BACKGROUND: Exposure to repetitive pain during the neonatal period has been shown to have important short and long-term effects on the neurodevelopment of the premature neonate and can contribute to experienced prolonged pain. A uniform taxonomy of neonatal prolonged pain is still lacking to this day which contributes to suboptimal prolonged pain management in neonatal intensive care units. Accordingly, a scoping review exploring the state of knowledge about prolonged pain in preterm neonates hospitalised in the neonatal intensive care unit will contribute to the developing field of neonatal prolonged pain and provide recommendations for clinical prolonged pain management.
OBJECTIVE: To determine the scope, extent, and nature of the available literature on prolonged pain in premature neonates hospitalised in neonatal intensive care units.
METHODS: Scoping review.
METHODS: An electronic search was conducted from inception to November 2023 in the databases of CINAHL, PubMed, Medline, Web of Science, GeryLit.org and Grey Source Index. Included studies discussed concepts related to neonatal prolonged pain such as definitions of prolonged pain, indicators of prolonged pain, contexts that result in prolonged pain, prolonged pain evaluation tools, consequences of prolonged pain and interventions for prolonged pain management.
RESULTS: Key concepts of neonatal prolonged pain were identified in the 86 included articles of this scoping review such as definitions (n = 26), indicators (n = 39), contexts (n = 49), scales (n = 56), consequences of prolonged pain (n = 30) and possible interventions for prolonged pain management (n = 22). Whilst a consensus on a definition has yet to be achieved, no proximate event was shown to cause prolonged pain and a time criterion was identified by authors as being relevant in defining prolonged pain. Interestingly, the context of hospitalisation was identified as being the most indicative of prolonged pain in premature neonates and should guide its evaluation and management, whilst only limited pain management interventions and consequences were discussed.
CONCLUSIONS: The findings of this scoping review contribute to the foundation of growing knowledge in neonatal prolonged pain and shed light on the ambiguity that currently exists on this topic in the scientific literature. This review summarises knowledge of key concepts necessary for a better understanding of prolonged pain and stresses the importance of considering contexts of hospitalisation for prolonged pain evaluation and management in neonatal intensive care units, with the objective of improving developmental outcomes of premature neonates.
CONCLUSIONS: A scoping review reveals that the contexts of prolonged pain in premature neonates hospitalised in the neonatal intensive care unit are essential in guiding its evaluation and management.

BACKGROUND: Emerging evidence suggests the clinical utility of N terminal pro B type natriuretic peptide (NT-proBNP) in multiple cardiac and pulmonary abnormalities both in adult and pediatric populations. To date, however, there is no consensus regarding its efficacy for the prediction and severity of bronchopulmonary dysplasia in premature neonates. The objective of the present meta-analysis was to determine differences in NT-proBNP among neonates that develop BPD or die from BPD and to evaluate if there is relative information on the diagnostic accuracy of the method.
METHODS: We conducted a systematic search according to the PRISMA guidelines and looked into Medline (1966-2023), Scopus (2004-2023), Clinicaltrials.gov (2008-2023), EMBASE (1980-2023), Cochrane Central Register of Controlled Trials CENTRAL (1999-2022) and Google Scholar (2004-2023) together with the reference lists from included studies. The potential risk of bias encountered in our study was evaluated using the QUADAS -2 tool. Finally, a total of 9 studies met the eligibility criteria, comprising 1319 newborns, from which 397 developed BPD and 922 were unaffected controls.
RESULTS: The results retrieved from our meta-analysis showed that newborns suffering from BPD had notably elevated NT-proBNP levels after birth when compared with healthy neonates (SMD 2.57, 95% CI 0.41, 4.72). The summary effect of the AUC meta-analysis showed that NT-proBNP was very accurate in detecting neonates at risk of developing severe BPD or dying from the disease (AUC -0.16, 95% CI -0.23, -0.08). No studies reported data relevant to the sensitivity and/or specificity of the method in diagnosing BPD.
CONCLUSIONS: Serum NT-proBNP levels represent a potential future biomarker with great diagnostic validity for the prediction of BPD complicating preterm deliveries. The limited amount of studies included and the significant variations in cutoff values and timing of measurement still restrict the application of NT-proBNP as an established clinical biomarker for BPD. The design of larger prospective studies will provide a more representative number of participants and will address the discrepancies in existing literature.

Supporting therapies that provide stress and pain control of preterm and term newborns infants contribute positively to the neuropsychomotor development. Non-pharmacological interventions that involve manual techniques are described, considering protocols that can be reproduced by physical therapists, with positive and negative outcomes reports.
Systematic review follows PRISMA 2020 statements guidelines. Primary and specific health sciences databases (Science Direct, Pubmed, Scielo, Embase and Scopus) were consulted between October 2021 and May 2022. Articles considered were clinical trials, randomized or not, that included descriptions of the type of intervention as non-pharmacological and that studied the following outcomes: \"pain\" and \"stress\".
Fifteen articles were selected for analysis, reaching a methodological quality of at least 3 on the Jadad Scale for the Quality of Researched Sources. The non-pharmacological therapies most applied in isolation were massage, swaddling or wrapping, gentle touch and kinesthetic stimulation, and the combined therapies were non-nutritive sucking and swaddling, oral sucrose and swaddling, sensory stimulation and familiar odors, and sensory saturation. The outcomes found were relaxation, pain, and stress reduction after the application of painful procedures. The behavioral changes included crying, grimacing, yawning, sneezing, jerky arm or leg movements, startles, and finger flaring. The vital signs included heart rate, blood oxygen saturation level, and pulse respiration.
Combined techniques lead to better results in controlling neonatal pain when compared to isolated techniques. They can be applied both in preterm and term infants in a safe way and are reproducible in any health unit in a simple and economical way.

