An Evidence-Based Discussion of Fetal Pain and Stress.

BACKGROUND: The concept of fetal pain results from procedures conducted without anesthesia in preterm newborns and fetuses, which indicate that it is possible to examine fetal pain based on stress hormone, metabolic, and behavioral changes. Anatomical and physiological data suggest that fetuses become capable of processing nociceptive stimuli around midgestation, although the associated changes in fetal brain development remain unclear. What constitutes fetal pain remains controversial in the light of the definition of pain adopted by the International Association for the Study of Pain (IASP), which posits pain as an "unpleasant sensory and emotional experience." SUMMARY: Here, we examine the notion that human fetuses cannot "experience" pain and potential implications of this claim. We highlight the key scientific evidence related to fetal pain, including clinical studies on pain in fetuses and preterm newborns. We argue that consistent patterns of stress hormones, metabolic changes, body movements, hemodynamic changes, and pain-related facial expressions in fetuses exposed to invasive procedures overcome the need for subjective proof of pain as articulated in the IASP definition. No study to date has conclusively proven the absence of fetal pain beyond the age of viability. KEY MESSAGES: Based on the current evidence, we propose that all fetuses receive anesthesia regardless of the invasive procedures being performed to guarantee the least possible pain and physiological, behavioral, or hormonal responses without exposing the mother or her baby to unnecessary complications.

Incidence of mental health conditions following pediatric hospital admissions: analysis of a national database.

Introduction: Despite increasing survival of children following hospitalization, hospitalization may increase iatrogenic risk for mental health (MH) disorders, including acute stress, post-traumatic stress, anxiety, or depression. Using a population-based retrospective cohort study, we assessed the rates of new MH diagnoses during the 12 months after hospitalization, including the moderating effects of ICU exposure. Study design/methods: This was a retrospective case control study using the Truven Health Analytics insurance database. Inclusion criteria included children aged 3-21 years, insurance enrollment for >12 months before and after hospital admission. We excluded children with hospitalization 2 years prior to index hospitalization and those with prior MH diagnoses. We extracted admission type, ICD-10 codes, demographic, clinical, and service coordination variables from the database. We established age- and sex-matched cohorts of non-hospitalized children. The primary outcome was a new MH diagnosis. Multivariable regression methods examined the risk of incident MH disorder(s) between hospitalized and non-hospitalized children. Among hospitalized children, we further assessed effect modification from ICU (vs. non-ICU) stay, admission year, length of stay, medical complexity, and geographic region. Results: New MH diagnoses occurred among 19,418 (7%) hospitalized children, 3,336 (8%) ICU-hospitalized children and 28,209 (5%) matched healthy controls. The most common MH diagnoses were anxiety (2.5%), depression (1.9%), and stress/trauma (2.2%) disorders. Hospitalization increased the odds of new MH diagnoses by 12.3% (OR: 1.123, 95% CI: 1.079-1.17) and ICU-hospitalization increased these odds by 63% (OR: 1.63, 95% CI: 1.483-1.79) as compared to matched, non-hospitalized children. Children with non-complex chronic diseases (OR: 2.91, 95% CI: 2.84-2.977) and complex chronic diseases (OR: 5.16, 95% CI: 5.032-5.289) had a substantially higher risk for new MH diagnoses after hospitalization compared to patients with acute illnesses. Conclusion: Pediatric hospitalization is associated with higher, long-term risk of new mental health diagnoses, and ICU hospitalization further increases that risk within 12 months of the acute episode. Acute care hospitalization confers iatrogenic risks that warrant long-term mental and behavioral health follow-up.

Stress Symptoms Among Children and Their Parents After ICU Hospitalization.

