prematurity. Realizing AI's potential necessitates collaboration between diverse stakeholders across the entire process of incorporating AI tools in the NICU to address testability, usability, bias, and transparency. With multi-center and multi-disciplinary collaboration, AI holds tremendous potential to transform the future of neonatology.

SARS-CoV-2 perinatal transmission and neonatal outcomes across four different waves of COVID-19 pandemic: A nationwide prospective cohort study from the Italian Society of Neonatology.

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.

[Comparative study of production and control processes of parenteral nutritional admixtures in neonatology]. / Étude comparative des processus de production et de contrôle analytique des préparations magistrales de mélanges nutritifs parentéraux en néonatalogie.

OBJECTIVES: To assess the impact of disparities in production and analytical control processes on the quality of parenteral nutrition (PN) preparations produced in the Auvergne-Rhône-Alpes region. METHODS: This study was carried out in four hospital pharmacies of the Auvergne-Rhône-Alpes region. To assess the impact of production processes, each centre produced ten PN preparations from the same prescription. Analytical controls (sodium, potassium and calcium dosage) were carried out on all the preparations. To assess the impact of the control processes, a batch of ten preparations was produced from the same prescription. Samples were sent to the four hospital pharmacies for analytical control (sodium, potassium and calcium dosage). RESULTS: Measurements of relative production bias show that there is a significant difference between the preparations from the four centres in terms of sodium and potassium content. Each centre had at least one production bias for one of the three electrolytes measured. Concerning analytical controls, there was a significant difference between the four centres in the sodium and potassium levels measured. With the exception of calcium, all the centres reported measurements within the usual specifications of±10% of the target value. The results obtained have no clinically significant impact. CONCLUSION: The diversity of NP practices has a real impact on the quality of the preparations made. A regional collaboration should be envisaged to standardise patient care.

Development and Pilot Implementation of Neotree, a Digital Quality Improvement Tool Designed to Improve Newborn Care and Survival in 3 Hospitals in Malawi and Zimbabwe: Cost Analysis Study.

Background: Two-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost evidence-based interventions for all sick and small newborns. An open-source digital quality improvement tool (Neotree) combining data capture with education and clinical decision support is a promising solution for this implementation gap. Objective: We present results from a cost analysis of a pilot implementation of Neotree in 3 hospitals in Malawi and Zimbabwe. Methods: We combined activity-based costing and expenditure approaches to estimate the development and implementation cost of a Neotree pilot in 1 hospital in Malawi, Kamuzu Central Hospital (KCH), and 2 hospitals in Zimbabwe, Sally Mugabe Central Hospital (SMCH) and Chinhoyi Provincial Hospital (CPH). We estimated the costs from a provider perspective over 12 months. Data were collected through expenditure reports, monthly staff time-use surveys, and project staff interviews. Sensitivity and scenario analyses were conducted to assess the impact of uncertainties on the results or estimate potential costs at scale. A pilot time-motion survey was conducted at KCH and a comparable hospital where Neotree was not implemented. Results: Total cost of pilot implementation of Neotree at KCH, SMCH, and CPH was US $37,748, US $52,331, and US $41,764, respectively. Average monthly cost per admitted child was US $15, US $15, and US $58, respectively. Staff costs were the main cost component (average 73% of total costs, ranging from 63% to 79%). The results from the sensitivity analysis showed that uncertainty around the number of admissions had a significant impact on the costs in all hospitals. In Malawi, replacing monthly web hosting with a server also had a significant impact on the costs. Under routine (nonresearch) conditions and at scale, total costs are estimated to fall substantially, up to 76%, reducing cost per admitted child to as low as US $5 in KCH, US $4 in SMCH, and US $14 in CPH. Median time to admit a baby was 27 (IQR 20-40) minutes using Neotree (n=250) compared to 26 (IQR 21-30) minutes using paper-based systems (n=34), and the median time to discharge a baby was 9 (IQR 7-13) minutes for Neotree (n=246) compared to 3 (IQR 2-4) minutes for paper-based systems (n=50). Conclusions: Neotree is a time- and cost-efficient tool, comparable with the results from limited similar mHealth decision-support tools in low- and middle-income countries. Implementation costs of Neotree varied substantially between the hospitals, mainly due to hospital size. The implementation costs could be substantially reduced at scale due to economies of scale because of integration to the health systems and reductions in cost items such as staff and overhead. More studies assessing the impact and cost-effectiveness of large-scale mHealth decision-support tools are needed.

Óbitos neonatais por enterocolite necrosante: estudo de coorte retrospectiva / Neonatal deaths from necrotizing enterocolitis: a retrospective cohort study / Muertes neonatales por enterocolitis necrozante: estudio de cohorte retrospectivo