Systemic infections caused by the black yeast-like fungus Exophiala dermatitidis are rare, but are associated with high mortality especially in immunocompromised patients. We report the first case of E. dermatitidis fungemia in a premature extremely low birth weight (ELBW) neonate who succumbed despite antifungal therapy with liposomal amphotericin (AMB) and fluconazole. A systematic review of all fungemia cases due to E. dermatitidis was also conducted aiming for a better understanding of the risk factors, treatment strategies and outcomes.
A male, ELBW premature neonate, soon after his birth, developed bradycardia, apnoea and ultimately necrotizing enterocolitis with intestinal perforation requiring surgical intervention. Meanwhile, he had also multiple risk factors for developing bloodstream infection, such as intubation, mechanical ventilation, central venous catheter (CVC), parenteral nutrition, empirical and prolonged antibiotic use. His blood cultures were positive, firstly for Acinetobacter junii and then for Klebsiella pneumoniae together with E. dermatitidis while on fluconazole prophylaxis and antibiotic empiric therapy. Despite the treatment with broad spectrum antibiotics, liposomal AMB and fluconazole, the newborn succumbed. A literature review identified another 12 E. dermatitidis bloodstream infections, mainly in patients with hematologic malignancies and solid organ transplant recipients (61%), with overall mortality 38% despite CVC removal and antifungal therapy.
Due to the rarity of E. dermatitidis infections, little is known about the characteristics of this yeast, the identification methods and the optimal therapy. Identification by common biochemical tests was problematic requiring molecular identification. Resolution of neonatal fungemia is difficult despite proper antifungal therapy especially in cases with multiple and severe risk factors like the present one. Therapeutic intervention may include CVC removal and treatment for at least 3 weeks with an azole (itraconazole or fluconazole after susceptibility testing) or AMB monotherapy but not echinocandins or AMB plus azole combination therapy.

Feeding preterm infants with mother\'s own milk is associated with a reduction in postnatal complications and an improved neurocognitive outcome. Therefore, the bioactive factor composition of human milk has been used as a tool for the development of nutritional supplements with a potential prophylactic or therapeutic effect. The aim of this systematic review was to provide an overview on bioactive factors which have been studied as supplement to enteral nutrition in randomized controlled trials, and to provide an overview of ongoing trials. MEDLINE, EMBASE, CENTRAL, and clinical trial registers were searched. Studies on the antimicrobial protein lactoferrin were excluded as these were summarized very recently in three separate systematic reviews. Studies on vitamins D, K and iron were also excluded as they are already incorporated in most international guidelines. We identified 17 different bioactive factors, which were investigated in 26 studies. Despite the encouraging potential effects of several bioactive factors, more high-quality studies with a sufficient number of preterm infants are required before a certain factor may be implemented into clinical practice. Three large trials (n > 500) that investigate the effects of either enteral insulin or vitamin A are currently ongoing and could provide more definite answers on these specific supplements.

The INtubation-SURfactant-Extubation (INSURE) procedure is a widely-used surfactant administration method to treat preterm infants with respiratory distress syndrome (RDS) but is not always successful. We conducted a systematic review to identify early predictive factors for failure of this procedure. A systematic literature search was performed until July 2018 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Original studies comparing INSURE success with INSURE failure in preterm infants with RDS were included. A predefined data extraction form was used to retrieve data from articles, and methodological quality was assessed using the SIGN checklists. Fifteen studies out of 690 identified records met inclusion criteria. Methodological quality varied, only 8 studies performed multivariate analysis. We identified 20 different risk factors in total. Evidence for birth weight (BW) as a predictor for INSURE failure was inconsistent, but there was a significant association between decreasing gestational age (GA) and failure risk. RDS severity was assessed in multiple ways, using arterial blood gas values, imaging, and scoring systems. In conclusion, extremely low BW, low GA, and severe RDS appear to be risk factors for INSURE failure. However, evidence is inconsistent due to important methodological heterogeneity. Therefore, clinical applicability of these results is limited and implies the need for future large cohort studies on this subject.

The aim of this study was to carry out a literature review and develop clinical guidelines for pain prevention and control during screening and laser photocoagulation for retinopathy of prematurity (ROP) in neonatal intensive care units (NICUs).
The Italian Society of Neonatology assessed papers published between 1986 and June 2017 and used the Grading of Recommendations, Assessment, Development and Evaluation approach, to develop new guidelines on pain and ROP.
The Society\'s pain experts assessed the full texts of 47 papers, including randomised or quasi-randomised controlled trials and case-control studies on nonpharmacological and pharmacological measures used in NICUs during the screening and laser photocoagulation of neonates for ROP. The literature suggested methods for reducing the stress and pain associated with ROP screening procedures. The panel concluded that the literature showed that it was feasible to provide laser photocoagulation for ROP in spontaneously breathing patients with adequate analgesia.
This literature review on managing pain in infants with ROP in NICUs led to the development of national guidelines, which will help physicians and nurses to reduce the stress and pain experienced by premature newborn infants during unavoidable screening and treatment for ROP.