Neonates admitted to neonatal intensive care units (NICUs), as well as maternity nurseries, typically undergo painful invasive procedures during their hospital stay. We aim to report on current bedside analgesia/sedation and pain assessment practices, 10 years after the previous Italian survey.

This study employed a cross-sectional electronic survey. A 21-item questionnaire was distributed to directors of birth centers and NICUs to ascertain the policy for pain assessment and management in their respective units. A separate questionnaire was dispatched to neonatologists and nurses registered with the Italian Society of Neonatology. They reported on the analgesic strategies implemented for various painful bedside procedures. Both non-pharmacological and pharmacological analgesia interventions, as well as pain assessment, were analyzed. A regression model was utilized to identify factors that predict pain management practices.

Data on pain management practices were collected from the directors of 153 NICUs and birth centers. Of these, 88.9% reported pain control following guidelines and 47.7% confirmed the presence of a local pain specialist promoting pain management in their unit. A minority, ranging from 16.3% to 41.8%, reported the use of a pain scale, a finding corroborated by the 200 doctors and 239 nurses who responded. At least one non pharmacological intervention (i.e., pacifier, sweet solution, or sensory saturation) was reported in 97.8% of the heel lances performed in the NICU and 96.5% in the maternity nursery, meanwhile for intramuscular injections in 73.8% and 70.3%, respectively. Additionally, it was reported that 22.9% of laryngoscopies were still performed without analgesia. Observations were made over 297 mechanical ventilation and 277 non-invasive ventilation courses, with non-pharmacological analgesia administered in 56.4% and 86.9% and the use of analgesic or sedative drugs in 81.7% and 17.1% of the cases, respectively. Furthermore, routine pain assessment was only undertaken in 68.0% and 64.9% of the cases.

We found a largely common propensity among Italian directors, neonatologists, and nurses to perform analgesic interventions for the most frequently encountered invasive neonatal painful procedures, though the practices are still highly variable. The availability of written guidelines and local pain specialists are confirmed as factors that contribute to the proper management of pain. However, pain assessment is still inadequate and urgently needs to be implemented to allow for tailored pain and stress control and prevention in all infants.

This study aims to quantify stress exposure related to clinical stressors in preterm infants during NICU admission and identify risk factors for high stress exposure. In this national cohort study, preterm infants (gestational age < 29 weeks) were prospectively followed during the first 28 days of their admission to one of the 10 NICUs in the Netherlands. The NeO-stress score, consisting of 38 clinical stressors graded with a severity index, was applied to describe stress exposure. We assessed the impact of infant characteristics at birth and postnatal age on NeO-stress scores using linear mixed modelling. In total, 446 infants were included with a median gestational age of 27+2 weeks (IQR 26+2-28+2). The median NeO-stress score per day was 61 (IQR 39-87) and highest (74, IQR 52-101) on the day of admission. Nasal/oral (37%) and endotracheal (14%) suctioning were key contributors to the cumulative NeO-stress scores. Linear mixed modelling showed that lower gestational age (B = -0.69, 95% CI - 0.94-0.44, p < 0.001), no antenatal administration of corticosteroids (B = 13.2, 95% CI 3.2-23.1, p = 0.010) and lower 5-min Apgar score (B = - 1.6, 95% CI - 3.0-0.25, p = 0.02) were significantly related with higher daily NeO-stress scores. Our model predicts that the NeO-stress score increases over time for the youngest infants.

Stress exposure in preterm infants during NICU admission varies over time with infants with the lowest gestational age at risk for experiencing the highest levels of stress throughout NICU admission. This highlights the importance stress reduction and provides opportunities for future interventions aimed at reducing stress exposure.

• Preterm birth and admission to a Neonatal Intensive Care Unit is very stressful. • High stress exposure in neonatal life is associated with adverse long term outcome.

• Stress exposure is highest in infants with the youngest gestational ages where it remains high or even increases during the first month of life. • Lower gestational age, no antenatal administration of corticosteroids and lower 5-min Apgar score were significantly related with higher daily NeO-stress scores.

Studies on pain in preterm infants have usually been confined to observations of painful procedures, and information from extremely preterm infants is limited. Using registry data from a Swedish nationwide cohort, this study explored the epidemiology of pain in very preterm infants, its causes, assessments, and treatment strategies. We included liveborn infants <32 weeks' gestational age (GA) discharged between January 2020 and June 2024. Proportions of infants exposed to potentially painful procedures, experiencing pain, assessed with pain scales, and receiving pharmacological treatment were calculated by each postnatal day. Among 3686 infants (mean birthweight 1176 g, GA 28.2 weeks), 11.6% had a painful condition and 84.1% were exposed to at least 1 potentially painful procedure. In total, 74.6% experienced pain, corresponding to 28,137/185,008 (15.2%) days of neonatal care. For every 2-week increase in GA, significantly lower proportions of infants experienced pain. In infants <28 weeks of GA, proportions with reported pain were approximately half the rate of painful procedures, while in infants born at 28 to 31 weeks, reported pain closely matched exposure to painful procedures. Pain scales were used in 75.0% of the infants. Pharmacological pain treatment was administered to 81.7% of infants, primarily topically or orally. Among infants with pain, proportions treated intravenously were larger at higher GAs. Despite effective analgesia/anesthesia, many very preterm infants experience pain. Visualizing pain epidemiology, procedures, conditions, and treatment by postnatal and gestational age may guide clinical management and generate research hypotheses to reduce short- and long-term adverse effects.

Currently, pain assessment using electroencephalogram signals and machine learning methods in clinical studies is of great importance, especially for those who cannot express their pain. Since newborns are among the high-risk group and always experience pain at the beginning of birth, in this research, the severity of newborns has been investigated and evaluated. Other studies related to the annoyance of newborns have used the EEG signal of newborns alone; therefore, in this study, the intensity of newborn pain was measured using the electroencephalogram signal of 107 infants who were stimulated by the heel lance in three levels: no pain, low pain and moderate pain were recorded as a single trial and evaluated. The support vector machine (SVM), K-Nearest Neighbors (KNN) and Ensemble bagging classifiers were trained using the K-fold cross-validation method and features of the brain's time-frequency domain. The results were obtained with accuracies of 72.8 ± 2, 84.4 ± 1.3 and 82.9 ± 1.6%, respectively. Also, in examining the problem of distinguishing pain and no pain, the electroencephalogram signal of 74 infants was evaluated, and similar to the three-class mode, with the 10-fold validation method, we reached the highest accuracy of 100% in Bagging classifier and 98.6 ± 0.1 accuracy in KNN and SVM classifiers.

Repeated and prolonged exposure to pain can impair neurodevelopmental, behavioral, and cognitive outcomes in newborns. Effective pain management of newborns is essential, but there is no comprehensive analysis of the status of neonatal pain non-pharmacologic management research. Original publications related to the non-pharmacological management of neonatal pain were obtained from the Web of Science Core Collection (WOSCC) between 1989 and 2024. CiteSpace and VOSviewer were used to extract information about countries/regions, institutions, authors, keywords, and references to identify and analyze the research hotspots and trends in this field. 1331 authors from 51 countries and 548 institutions published studies on the non-pharmacological management of neonatal pain between 1989 and 2024, with the number of publications showing an overall upward trend. Canada emerged as the leading country in terms of publication volume, with the University of Toronto and The Hospital for Sick Children identified as key research institutions. High-frequency keywords included "procedural pain," "management," "sucrose," "analgesia," and "preterm infant," resulting in 11 clusters. Keyword emergence analysis revealed that "neonatal pain," "analgesia," "oral sucrose," and "oral glucose" were research hotpots. Analysis of highly cited papers showed that the most referenced articles were published in the Clinical Journal of Pain. Researchers' interest in neonatal procedural pain has increased significantly over the past 30 years. This article can serve as a theoretical reference for future research on mild to moderate pain in neonates and infants, and it can provide ideas for exploring novel and secure pain management strategies.