Objective: Child survival after intensive care unit (ICU) hospitalization has increased, yet many children experience acute stress that may precipitate mental/behavioral health comorbidities. Parents report stress after their child's hospitalization. Little is known about the individual and family characteristics that may moderate intergenerational relationships of acute stress. Design: Following ICU admission at a large academic medical center, a prospective cross-sectional cohort study assessed the associations between intergenerational characteristics and acute stress among children and families. Patients: Parent-child dyads (N = 88) were recruited from the pediatric ICU and pediatric cardiovascular ICU (CVICU) following ICU discharge. Eligible children were between 8 and 18 years old with ICU stays longer than 24 hours. Children with developmental delays were excluded. Caregivers were proficient in English or Spanish. Surveys were collected before hospital discharge. Measurements/Main Results: The primary outcome was "child stress" defined as a score≥17, measured by the Children's Revised Impact of Events Scale (CRIES-8). "Parent stress" was defined as an elevated composite score on the Stanford Acute Stress Reaction Questionnaire. We used validated scales to assess the child's clinical and family social characteristics. Acute stress was identified in 34 (39.8%) children and 50 (56.8%) parents. In multivariate linear regression analyses adjusting for social characteristics, parent stress was associated with increased risk of child stress (adjusted odds ratio 2.58, 95% confidence interval 0.69, 4.46, p < .01). In unadjusted analyses, Hispanic ethnicity was associated with greater child stress. In adjusted analyses, race, income, ICU length of stay, and language were not associated with child stress and did not moderate the parent-child stress relationship. Conclusions: Parent stress is closely correlated with child stress during ICU hospitalization. Hispanic ethnicity may be associated with increased risk for child stress, but further studies are required to define the roles of other social and clinical measures.

Linear hair growth rates in preschool children.

BACKGROUND: Human scalp hair is a validated bio-substrate for monitoring various exposures in childhood including contextual stressors, environmental toxins, prescription or non-prescription drugs. Linear hair growth rates (HGR) are required to accurately interpret hair biomarker concentrations. METHODS: We measured HGR in a prospective cohort of preschool children (N = 266) aged 9-72 months and assessed demographic factors, anthropometrics, and hair protein content (HPC). We examined HGR differences by age, sex, race, height, hair pigment, and season, and used univariable and multivariable linear regression models to identify HGR-related factors. RESULTS: Infants below 1 year (288 ± 61 µm/day) had slower HGR than children aged 2-5 years (p = 0.0073). Dark-haired children (352 ± 52 µm/day) had higher HGR than light-haired children (325 ± 50 µm/day; p = 0.0019). Asian subjects had the highest HGR overall (p = 0.016). Younger children had higher HPC (p = 0.0014) and their HPC-adjusted HGRs were slower than older children (p = 0.0073). Age, height, hair pigmentation, and HPC were related to HGR in multivariable regression models. CONCLUSIONS: We identified age, height, hair pigment, and hair protein concentration as significant determinants of linear HGRs. These findings help explain the known hair biomarker differences between children and adults and aid accurate interpretation of hair biomarker results in preschool children. IMPACT: Discovery of hair biomarkers in the past few decades has transformed scientific disciplines like toxicology, pharmacology, epidemiology, forensics, healthcare, and developmental psychology. Identifying determinants of hair growth in children is essential for accurate interpretation of hair biomarker results in pediatric clinical studies. Childhood hair growth rates define the time-periods of biomarker incorporation into growing hair, essential for interpreting the biomarkers associated with environmental exposures and the mind-brain-body connectome. Our study describes age-, sex-, and height-based distributions of linear hair growth rates and provides determinants of linear hair growth rates in a large population of children. Age, height, hair pigmentation, and hair protein content are determinants of hair growth rates and should be accounted for in child hair biomarkers studies. Our findings on hair protein content and linear hair growth rates may provide physiological explanations for differences in hair growth rates and biomarkers in preschool children as compared to adults.

Missing Race and Ethnicity Data in Pediatric Studies.

This Viewpoint discusses missing race and ethnicity data in pediatric studies.

Prevalence of burnout and its relation to the neuroendocrine system among pediatric residents during the early Covid-19 pandemic: A pilot feasibility study.