Introdução:A enterocolite necrosante é uma doença que pode afetar o trato gastrointestinal de recém-nascidos,cujas manifestações clínicas podem ser caracterizadas por vômitos biliosos, sangue nas fezes, distensão abdominal, além de alterações nos parâmetros hemodinâmicos e instabilidade térmica. As populações mais vulneráveis a essa enfermidade são recém-nascidos de baixo peso,expostos ao ambiente de terapia intensiva neonatal. Objetivos: Identificar o perfil de recém-nascidos e os fatores maternos e neonatais associados à ocorrência de óbitos por enterocolite necrosante, em maternidade de referência do Ceará-Brasil. Metodologia: Trata-se de coorte retrospectiva, estudo que objetiva a descrição da incidência de determinado evento ao longo do tempo, além do estabelecimento de relações causais entre os fatores associados ao acontecimento. Incluíram-serecém-nascidos que tiveram óbitos por enterocolite necrosante entre 2019 e 2021, comficha de investigação de óbitos neonatais preenchida corretamente, não sendo excluído nenhum recém-nascido, totalizando amostra de 29 óbitos.Resultados: Identificou-se que o perfil dos recém-nascidos foi,em maioria, deprematuros e com baixo peso e fatores de risco para outras doenças associadas,como a sepse, o que acarretourealização de procedimentos invasivos e internação em ambiente de terapia intensiva neonatal.Conclusões: A prematuridade e o baixo peso ao nascer foram as variáveis relevantes no estudo e podem estar associadas à piora das condições clínicas do recém-nascido e ao desenvolvimento de enterocolite necrosante (AU).

Introduction: Necrotizing Enterocolitis is a disease that can affect the gastrointestinal tract of newborns, whose clinical manifestations can be characterized by bilious vomiting, blood in stool, abdominal distension, in addition to changes in hemodynamic parameters and thermal instability. The populations most vulnerable to this disease are low birth weight newborns exposed to the neonatal intensive care environment. Objectives: This study aimed to identify the profile of newborns and maternal and neonatal factors associated with the occurrence of deaths from necrotizing enterocolitis in a reference maternity hospital in Ceará, Brazil. Methodology: This is a retrospective cohort study seeking to describe the incidence ofa particular event over time, as well as establish causal relationships between the factors associated with the event. The study population comprised newborns who died from necrotizing enterocolitis between 2019 and 2021, who had neonatal death investigation forms filled out correctly, with no newborns being excluded, totaling a sample of 29 deaths. Results: It was identified that the profile of newborns was mostly premature, of low birth weight and with risk factors for other associated diseases such as sepsis, leading to invasive procedures and hospitalization in a neonatal intensive care environment. Conclusions: Prematurity and low birth weight were relevant variables in the study and may be associated with worsening of the newborn's clinical conditionsand development of necrotizing enterocolitis (AU).

ntroducción:La Enterocolitis Necrotizante es enfermedad que puede afectar el tracto gastrointestinal del recién nacido, cuyas manifestaciones clínicas pueden caracterizarse por vómitos biliosos, sangre en las heces, distensión abdominal, además de cambios en los parámetros hemodinámicos e inestabilidad térmica.Las poblaciones más vulnerables a esta enfermedad son recién nacidos con bajo peso expuestos al entorno de cuidados intensivos neonatales.Objetivos: Identificar el perfil de recién nacidos y los factores maternos y neonatales asociados a la ocurrencia de muertes por enterocolitis necrotizante, en maternidad de referencia en el Ceará-Brasil.Metodología: Estudio de cohorte retrospectivo, para describir la incidencia de determinado evento a lo largo del tiempo, además de establecer relaciones causales entre los factores asociados al evento.Se incluyeron recién nacidos fallecidos por enterocolitis necrotizante entre 2019 y 2021, quienes tuvieron formulario de investigación de muerte neonatal correctamente diligenciado, no excluyéndose ningún recién nacido, totalizando muestra de 29 defunciones.Resultados:El perfil de los recién nacidos fue mayoritariamente prematuro y de bajo peso al nacer y con factores de riesgo para otras enfermedades asociadas, como sepsis, con procedimientos invasivos y hospitalización en ambiente de cuidados intensivosneonatales.Conclusiones:La prematuridad y el bajo peso al nacer fueron variables relevantes en el estudio y pueden estar asociados con empeoramiento de las condiciones clínicas de recién nacidos y desarrollo de enterocolitis necrotizante (AU).

Measuring practice preference variation for quality improvement: development of the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT).

BACKGROUND: Understanding behavioural psychology and the human side of change are guiding principles for quality improvement (QI). Tools to measure these to guide improvement efforts are lacking. METHODS: We created a clinical vignette-based survey to measure provider preferences for respiratory care in the neonatal intensive care unit. Fourteen vignettes were included, each vignette offering two reasonable practice choices. Responses were based on a 5-point Likert scale, ranging from neutral to strong preference for either choice. The survey was completed by physicians, nurses, advanced practice providers and respiratory therapists in 2017 and again in 2019. Net preference was measured as the median value of responses, and agreement was measured as the SD of responses. Net preference and agreement were assessed for all responses, by discipline, and by year. RESULTS: Response rates were 51% of all staff in 2017 and 57% in 2019. Vignettes asking about non-invasive respiratory support showed more defined net preferences and higher agreement between years, coinciding with QI efforts and guideline implementation in this area during the interval time. Results on other areas of practice were consistent between years. Discipline comparisons showed nurses and physicians agreed the least often. Six response patterns were identified, ranging from net preference and high agreement to no net preference and low agreement. CONCLUSION: We propose this survey, called the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool, is a novel method for measurement of hospital unit psychology and culture. Demonstrated improvement where QI efforts were focused and consistency in results in other areas support the validity of this tool. Measuring the human side of change may impact QI efforts.