"Everyday" exposures in the neonatal period, such as pain, may impact brain health in preterm infants. Specifically, greater exposure to painful procedures in the initial weeks after birth have been related to abnormalities in brain maturation and growth and poorer neurodevelopmental outcomes in preterm infants. Despite an increasing focus on the importance of treating pain in preterm infants, there is a lack of consensus of optimal approaches to managing pain in this population. This may be due to recent findings suggesting that commonly used analgesic and sedative medications in preterm infants may also have adverse effects of brain maturation and neurodevelopmental outcomes. This review provides an overview of potential impacts of pain and analgesia exposure on preterm brain health while highlighting research areas in need of additional investigations for the development of optimal pain management strategies in this population.

We prospectively compared cerebral oxygen saturation (CrSO2) and pain score changes during procedures in late preterm (LPT) versus term infants.

Near-infrared spectroscopy, pulse oximetry, Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile-Revised (PIPP-R) scores were assessed and CrSO2 data analyzed.

Thirty infants in each group were evaluated. LPT infants displayed a milder significant drop in Minimum post-procedural CrSO2 and smaller Maximum-Minimum post-procedural CrSO2 disparity. CrSO2 minute changes between the groups were non-significant. Moderate correlations were observed in both groups between NIPS and Minimum post-procedural CrSO2, and a moderate correlation was found in the Maximum-Minimum post-procedural CrSO2 difference in LPT infants. No correlation between PIPP-R and CrSO2 values was noted.

LPT and term infants demonstrated decreased CrSO2 in response to painful procedures. Correlations between CrSO2 and PIPP-R or NIPS scores were poor to moderate, reflecting the complex nature of these associations relative to gestational age.

Measurement of total bilirubin (TBil) concentration in serum is the gold standard approach for diagnosing neonatal unconjugated hyperbilirubinemia. It is of utmost importance that the measured TBil concentration is sufficiently accurate to prevent under treatment, unnecessary escalation of care, or overtreatment. However, it is widely recognized that TBil measurements urgently require improvement in neonatal clinical chemistry. External quality assessment (EQA) programs for TBil assess for differences between laboratories and provide supporting evidence of significant differences between various methods, manufacturers and measurement platforms. At the same time, many countries have adopted or only slightly adapted the neonatal hyperbilirubinemia management guidelines from the USA or UK, often without addressing differences in the methodology of TBil measurements. In this report, we provide an overview of the components of bilirubin that are measured by laboratory platforms, the availability of current reference measurement procedures and reference materials, and the role of EQA surveys in this context. Furthermore, the current status of agreement in neonatal bilirubin against clinical decision thresholds is reviewed. We advocate for enhancements in accuracy and comparability of neonatal TBil measurements, propose a path forward to accomplish this, and reflect on the position of the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Working Group Neonatal Bilirubin (WG-NB) in this matter.

Critically ill newborns experience numerous painful procedures as part of lifesaving care in the Neonatal Intensive Care Unit. However, painful exposures in the neonatal period have been associated with alterations in brain maturation and poorer neurodevelopmental outcomes in childhood. The most frequently used medications for pain and sedation in the NICU are opioids, benzodiazepines and sucrose; these have also been associated with abnormalities in brain maturation and neurodevelopment making it challenging to know what the best approach is to treat neonatal pain. This article provides clinicians with an overview of how neonatal exposure to pain as well as analgesic and sedative medications impact brain maturation and neurodevelopmental outcomes in critically ill infants. We also highlight areas in need of future research to develop standardized neonatal pain monitoring and management strategies.

To evaluate the impact of diaper change frequency, clinical characteristics, and skin health metrics on development of the skin microbiota in preterm infants.

A randomized controlled parallel design was used.

Medically stable preterm infants born <33 weeks' gestation were randomized to receive diaper changes at a frequency of every 3-hours or every 6-hours. Skin swabs were collected longitudinally from the diapered skin (buttocks) and chest. Skin pH and transepidermal water loss were measured with each sample collection. Stool samples were collected from the diaper. The microbiome at each site was characterized by 16S rRNA gene sequencing. Associations between microbiome features, diaper change frequency, and other covariates were examined using mixed effect models and redundancy analysis.

A total of 1179 samples were collected from 46 preterm infants, beginning at a median postnatal age of 44 days and continuing through hospital discharge. Alpha-diversity of the skin microbiota increased over time, but did not differ significantly between 3-hour (n = 20) and 6-hour (n = 26) diaper change groups. Alpha-diversity of the skin microbiota was inversely correlated with skin pH, but not transepidermal water loss. Microbiota community structure differed significantly between body sites (buttocks, chest, and stool) and between individuals. Among samples collected from the diapered skin, diaper change frequency, infant diet, antibiotic exposure, and delivery mode accounted for minor proportions of the variation in microbiota community structure between samples. Relative abundances of multiple genera differed between 3- and 6-hour diaper change groups over time.

The diversity and composition of the diapered skin microbiota is dynamic over time and differs from other body sites. Multiple factors including interindividual effects, diaper change frequency, diet, and antibiotics contribute to variation in the diapered skin microbiota.

Routine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA).

We examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020.

485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1-10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements.

We found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain.

 Evaluate the pain of critically ill newborns is a challenge because of the devices for cardiorespiratory support. This study aim to verify the adults' gaze when assessing the critically ill neonates' pain at bedside.

 Cross-sectional study in which pediatricians, nursing technicians, and parents evaluated critically ill neonates' pain at bedside, for 20 seconds with eye-tracking glasses. At the end, they answered whether the neonate was in pain or not. Visual tracking outcomes: number and time of visual fixations in four areas of interest (AOI) (face, trunk, and upper [UL] and lower [LL] limbs) were compared between groups and according to pain perception (present/absent).

 A total of 62 adults (21 pediatricians, 23 nursing technicians, 18 parents) evaluated 27 neonates (gestational age: 31.8 ± 4.4 weeks; birth weight: 1,645 ± 1,234 g). More adults fixed their gaze on the face (96.8%) and trunk (96.8%), followed by UL (74.2%) and LL (66.1%). Parents performed a greater number of fixations on the trunk than nursing technicians (11.0 vs. 5.5 vs. 6.0; p = 0.023). Controlled for visual tracking variables, each second of eye fixation in AOI (1.21; 95% confidence interval [CI]: 1.03-1.42; p = 0.018) and UL (1.07; 95% CI: 1.03-1.10; p < 0.001) increased the chance of perceiving the presence of pain.

 Adults, when assessing at bedside critically ill newborns' pain, fixed their eyes mainly on the face and trunk. The time spent looking at the UL was associated with the perception of pain presence.

· Pain assessment in critically ill newborns is a challenge.. · To assess critically ill neonates' pain, adults mainly look at the face and trunk.. · Looking at the upper limbs also helps in assessing critically ill neonates' pain..