Background: Measuring burnout relies on infrequent and subjective surveys, which often do not reflect the underlying factors or biological mechanisms that promote or prevent it. Burnout correlates with cortisol levels and dysregulation of the hypothalamic-pituitary-adrenal axis, but the chronology and strength of this relationship are unknown. Objective: To determine the prevalence and feasibility of studying burnout in pediatric residents using hair cortisol and hair oxytocin concentrations. Design: /Methods: Longitudinal observational cohort study of pediatric residents. We assessed burnout using the Stanford Professional Fulfillment Index and hair cortisol (HCC), and hair oxytocin concentrations (HOC) at four 3-month intervals from January 2020-January 2021. We evaluated test-retest reliability, sensitivity to change using Pearson product-moment correlations, and relationships between burnout and hair biomarkers using hierarchical mixed-effects linear regression. Results: 17 Pediatrics residents provided 78 wellness surveys and 54 hair samples. Burnout symptoms were present in 39 (50%) of the surveys, with 14 (82%) residents reporting burnout in at least one time point. The lowest (41%) and highest (60%) burnout prevalence occurred in 04/2020 and 01/2021, respectively. No significant associations between burnout scores and HCC (ß -0.01, 95%CI: 0.14-0.13), HOC (ß 0.06, 95%CI: 0.06-0.19), or the HCC:HOC ratio (ß -0.04, 95%CI: 0.09-0.02) were noted in separate analyses. Intra-individual changes in hair cortisol concentration were not associated with changes in burnout score. Conclusions: Burnout was prevalent among Pediatrics residents, with highest prevalence noted in January 2021. This pilot longitudinal study demonstrates the feasibility of evaluating burnout with stress and resilience biomarkers in Pediatrics residents.

Performance effectiveness of vital parameter combinations for early warning of sepsis-an exhaustive study using machine learning.

Objective: To carry out exhaustive data-driven computations for the performance of noninvasive vital signs heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), and temperature (Temp), considered both independently and in all possible combinations, for early detection of sepsis. Materials and methods: By extracting features interpretable by clinicians, we applied Gradient Boosted Decision Tree machine learning on a dataset of 2630 patients to build 240 models. Validation was performed on a geographically distinct dataset. Relative to onset, predictions were clocked as per 16 pairs of monitoring intervals and prediction times, and the outcomes were ranked. Results: The combination of HR and Temp was found to be a minimal feature set yielding maximal predictability with area under receiver operating curve 0.94, sensitivity of 0.85, and specificity of 0.90. Whereas HR and RR each directly enhance prediction, the effects of SpO2 and Temp are significant only when combined with HR or RR. In benchmarking relative to standard methods Systemic Inflammatory Response Syndrome (SIRS), National Early Warning Score (NEWS), and quick-Sequential Organ Failure Assessment (qSOFA), Vital-SEP outperformed all 3 of them. Conclusion: It can be concluded that using intensive care unit data even 2 vital signs are adequate to predict sepsis upto 6 h in advance with promising accuracy comparable to standard scoring methods and other sepsis predictive tools reported in literature. Vital-SEP can be used for fast-track prediction especially in limited resource hospital settings where laboratory based hematologic or biochemical assays may be unavailable, inaccurate, or entail clinically inordinate delays. A prospective study is essential to determine the clinical impact of the proposed sepsis prediction model and evaluate other outcomes such as mortality and duration of hospital stay.

Can Translational Social Neuroscience Research Offer Insights to Mitigate Structural Racism in the United States?

Social isolation and conflict due to structural racism may result in human suffering and loneliness across the life span. Given the rising prevalence of these problems in the United States, combined with disruptions experienced during the COVID-19 pandemic, the neurobiology of affiliative behaviors may offer practical solutions to the pressing challenges associated with structural racism. Controlled experiments across species demonstrate that social connections are critical to survival, although strengthening individual resilience is insufficient to address the magnitude and impact of structural racism. In contrast, the multilevel construct of social resilience, defined by the power of groups to cultivate, engage in, and sustain positive relationships that endure and recuperate from social adversities, offers unique insights that may have greater impact, reach, and durability than individual-level interventions. Here, we review putative social resilience-enhancing interventions and, when available, their biological mediators, with the hope to stimulate discovery of novel approaches to mitigate structural racism. We first explore the social neuroscience principles underlying psychotherapy and other psychiatric interventions. Then, we explore translational efforts across species to tailor treatments that increase social resilience, with context and cultural sensitivity in mind. Finally, we conclude with some practical future directions for understudied areas that may be essential for progress in biological psychiatry, including ethical ways to increase representation in research and developing social paradigms that inform dynamics toward or away from socially resilient outcomes.

What is the definition of acute episodic and chronic pain in critically ill neonates and infants? A global, four-stage consensus and validation study.