Infants in neonatal intensive care units (NICUs) are exposed to frequent stressors that impact their neurodevelopmental outcomes. Parent presence and engagement are considered critical to improving infant outcomes, yet associations between cumulative NICU parent presence, engagement, and infant stress are infrequently examined.

To examine associations between NICU infant stress and the amount (hours per week) or frequency (days per week) of parent presence and skin-to-skin care (SSC).

A secondary analysis of a data set representing 78 NICU families was conducted. Infant acuity was measured using Neonatal Medical Index (NMI) scores. Parent presence and SSC data were collected from electronic medical records. Infant stress was measured using resting salivary cortisol levels collected at NICU discharge (median = 33 days of life).

More cumulative SSC was associated with lower discharge cortisol in NICU infants for SSC measured in hours per week (P = .03) or days per week (P = .05). Cumulative parent presence was not significantly associated with infant cortisol at discharge. Hierarchical regression analyses examining timing of parent presence supported a model including admission cortisol, NMI score, and parent presence during weeks 1 to 4 of life for explaining infant stress at discharge (R2 = 0.44, P = .004). Analyses examining timing of SSC supported a model including admission cortisol, NMI score, and frequency of SSC during week 1 for explaining infant stress at discharge (R2 = 0.21, P = .04).

Early, frequent SSC to mitigate stress in NICU infants was supported. Results suggested that timing of parent presence impacts NICU infant stress; however, additional study is recommended.

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown.

To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants.

This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023.

Pain was quantified in the initial weeks after birth as the total number of invasive procedures.

Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education.

A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes.

In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

Premature infants are exposed to numerous stressors in neonatal intensive care unit (NICU) during a crucial period for brain development; this period exerts long-term influences on cognitive and behavioral development.

To evaluate the effect of NICU-related stress on neonatal rat pups and explore the effect of Chinese medicine treatment (CMT).

Sixty male rat pups were randomly assigned to three groups: the control group, the NICU group (NICU-related stress), and the CMT group (NICU-related stress plus CMT). All stressors and interventions were administered from 0 to 7 days after birth. Body weight, serum corticosterone levels, and behavior in the open field (OF) test, elevated plus maze (EPM) test, sucrose preference test, and Morris water maze (MWM) test were recorded, and blood samples were collected at five different time points (T0, T1, T2, T3, and T4).

The body weights of rats in the CMT and control groups were heavier than those in the NICU group in both early life and adulthood (P < 0.05). Serum corticosterone levels significantly differed with time (except T0 vs. T1 and T3 vs. T4) but did not significantly differ among the three groups (F = 0.441, P = 0.894). Regardless of age, spatial memory and anxiety-like and depression-like behavior did not differ among the three groups.

NICU-related stress exerted a long-term effect on rat growth and development but did not affect spatial memory, anxiety-like behavior, depression-like behavior, or serum corticosterone levels. CMT alleviated the impact of NICU-related stress on rats and promoted the growth and development of neonatal rats.

Although the pediatric perioperative pain management has been improved in recent years, the valid and reliable pain assessment tool in perioperative period of children remains a challenging task. Pediatric perioperative pain management is intractable not only because children cannot express their emotions accurately and objectively due to their inability to describe physiological characteristics of feeling which are different from those of adults, but also because there is a lack of effective and specific assessment tool for children. In addition, exposure to repeated painful stimuli early in life is known to have short and long-term adverse sequelae. The short-term sequelae can induce a series of neurological, endocrine, cardiovascular system stress related to psychological trauma, while long-term sequelae may alter brain maturation process, which can lead to impair neurodevelopmental, behavioral, and cognitive function. Children's facial expressions largely reflect the degree of pain, which has led to the developing of a number of pain scoring tools that will help improve the quality of pain management in children if they are continually studied in depth. The artificial intelligence (AI) technology represented by machine learning has reached an unprecedented level in image processing of deep facial models through deep convolutional neural networks, which can effectively identify and systematically analyze various subtle features of children's facial expressions. Based on the construction of a large database of images of facial expressions in children with perioperative pain, this study proposes to develop and apply automatic facial pain expression recognition software using AI technology. The study aims to improve the postoperative pain management for pediatric population and the short-term and long-term quality of life for pediatric patients after operational event.

To assess whether music therapy (MT) is effective to reduce pain during daily personal hygiene care (DPHC), a procedure performed in all patients in a pediatric intensive care unit.

Fifty critically ill children were enrolled in a crossover controlled clinical trial with random ordering of the intervention, that is, passive MT, and standard conditions, and blind assessment of pain on film recordings. The primary outcome was variation of the Face Legs Activity Cry Consolability (FLACC) score (range, 0-10) comparing before and during DPHC. Secondary outcomes were changes in heart rate, respiratory rate, and mean arterial blood pressure, and administration of analgesic or sedative drugs during DPHC. Mixed-effects linear model analysis was used to assess effect size (95% CI).

The median (Q25-Q75) age and weight of the patients were 3.5 years (1.0-7.6 years) and 15.0 kg (10.0-26.8 kg). Consecutive DPHC were assessed on days 3 (2-5) and 4 (3-7) of hospitalization. In standard conditions, FLACC score was 0.0 (0.0-3.0) at baseline and 3.0 (1.0-5.5) during DPHC. With MT, these values were, respectively, 0.0 (0.0-1.0) and 2.0 (0.5-4.0). Rates of FLACC scores of >4 during DPHC, which indicates severe pain, were 42% in standard conditions and 17% with MT (P = .013). Mixed-effects model analysis found smaller increases in FLACC scores (-0.54 [-1.08 to -0.01]; P = .04) and heart rate (-9.00; [-14.53; -3.40]; P = .001) with MT.

MT is effective to improve analgesia in critically ill children exposed to DPHC.

This study was recorded (April 16, 2019) before patient recruitment on the National Library of Medicine registry (NCT03916835; https://clinicaltrials.gov/ct2/show/NCT03916835).

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.

Stress exposure in the neonatal intensive care unit (NICU) is associated with poor outcomes in preterm infants. However, factors predicting subsequent NICU stress exposure have not been identified.

To characterize NICU stressors experienced by preterm infants during the first 2 weeks of life and identify demographic, perinatal, and institutional variables associated with stress exposure.

A secondary analysis of data from a nonexperimental, prospective study was conducted using data from 60 very preterm infants born 28 to 31 weeks gestational age. Stress exposures during the first 2 weeks of life, operationalized as number of invasive procedures, were characterized by type and quantity for each infant using data extracted from electronic health records. Associations between number of invasive procedures and demographic, perinatal, or institutional variables were analyzed using linear regressions with robust standard errors.

Preterm infants experienced, on average, 98 (SD = 41.8) invasive procedures. Of these invasive procedures, nasal and/or oral suctioning episodes (58.1%), followed by skin-breaking procedures (32.6%), were most frequent. Differences in the number of invasive procedures were found for maternal race; infants born to Black mothers experienced fewer total invasive procedures than infants born to White mothers. The number of invasive procedures also varied across NICUs.

Preterm infant stress exposure differed by maternal race and NICU, consistent with research findings of differential treatment of diverse infants. Further research is needed to understand the reasons for these differences and to identify best practices to standardize neonatal care.

In neonates, uncontrolled pain and opioid exposure are both correlated with short- and long-term adverse events. Therefore, managing pain using opioid-sparing approaches is critical in neonatal populations. Multimodal pain control offers the opportunity to manage pain while reducing short- and long-term opioid-related adverse events. Intravenous (IV) acetaminophen may represent an appropriate adjunct to opioid-based postoperative pain control regimes. However, no trials assess this drug in patients less than 36 weeks post-conceptual age or weighing less than 1500 g.

The proposed study aims to determine the feasibility of conducting a randomized control trial to compare IV acetaminophen and fentanyl to a saline placebo and fentanyl for patients admitted to the neonatal intensive care unit (NICU) undergoing major abdominal or thoracic surgery.

This protocol is for a single-centre, external pilot randomized controlled trial (RCT). Infants in the NICU who have undergone major thoracic or abdominal surgery will be enrolled. Sixty participants will undergo 1:1 randomization to receive intravenous acetaminophen and fentanyl or saline placebo and fentanyl. After surgery, IV acetaminophen or placebo will be given routinely for eight days (192 hours). Appropriate dosing will be determined based on the participant's gestational age. Patients will be followed for eight days after surgery and will undergo a chart review at 90 days. Primarily feasibility outcomes include recruitment rate, follow-up rate, compliance, and blinding index. Secondary clinical outcomes will be collected as well.

This external pilot RCT will assess the feasibility of performing a multicenter RCT comparing IV acetaminophen and fentanyl to a saline placebo and fentanyl in NICU patients following major abdominal and thoracic surgery. The results will inform the design of a multicenter RCT, which will have the appropriate power to determine the efficacy of this treatment.

ClinicalTrials.gov NCT05678244, Registered December 6, 2022.

In the short term, parental presence while a human infant is in pain buffers the immediate pain responses, although emerging evidence suggests repeated social buffering of pain may have untoward long-term effects.

To explore the short- and long-term impacts of social buffering of pain, we first measured the infant rat pup's [postnatal day (PN) 8, or 12] response to mild tail shock with the mother present compared to shock alone or no shock. Shock with the mother reduced pain-related behavioral activation and USVs of pups at both ages and reduced Fos expression in the periaqueductal gray, hypothalamic paraventricular nucleus, and the amygdala at PN12 only. At PN12, shock with the mother compared to shock alone differentially regulated expression of several hundred genes related to G-protein-coupled receptors (GPCRs) and neural development, whereas PN8 pups showed a less robust and less coherent expression pattern. In a second set of experiments, pups were exposed to daily repeated Shock-mother pairings (or controls) at PN5-9 or PN10-14 (during and after pain sensitive period, respectively) and long-term outcome assessed in adults. Shock+mother pairing at PN5-9 reduced adult carrageenan-induced thermal hyperalgesia and reduced Fos expression, but PN10-14 pairings had minimal impact. The effect of infant treatment on adult affective behavior showed a complex treatment by age dependent effect. Adult social behavior was decreased following Shock+mother pairings at both PN5-9 and PN10-14, whereas shock alone had no effect. Adult fear responses to a predator odor were decreased only by PN10-14 treatment and the infant Shock alone and Shock+mother did not differ.

Overall, integrating these results into our understanding of long-term programming by repeated infant pain experiences, the data suggest that pain experienced within a social context impacts infant neurobehavioral responses and initiates an altered developmental trajectory of pain and affect processing that diverges from experiencing pain alone.

Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits.

Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment.

We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months.

These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.

Pain management in neonates and infants has many unique and important facets, particularly in former preterm infants. Untreated pain and surgical stress in neonates are associated with myriad negative sequelae, including deleterious inflammatory, autonomic, hormonal, metabolic, and neurologic effects. Meanwhile, opioid side effects are also very impactful and affect multiple systems and pathways, particularly in the neonatal and infant population. Regional anesthesia presents a unique opportunity to provide highly effective analgesia; prevent deleterious signaling cascade pathways within the endocrine, immune, and nervous systems from occurring; and create conditions to facilitate reduced reliance on opioids and other analgesics. In some cases, clinicians can completely avoid general anesthesia and systemic anesthetics. This review will discuss some of the unique aspects of pain management in neonates and infants and provide an overview of the different regional anesthetic options available, namely, spinal anesthesia, epidural anesthesia, and peripheral nerve blocks.

Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure. Without adequate analgesia, LP can cause considerable pain and discomfort. As newborns have increased sensitivity to pain, it is crucial to adequately manage the procedural pain of LP in this population.

To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non-pharmacological interventions, or other pharmacological interventions.

We searched CENTRAL, PubMed, Embase, and three trial registries in December 2022. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches.

We included randomized controlled trials (RCTs) and quasi-RCTs comparing drugs used for pain management, sedation, or both, during LP. We considered the following drugs suitable for inclusion. • Topical anesthetics (e.g. eutectic mixture of local anesthetics [EMLA], lidocaine) • Opioids (e.g. morphine, fentanyl) • Alpha-2 agonists (e.g. clonidine, dexmedetomidine) • N-Methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) • Other analgesics (e.g. paracetamol) • Sedatives (e.g. benzodiazepines such as midazolam) DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) or standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CIs). Our main outcomes were successful LP on first attempt, total number of LP attempts, episodes of bradycardia, pain assessed with validated scales, episodes of desaturation, number of episodes of apnea, and number of infants with one or more episodes of apnea. We used the GRADE approach to evaluate the certainty of the evidence.

We included three studies (two RCTs and one quasi-RCT) that enrolled 206 newborns. One study included only term infants. All studies assessed topical treatment versus placebo or no intervention. The topical anesthetics were lidocaine 4%, lidocaine 1%, and EMLA. We identified no completed studies on opioids, non-steroidal anti-inflammatory drugs, alpha-2 agonists, NMDA receptor antagonists, other analgesics, sedatives, or head-to-head comparisons (drug A versus drug B). Based on very low-certainty evidence from one quasi-RCT of 100 LPs in 76 infants, we are unsure if topical anesthetics (lidocaine), compared to no anesthesia, has an effect on the following outcomes. • Successful LP on first attempt (first-attempts success in 48% of LPs in the lidocaine group and 42% of LPs in the control group) • Number of attempts per LP (mean 1.9 attempts, [standard error of the mean 0.2] in the lidocaine group, and mean 2.1 attempts [standard error of the mean 2.1] in the control group) • Episodes of bradycardia (0% of LPs in the lidocaine group and 4% of LPs in the control group) • Episodes of desaturation (0% of LPs in the lidocaine group and 8% of LPs in the control group) • Occurrence of apnea (RR 3.24, 95% CI 0.14 to 77.79; risk difference [RD] 0.02, 95% CI -0.03 to 0.08). Topical anesthetics compared to placebo may reduce pain assessed with the Neonatal Facial Coding System (NFCS) score (SMD -1.00 standard deviation (SD), 95% CI -1.47 to -0.53; I² = 98%; 2 RCTs, 112 infants; low-certainty evidence). No studies in this comparison reported total number of episodes of apnea. We identified three ongoing studies, which will assess the effects of EMLA, lidocaine, and fentanyl. Three studies are awaiting classification.

The evidence is very uncertain about the effect of topical anesthetics (lidocaine) compared to no anesthesia on successful lumbar puncture on first attempt, the number of attempts per lumbar puncture, episodes of bradycardia, episodes of desaturation, and occurrence of apnea. Compared to placebo, topical anesthetics (lidocaine or EMLA) may reduce pain assessed with the NFCS score. One ongoing study will assess the effects of systemic treatment.

Sucrose has been examined for calming and pain-relieving effects in neonates for invasive procedures such as heel lance.

To assess the effectiveness of sucrose for relieving pain from heel lance in neonates in terms of immediate and long-term outcomes SEARCH METHODS: We searched (February 2022): CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and three trial registries.

We included randomised controlled trials where term and/or preterm neonates received sucrose for heel lances. Comparison treatments included water/placebo/no intervention, non-nutritive sucking (NNS), glucose, breastfeeding, breast milk, music, acupuncture, facilitated tucking, and skin-to-skin care.

We used standard Cochrane methods. We reported mean differences (MD) with 95% confidence intervals (CI) using the fixed-effect model for continuous outcome measures. We assessed heterogeneity by the I2 test. We used GRADE to assess certainty of evidence.

We included 55 trials (6273 infants): 29 included term neonates, 22 included preterm neonates, and four included both. Heel lance was investigated in 50 trials; 15 investigated other minor painful procedures in addition to lancing. Sucrose vs control The evidence suggests that sucrose probably results in a reduction in PIPP scores compared to the control group at 30 seconds (MD -1.74 (95% CI -2.11 to -1.37); I2 = 62%; moderate-certainty evidence) and 60 seconds after lancing (MD -2.14, 95% CI -3.34 to -0.94; I2 = 0%; moderate-certainty evidence). The evidence is very uncertain about the effects of sucrose on DAN scores compared to water at 30 seconds after lancing (MD -1.90, 95% CI -8.58 to 4.78; heterogeneity not applicable (N/A); very low-certainty evidence). The evidence suggests that sucrose probably results in a reduction in NIPS scores compared to water immediately after lancing (MD -2.00, 95% CI -2.42 to -1.58; heterogeneity N/A; moderate-certainty evidence). Sucrose vs NNS The evidence is very uncertain about the effect of sucrose on PIPP scores compared to NNS during the recovery period after lancing (MD 0.60, 95% CI -0.30 to 1.50; heterogeneity not applicable; very low-certainty evidence) and on DAN scores at 30 seconds after lancing (MD -1.20, 95% CI -7.87 to 5.47; heterogeneity N/A; very low-certainty evidence). Sucrose + NNS vs NNS The evidence is very uncertain about the effect of sucrose + NNS on PIPP scores compared to NNS during lancing (MD -4.90, 95% CI -5.73 to -4.07; heterogeneity not applicable; very low-certainty evidence) and during recovery after lancing (MD -3.80, 95% CI -4.47 to -3.13; heterogeneity N/A; very low-certainty evidence). The evidence is very uncertain about the effects of sucrose + NNS on NFCS scores compared to water + NNS during lancing (MD -0.60, 95% CI -1.47 to 0.27; heterogeneity N/A; very low-certainty evidence). Sucrose vs glucose The evidence suggests that sucrose results in little to no difference in PIPP scores compared to glucose at 30 seconds (MD 0.26, 95% CI -0.70 to 1.22; heterogeneity not applicable; low-certainty evidence) and 60 seconds after lancing (MD -0.02, 95% CI -0.79 to 0.75; heterogeneity N/A; low-certainty evidence). Sucrose vs breastfeeding The evidence is very uncertain about the effect of sucrose on PIPP scores compared to breastfeeding at 30 seconds after lancing (MD -0.70, 95% CI -0.49 to 1.88; I2 = 94%; very low-certainty evidence). The evidence is very uncertain about the effect of sucrose on COMFORTneo scores compared to breastfeeding after lancing (MD -2.60, 95% CI -3.06 to -2.14; heterogeneity N/A; very low-certainty evidence). Sucrose vs expressed breast milk The evidence suggests that sucrose may result in little to no difference in PIPP-R scores compared to expressed breast milk during (MD 0.3, 95% CI -0.24 to 0.84; heterogeneity not applicable; low-certainty evidence) and at 30 seconds after lancing (MD 0.3, 95% CI -0.11 to 0.71; heterogeneity N/A; low-certainty evidence). The evidence suggests that sucrose probably may result in slightly increased PIPP-R scores compared to expressed breast milk 60 seconds after lancing (MD 1.10, 95% CI 0.34 to 1.86; heterogeneity N/A; low-certainty evidence). The evidence is very uncertain about the effect of sucrose on DAN scores compared to expressed breast milk 30 seconds after lancing (MD -1.80, 95% CI -8.47 to 4.87; heterogeneity N/A; very low-certainty evidence). Sucrose vs laser acupuncture There was no difference in PIPP-R scores between sucrose and music groups; however, data were reported as medians and IQRs. The evidence is very uncertain about the effect of sucrose on NIPS scores compared to laser acupuncture during lancing (MD -0.86, 95% CI -1.43 to -0.29; heterogeneity N/A; very low-certainty evidence). Sucrose vs facilitated tucking The evidence is very uncertain about the effect of sucrose on total BPSN scores compared to facilitated tucking during lancing (MD -2.27, 95% CI -4.66 to 0.12; heterogeneity N/A; very low-certainty evidence) and during recovery after lancing (MD -0.31, 95% CI -1.72 to 1.10; heterogeneity N/A; very low-certainty evidence). Sucrose vs skin-to-skin + water (repeated lancing) The evidence suggests that sucrose results in little to no difference in PIPP scores compared to skin-to-skin + water at 30 seconds after 1st (MD 0.13, 95% CI -0.70 to 0.96); 2nd (MD -0.56, 95% CI -1.57 to 0.45); or 3rd lancing (MD-0.15, 95% CI -1.26 to 0.96); heterogeneity N/A, low-certainty evidence for all comparisons. The evidence suggests that sucrose results in little to no difference in PIPP scores compared to skin-to-skin + water at 60 seconds after 1st (MD -0.61, 95% CI -1.55 to 0.33); 2nd (MD -0.12, 95% CI -0.99 to 0.75); or 3rd lancing (MD-0.40, 95% CI -1.48 to 0.68); heterogeneity N/A, low-certainty evidence for all comparisons. Minor adverse events required no intervention.

Sucrose compared to control probably results in a reduction of PIPP scores 30 and 60 seconds after single heel lances (moderate-certainty evidence). Evidence is very uncertain about the effect of sucrose compared to NNS, breastfeeding, laser acupuncture, facilitated tucking, and the effect of sucrose + NNS compared to NNS in reducing pain. Sucrose compared to glucose, expressed breast milk, and skin-to-skin care shows little to no difference in pain scores. Sucrose combined with other nonpharmacologic interventions should be used with caution, given the uncertainty of evidence.

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted.

To investigate the impact of the level of pain experienced by infants born preterm on neurodevelopmental outcomes during their stay in a neonatal intensive care unit.

In this retrospective data analysis we included all surviving infants born preterm with a gestational age between 23 and 32 weeks from 2011 to 2015, who were assessed using the Neonatal Pain, Agitation, and Sedation Scale and examined at 1 year of age using the Bayley Scales of Infant Development. We excluded all infants who had suffered severe neurological morbidities and undergone surgical interventions.

A total of 196 infants born preterm were included in the analyses: 105 in the 'no pain group' and 91 in the 'pain group'. Significant differences between the groups were detected for both mental and motor development (p = 0.003, 95% confidence interval [CI] 2.23-10.92; p = 0.025, 95% CI 0.64-9.78). The results remained significant after controlling for other important medical conditions (p = 0.001, 95% CI -19.65 to -5.40; p = 0.010, 95% CI -16.18 to -2.29).

Neonatal pain exposure was associated with altered neurodevelopmental outcomes of infants born very preterm at a corrected age of 12 months. This observation highlights the importance of adequate pain management to reduce the risk of poor neurodevelopmental outcomes in these vulnerable patients.

Studies have clearly shown that development of pain receptors starts as early as 20-weeks' gestation. Despite contrary belief, the human fetus develops a similar number of receptive pain fibers as seen in adults. These receptors' maturation is based on response to sensory stimuli received after birth which makes the NICU a critical place for developing central nervous system's pain perception. In practice, the assessment of pain relies mostly on bedside staff. In this review we will discuss the various developing features of pain pathways in the neonatal brain and the modification of pain perception secondary to various interactions immediately after birth. We also discuss the various tools utilized in the NICU for pain assessment that rely on physiological and behavioral patterns. Finally, we address the management of pain in the NICU by either pharmacological or non-pharmacological intervention while highlighting potential benefits, disadvantages, and situations where one may be preferred over another.

Recording multimodal responses to sensory stimuli in infants provides an integrative approach to investigate the developing nervous system. Accurate time-locking across modalities is essential to ensure that responses are interpreted correctly, and could also improve clinical care, for example, by facilitating automatic and objective multimodal pain assessment. Here we develop and assess a system to time-lock stimuli (including clinically-required heel lances and experimental visual, auditory and tactile stimuli) to electrophysiological research recordings and data recorded directly from a hospitalised infant's vital signs monitor. The electronic device presented here (that we have called 'the PiNe box') integrates a previously developed system to time-lock stimuli to electrophysiological recordings and can simultaneously time-lock the stimuli to recordings from hospital vital signs monitors with an average precision of 105 ms (standard deviation: 19 ms), which is sufficient for the analysis of changes in vital signs. Our method permits reliable and precise synchronisation of data recordings from equipment with legacy ports such as TTL (transistor-transistor logic) and RS-232, and patient-connected networkable devices, is easy to implement, flexible and inexpensive. Unlike current all-in-one systems, it enables existing hospital equipment to be easily used and could be used for patients of any age. We demonstrate the utility of the system in infants using visual and noxious (clinically-required heel lance) stimuli as representative examples.

The present envelope frequency-following response (FFR ENV ) study aimed at characterizing the neural encoding of the fundamental frequency of speech sounds in neonates born at the higher end of the birth weight continuum (>90th percentile), known as large-for-gestational age (LGA).

Twenty-five LGA newborns were recruited from the maternity unit of Sant Joan de Déu Barcelona Children's Hospital and paired by age and sex with 25 babies born adequate-for-gestational age (AGA), all from healthy mothers and normal pregnancies. FFR ENV s were elicited to the/da/ syllable and recorded while the baby was sleeping in its cradle after a successful universal hearing screening. Neural encoding of the stimulus' envelope of the fundamental frequency (F 0ENV ) was characterized through the FFR ENV spectral amplitude. Relationships between electrophysiological parameters and maternal/neonatal variables that may condition neonatal neurodevelopment were assessed, including pregestational body mass index (BMI), maternal gestational weight gain and neonatal BMI.

LGA newborns showed smaller spectral amplitudes at the F 0ENV compared to the AGA group. Significant negative correlations were found between neonatal BMI and the spectral amplitude at the F 0ENV .

Our results indicate that in spite of having a healthy pregnancy, LGA neonates' central auditory system is impaired in encoding a fundamental aspect of the speech sounds, namely their fundamental frequency. The negative correlation between the neonates' BMI and FFR ENV indicates that this impaired encoding is independent of the pregnant woman BMI and weight gain during pregnancy, supporting the role of the neonatal BMI. We suggest that the higher adipose tissue observed in the LGA group may impair, via proinflammatory products, the fine-grained central auditory system microstructure required for the neural encoding of the fundamental frequency of speech sounds.

Probiotics have shown a benefit in reducing necrotising enterocolitis in the premature infant, however the study of their effect on premature neonates' neurodevelopment is limited. The aim of our study was to elucidate whether the effect of Bifidobacterium bifidum NCDO 2203 combined with Lactobacillus acidophilus NCDO 1748 could positively impact the neurodevelopment of the preterm neonates. Quasi-experimental comparative study with a combined treatment of probiotics in premature infants < 32 weeks and < 1500 g birth weight, cared for at a level III neonatal unit. The probiotic combination was administered orally to neonates surviving beyond 7 days of life, until 34 weeks postmenstrual age or discharge. Globally, neurodevelopment was evaluated at 24 months corrected age. A total of 233 neonates were recruited, 109 in the probiotic group and 124 in the non-probiotic group. In those neonates receiving probiotics, there was a significant reduction in neurodevelopment impairment at 2 years of age RR 0.30 [0.16-0.58], and a reduction in the degree of impairment (normal-mild vs moderate-severe, RR 0.22 [0.07-0.73]). Additionally, there was a significant reduction in late-onset sepsis (RR 0.45 [0.21-0.99]). The prophylactic use of this probiotic combination contributed to improving neurodevelopmental outcome and reduced sepsis in neonates born at < 32 weeks and < 1500 g.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.Accepted.

To examine the relationship between NICU stress exposure and the neurodevelopmental outcomes of preterm infants.

A multicenter, prospective cohort study was conducted between May 2021 and June 2022. Preterm infant participants (28-34 weeks gestational age) were recruited at birth from three NICUs of three tertiary hospitals by convenience sampling. The NICU stress includes acute NICU stress and chronic NICU stress which were measured over the total NICU hospitalization for each infant using the Neonatal Infant Stressor Scale (NISS). Neurodevelopmental outcomes of preterm infants were assessed at 3 months corrected age (CA) using the Ages and Stages Questionnaire, Third Edition (ASQ-3).

Of one hundred and thirty preterm infant participants, 108 preterm infants were included into analysis. Results showed that acute NICU stress exposure significantly predicted the neurodevelopmental abnormalities in communication function (RR: 1.001, 95%CI: 1.000-1.001, p = .011), while chronic NICU stress exposure was significantly associated with the problem-solving function (RR: 1.003, 95%CI: 1.001-1.005, p = .002) at 3 months CA. No significant associations were found between NICU stress exposure and other dimensions of neurodevelopmental outcomes, including gross motor, fine motor, and personal-social functions.

NICU stress exposure demonstrated a significant predicting relationship with abnormalities in communication and problem-solving functions of preterm infants at 3 months CA.

During the NICU hospitalization, neonatal health caregivers should systematically monitor the NICU stress exposure to prevent neurodevelopmental problems in preterm infants.

A prerequisite for successful pain management is identifying the pain and assessing its intensity. The aim of this study was to describe parents' perceptions of their child's pain assessment in hospital care.

This study was a descriptive cross-sectional study. A questionnaire was completed by parents (n = 261) whose child was hospitalized in one of the pediatric units (n = 6) of the University Hospital in Finland. Quantitative data were analyzed using statistical methods; open-ended data were analyzed using inductive content analysis.

Parents reported that their children experienced moderate (36%) to severe pain (42%) during hospitalization. The most intense pain experienced by the children was associated with needle-related procedures (41%). A large proportion of parents (83%) were involved in their child's pain assessment. Parents were satisfied with their child's pain assessment but perceived some shortcomings. Parents hoped that a variety of methods would be used to assess their child's pain and that the parents' and child's views on pain would be taken into account.

Most children experience moderate to severe pain during hospitalization. Parents are often involved in pain assessment but are rarely instructed to use pain scales.

Child's pain should be assessed regularly and frequently enough. It is important that the child and parents are involved in shared decision-making about pain assessment and treatment, and they have opportunities to ask questions. Guidance should be offered to parents about the use of pain assessment scales.

Neonates are an extremely vulnerable patient population, with 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU will undergo multiple painful procedures per day throughout their stay. There is increasing evidence that frequent and repetitive exposure to painful stimuli is associated with poorer outcomes later in life. To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. This review focused on non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and N-methyl-D-aspartate (NMDA) receptor antagonists, which alleviate pain through inhibiting cellular pathways to achieve analgesia.  The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. We therefore sought to summarize the evidence on the level of pain experienced by neonates both during and following procedures; relevant drug-related adverse events, namely episodes of apnea, desaturation, bradycardia, and hypotension; and the effects of combinations of drugs.  As the field of neonatal procedural pain management is constantly evolving, this review aimed to ascertain the scope of non-opioid analgesics for neonatal procedural pain to provide an overview of the options available to better inform evidence-based clinical practice.  OBJECTIVES: To determine the effects of non-opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration.

We searched the Cochrane Library (CENTRAL), PubMed, Embase, and two trial registries in June 2022. We screened the reference lists of included studies for studies not identified by the database searches.

We included all randomized controlled trials (RCTs), quasi-RCTs, and cluster-RCTs in neonates (term or preterm) undergoing painful procedures comparing NSAIDs and NMDA receptor antagonists to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our main outcomes were pain assessed during the procedure and up to 10 minutes after the procedure with a validated scale; episodes of bradycardia; episodes of apnea; and hypotension requiring medical therapy.

We included two RCTs involving a total of 269 neonates conducted in Nigeria and India.  NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention One RCT evaluated using oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision.  The evidence is very uncertain about the effect of ketamine on pain score during the procedure, assessed with the Neonatal Infant Pain Scale (NIPS), compared with placebo (mean difference (MD) -0.95, 95% confidence interval (CI) -1.32 to -0.58; 1 RCT; 145 participants; very low-certainty evidence). No other outcomes of interest were reported on. Head-to-head comparison of different analgesics One RCT evaluated using intravenous fentanyl versus intravenous ketamine during laser photocoagulation for retinopathy of prematurity. Neonates receiving ketamine followed an initial regimen (0.5 mg/kg bolus 1 minute before procedure) or a revised regimen (additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg), while those receiving fentanyl followed either an initial regimen (2 μg/kg over 5 minutes, 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion) or a revised regimen (titration of 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour). The evidence is very uncertain about the effect of ketamine compared with fentanyl on pain score assessed with the Premature Infant Pain Profile-Revised (PIPP-R) scores during the procedure (MD 0.98, 95% CI 0.75 to 1.20; 1 RCT; 124 participants; very low-certainty evidence); on episodes of apnea occurring during the procedure (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) -0.09, 95% CI -0.19 to 0.00; 1 study; 124 infants; very low-certainty evidence); and on hypotension requiring medical therapy occurring during the procedure (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI -0.03 to 0.10; 1 study; 124 infants; very low-certainty evidence). The included study did not report pain score assessed up to 10 minutes after the procedure or episodes of bradycardia occurring during the procedure. We did not identify any studies comparing NSAIDs versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention or different routes of administration of the same analgesics. We identified three studies awaiting classification.  AUTHORS' CONCLUSIONS: The two small included studies comparing ketamine versus either placebo or fentanyl, with very low-certainty evidence, rendered us unable to draw meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on NSAIDs or studies comparing different routes of administration. Future research should prioritize large studies evaluating non-opioid analgesics in this population. As the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as we identified no studies on NSAIDs, which are widely used in older infants, or comparing different routes of administration, such studies should be a priority going forward.

We aim to test the feasibility and effectiveness of Premature Triadic Music Therapy (PT-MT) in the premature baby unit.

The design was a clinical pre-test-post-test trial with a convenience sample. Inclusion criteria were a gestational age higher than 28 weeks for preterm infants and the absence of shock or extreme distress for parents. Six preterm children (with a gestational age of 33 to 36 weeks) and their parents participated in the study. For the children, we measured heart rate, blood perfusion, and blood saturation at three different times (pre-PT-MT, during PT-MT, after PT-MT) as quantitative indicators of distress. Their parents completed the Edinburgh Postnatal Depression Scale (EPDS) before and after the PT-MT intervention.

We found a statistically significant lower heart rate and a marginally statistically significant higher blood perfusion during PT-MT, as compared to the baseline. However, these changes were not present at the end of PT-MT. The parents' EPDS scores were not statistically significantly lower at the post-test, although, the Medians of the scores did decrease.

PT-MT is a promising intervention for the reduction of distress in both parents and children. Further studies should include a higher number of sessions and participants.

This study aims to characterise current pain management practices in extremely preterm infants (gestational age less than or equal to 28 weeks) admitted to neonatal intensive care unit (NICU).

Retrospective audit pertaining to patient characteristics, as well as minor painful procedures (MPP), pain mitigation and pain scoring in 25 extremely preterm infants admitted to a tertiary NICU in 2016 over the first 14 days of NICU admission. Opportunities to bundle MPP were identified according to pre-specified criteria. Bayley Scales of Infant Development, Third Edition (BSID-III) cognitive, language and motor composite scores were available from the neurodevelopmental follow-up clinic at 12- and 24-months of corrected age. Linear mixed methods regression was used to examine for correlation between increased exposure to MPP and BSID-III scores at follow-up.

Extremely preterm infants underwent an average of 11.24 ± 4.12 MPP per day for the first 14 days of NICU admission. Opportunities to bundle MPP were missed 75.98% (408/537) of the time; most of these were invasive blood collections. A total of 12.2% (481/3933) of MPP occurred within 4 h of pharmacological or non-pharmacological pain mitigation. BSID-III motor composite score was associated with an 11.75 (95% confidence interval 1.99, 21.27) decrease in patients experiencing more than or equal to the third quartile of MPP in the 14 days post-NICU admission (P = 0.0329, n = 42). Association was not found for BSID-III cognitive and language composite scores.

There is readily scope for quality improvement initiatives to reduce harm in extremely preterm infants admitted to NICU.

We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment.

Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition.

Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days).

Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants.

In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Pain disrupts neonatal vital signs and internal environment homeostasis and affects the recovery process, and recurrent pain stimulation is one of the important risk factors for neurodevelopmental disorders and some chronic diseases. In order to standardize pain management practice in neonatal wards in China and effectively prevent and reduce the adverse effects of pain on the physical and mental development of neonates, National Clinical Research Center for Child Health and Diseases (Children's Hospital of Chongqing Medical University) convened a multidisciplinary panel to formulate the evidence-based guideline for neonatal pain management in China (2023 edition) following the principles and methods for the guideline development issued by the World Health Organization. Based on the best evidence and expert consensus, this guideline gives 26 recommendations for nine clinical issues, i.e., the classification and definition of neonatal pain, common sources of pain, pain assessment principles, pain assessment methods, analgesic principle, non-pharmaceutical analgesic methods, pharmaceutical analgesic methods, parental participation in pain management, and recording methods for pain management, so as to provide medical staff with guidance and a decision-making basis for neonatal pain assessment and analgesia management.

Of all preterm births, approximately 82% are moderate to late preterm. Moderate to late preterm infants are often treated like full-term infants despite their physiological and metabolic immaturity, increasing their risk for mortality and morbidity.

To describe the relationship between routine caregiving methods and physiological markers of stress and hypoxemia in infants born between 32 and 36 weeks' gestation.

This descriptive study used a prospective observational design to examine the relationship between routine caregiving patterns (single procedure vs clustered care) and physiological markers of stress and hypoxemia such as regional oxygen saturation, quantified as renal and cerebral regional oxygen saturation (StO2), systemic oxygen saturation (Spo2), and heart rate (HR) in moderate to late preterm infants. Renal and cerebral StO2 was measured using near-infrared spectroscopy during a 6-hour study period. Spo2 and HR were measured using pulse oximetry.

A total of 231 procedures were captured in 37 participants. We found greater alterations in cerebral StO2, renal StO2, Spo2, and HR when routine procedures were performed consecutively in clusters than when procedures were performed singly or separately.

Our results suggest that the oxygen saturation and HR of moderate to late preterm infants were significantly altered when exposed to routine procedures that were performed consecutively, in clusters, compared with when exposed to procedures that were performed singly or separately. Adequately powered randomized controlled trials are needed to determine the type of caregiving patterns that will optimize the health outcomes of this vulnerable population.

We studied the reliability and validity of the COMFORTneo scale, designed to measure neonatal prolonged pain.

This prospective observational study evaluated four clinimetric properties of the COMFORTneo scale from NICU nurses' assessments of neonates' pain. Intra-rater reliability was determined from three video fragments at two time points. Inter-rater reliability and construct validity were determined in five neonates per nurse with the COMFORTneo and numeric rating scales (NRS) for pain and distress. Pain scores using N-PASS were correlated with COMFORTneo scores to further evaluate construct validity.

Intra-rater reliability: Twenty-two nurses assessed pain twice with an intraclass correlation coefficient (ICC) of 0.70. Inter-rater reliability: The ICC for 310 COMFORTneo scores together with 62 nurses was 0.93. Construct validity: Correlation between COMFORTneo and NRS pain, distress, and N-PASS was 0.34, 0.72, and 0.70, respectively.

The COMFORTneo can be used to reliably and validly assess pain in NICU patients.

The purpose of this study was to investigate correlates of preterm (PT) infant's cortisol reactivity and the association to infant negative affect, during a mother-infant interaction procedure. Participants included 48 infants born prematurely (gestational age < 37 weeks) and their mothers, assessed when infants were 12 months old corrected for prematurity. The examined variables comprised both neonatal and environmental dimensions including maternal interactive behavior. Infant negative affect and maternal interactive behavior were assessed with a standardized mother-infant interaction task. A baseline infant saliva sample was collected before the interaction began, and a second sample after the interaction episodes ended. Results revealed that decrease of infant's cortisol concentration was significantly associated with the exposure to more sensitive, and less intrusive maternal behaviors. However, once controlled for neonatal risk, family SES and maternal psychological distress, the associations were rendered non-significant. Although the association between cortisol reactivity and negative affect trended toward significance, maternal intrusiveness was the only significant predictor of observed infant negative affect. Findings suggest the importance of primary relational experiences on PT infants' early regulatory competencies.

We aimed to evaluate (1) whether sedation analgesia (SA) used during therapeutic hypothermia (TH) was efficient to support the wellbeing of neonates with hypoxic-ischemic encephalopathy, (2) the SA level and its adjustment to clinical pain scores, and (3) the impact of inadequate SA on short-term neonatal outcomes evaluated at discharge.

This was an observational retrospective study performed between 2011 and 2018 in two level III centers in Alsace, France. We analyzed the wellbeing of infants by using the COMFORT-Behavior (COMFORT-B) clinical score and SA level during TH, according to which we classified infants into four groups: those with excess SA, adequate SA, lack of SA, and variability of SA. We analyzed the variations in doses of SA and their justification. We also determined the impact of inadequate SA on neonatal outcomes at discharge by multivariate analyses with multinomial regression, with adequate SA as the reference.

A total of 110 patients were included, 89 from Strasbourg university hospital and 21 from Mulhouse hospital. The COMFORT-B score was assessed 95.5% of the time. Lack of SA was mainly found on the first day of TH (15/110, 14%). In all, 62 of 110 (57%) infants were in excess of SA over the entire duration of TH. Most dose variations were related to clinical pain scores. Inadequate SA was associated with negative short-term consequences. Infants with excess of SA had a longer duration of mechanical ventilation [mean ratio 1.46, 95% confidence interval (CI), 1.13-1.89, p = 0.005] and higher incidence of abnormal neurological examination at discharge (odds ratio 2.61, 95% CI, 1.10-6.18, p = 0.029) than infants with adequate SA.

Adequate SA was not easy to achieve during TH. Close and regular monitoring of SA level may help achieve adequate SA. Excess of SA can be harmful for newborns with hypoxic-ischemic encephalopathy who are undergoing TH.

The outcomes of pain and stress in preterm infants in the neonatal intensive care units (NICUs) compel the continued search for pain- and stress-reducing interventions.

To investigate how skin-to-skin contact (SSC) influences chronic pain and stress in preterm infants in the NICU.

The study included 140 preterm infants in the NICU with gestational age less than 34 weeks. The overall design was a baseline-response design. Urine and saliva were collected before (baseline) and after SSC to measure pain and stress markers by enzyme immunoassay method. The behavioral indicators of chronic pain were assessed using the EDIN (Échelle Douleur Inconfort Nouveau-Né-neonatal pain and discomfort).

There was a significant decrease in the dopamine level in preterm infants after SSC in comparison with baseline values (85.99 [69.35; 112.20] pg/ml vs. 132.20 [104.80; 183.70] pg/ml), p < 0.001. The β-endorphin and serotonin levels increased after SSC (40.09 [26.81; 70.63] pg/ml vs. 29.87 [20.61; 46.94] pg/ml, p = 0.009 and 25.49 [20.45; 40.08] ng/ml vs. 22.30 [15.13; 31.65] ng/ml, p = 0.011, respectively). A significant decrease in cortisol levels in saliva and urine after SSC in comparison with baseline values (0.125 [0.079; 0.225] μg/dl vs. 0.371 [0.188; 1.002] μg/dl, p = 0.000 and 27.06 [14.59; 35.35] ng/ml vs. 35.25 [19.78; 61.94] ng/ml, p = 0.001, with a simultaneous increase of oxytocin level (57.00 [36.55; 88.49] pg/ml vs. 38.20 [28.78; 56.04] pg/ml, p = 0.009 were revealed. The total pain EDIN score in infants after SSC was below 6 points, significantly decreasing compared to the baseline (p < 0.05).

Preterm infants in the NICU experience stress and pain, which were confirmed by the EDIN pain scale and laboratory markers. The level of dopamine and cortisol as pain and stress hormones were reliably high, and normalized after regular SSC. Simultaneously, pain-relieving and anti-stress markers of oxytocin, β-endorphin and serotonin reliably increased in preterm infants in response to the SSC.