OBJECTIVES: To define and validate types of pain in critically ill neonates and infants by researchers and clinicians working in the neonatal intensive care unit (NICU) and high dependency unit (HDU). DESIGN: A qualitative descriptive mixed-methods design. PROCEDURE/S: Each stage of the study was built on and confirmed the previous stages. Stage 1 was an expert panel to develop definitions; stage 2 was a different expert panel made up of neonatal clinicians to propose clinical characteristics associated with the definitions from stage 1; stage 3 was a focus group of neonatal clinicians to provide clinical case scenarios associated with each definition and clinical characteristics; and stage 4 was a survey administered to neonatal clinicians internationally to test the validity of the definitions using the clinical case scenarios. RESULTS: In stage 1, the panel (n=10) developed consensus definitions for acute episodic pain and chronic pain in neonates and infants. In stage 2, a panel (n=8) established clinical characteristics that may be associated with each definition. In stage 3, a focus group (n=11) created clinical case scenarios of neonates and infants with acute episodic pain, chronic pain and no pain using the definitions and clinical characteristics. In stage 4, the survey (n=182) revealed that the definitions allowed an excellent level of discrimination between case scenarios that described neonates and infants with acute episodic pain and chronic pain (area under the receiver operating characteristic=0.87 and 0.89, respectively). CONCLUSIONS: This four-stage study enabled the development of consensus-based and clinically valid definitions of acute episodic pain and chronic pain. There is a need to define and validate other pain types to inform a taxonomy of pain experienced by neonates and infants in the NICU and HDU.

Attentional Generative Multimodal Network for Neonatal Postoperative Pain Estimation.

Artificial Intelligence (AI)-based methods allow for automatic assessment of pain intensity based on continuous monitoring and processing of subtle changes in sensory signals, including facial expression, body movements, and crying frequency. Currently, there is a large and growing need for expanding current AI-based approaches to the assessment of postoperative pain in the neonatal intensive care unit (NICU). In contrast to acute procedural pain in the clinic, the NICU has neonates emerging from postoperative sedation, usually intubated, and with variable energy reserves for manifesting forceful pain responses. Here, we present a novel multi-modal approach designed, developed, and validated for assessment of neonatal postoperative pain in the challenging NICU setting. Our approach includes a robust network capable of efficient reconstruction of missing modalities (e.g., obscured facial expression due to intubation) using an unsupervised spatio-temporal feature learning with a generative model for learning the joint features. Our approach generates the final pain score along with the intensity using an attentional cross-modal feature fusion. Using experimental dataset from postoperative neonates in the NICU, our pain assessment approach achieves superior performance (AUC 0.906, accuracy 0.820) as compared to the state-of-the-art approaches.

Longitudinal Trajectories of Hair Cortisol: Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Early Childhood.

The objective of this study was to examine if longitudinal trajectories of hair cortisol concentrations (HCC) measured at two or three yearly time points can identify 1-3 year old children at risk for altered hypothalamic-pituitary-adrenal (HPA)-axis function due to early life stress (ELS). HCC was measured (N = 575) in 265 children using a validated enzyme-linked immunosorbent assay. Hair was sampled in Clinic Visits (CV) centered at years 1, 2, and 3 (n = 45); 1 and 2 (n = 98); 1 and 3 (n = 27); 2 and 3 (n = 95). Log-transformed HCC values were partitioned using latent class mixed models (LCMM) to minimize the Bayesian Information Criterion. Multivariable linear mixed effects models for ln-HCC as a function of fixed effects for age in months and random effects for participants (to account for repeated measures) were generated to identify the factors associated with class membership. Children in Class 1 (n = 69; 9% Black) evidenced declining ln-HCC across early childhood, whereas Class 2 members (n = 196; 43% Black) showed mixed trajectories. LCMM with only Class 2 members revealed Class 2A (n = 17, 82% Black) with sustained high ln-HCC and Class 2B (n = 179, 40% Blacks) with mixed ln-HCC profiles. Another LCMM limited to only Class 2B members revealed Class 2B1 (n = 65, 57% Black) with declining ln-HCC values (at higher ranges than Class 1), and Class 2B2 (n = 113, 30% Black) with sustained high ln-HCC values. Class 1 may represent hair cortisol trajectories associated with adaptive HPA-axis profiles, whereas 2A, 2B1, and 2B2 may represent allostatic load with dysregulated profiles of HPA-axis function in response to varying exposures to ELS. Sequential longitudinal hair cortisol measurements revealed the allostatic load associated with ELS and the potential for developing maladaptive or dysregulated HPA-axis function in early childhood.

Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort.

OBJECTIVE: To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in very premature infants who were ventilated. STUDY DESIGN: This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n = 450) vs naive (n = 472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2 years. RESULTS: Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P = .037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P = .063). These results were confirmed by sensitivity analyses using 5 alternative models. CONCLUSIONS: Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.

Using sensor-fusion and machine-learning algorithms to assess acute pain in non-verbal infants: a study protocol.

INTRODUCTION: Objective pain assessment in non-verbal populations is clinically challenging due to their inability to express their pain via self-report. Repetitive exposures to acute or prolonged pain lead to clinical instability, with long-term behavioural and cognitive sequelae in newborn infants. Strong analgesics are also associated with medical complications, potential neurotoxicity and altered brain development. Pain scores performed by bedside nurses provide subjective, observer-dependent assessments rather than objective data for infant pain management; the required observations are labour intensive, difficult to perform by a nurse who is concurrently performing the procedure and increase the nursing workload. Multimodal pain assessment, using sensor-fusion and machine-learning algorithms, can provide a patient-centred, context-dependent, observer-independent and objective pain measure. METHODS AND ANALYSIS: In newborns undergoing painful procedures, we use facial electromyography to record facial muscle activity-related infant pain, ECG to examine heart rate (HR) changes and HR variability, electrodermal activity (skin conductance) to measure catecholamine-induced palmar sweating, changes in oxygen saturations and skin perfusion, and electroencephalography using active electrodes to assess brain activity in real time. This multimodal approach has the potential to improve the accuracy of pain assessment in non-verbal infants and may even allow continuous pain monitoring at the bedside. The feasibility of this approach will be evaluated in an observational prospective study of clinically required painful procedures in 60 preterm and term newborns, and infants aged 6 months or less. ETHICS AND DISSEMINATION: The Institutional Review Board of the Stanford University approved the protocol. Study findings will be published in peer-reviewed journals, presented at scientific meetings, taught via webinars, podcasts and video tutorials, and listed on academic/scientific websites. Future studies will validate and refine this approach using the minimum number of sensors required to assess neonatal/infant pain. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03330496).

The social ecology of childhood and early life adversity.

An increasing prevalence of early childhood adversity has reached epidemic proportions, creating a public health crisis. Rather than focusing only on adverse childhood experiences (ACEs) as the main lens for understanding early childhood experiences, detailed assessments of a child's social ecology are required to assess "early life adversity." These should also include the role of positive experiences, social relationships, and resilience-promoting factors. Comprehensive assessments of a child's physical and social ecology not only require parent/caregiver surveys and clinical observations, but also include measurements of the child's physiology using biomarkers. We identify cortisol as a stress biomarker and posit that hair cortisol concentrations represent a summative and chronological record of children's exposure to adverse experiences and other contextual stressors. Future research should use a social-ecological approach to investigate the robust interactions among adverse conditions, protective factors, genetic and epigenetic influences, environmental exposures, and social policy, within the context of a child's developmental stages. These contribute to their physical health, psychiatric conditions, cognitive/executive, social, and psychological functions, lifestyle choices, and socioeconomic outcomes. Such studies must inform preventive measures, therapeutic interventions, advocacy efforts, social policy changes, and public awareness campaigns to address early life adversities and their enduring effects on human potential. IMPACT: Current research does not support the practice of using ACEs as the main lens for understanding early childhood experiences. The social ecology of early childhood provides a contextual framework for evaluating the long-term health consequences of early life adversity. Comprehensive assessments reinforced with physiological measures and/or selected biomarkers, such as hair cortisol concentrations to assess early life stress, may provide critical insights into the relationships between early adversity, stress axis regulation, and subsequent health outcomes.

The newborn infant parasympathetic evaluation index for acute procedural pain assessment in preterm infants.

BACKGROUND: Accurate assessments of pain in hospitalized preterm infants present a major challenge in improving the short- and long-term consequences associated with painful experiences. We evaluated the ability of the newborn infant parasympathetic evaluation (NIPE) index to detect acute procedural pain in preterm infants. METHODS: Different painful and stressful interventions were prospectively observed in preterm infants born at 25 + 0 to 35 + 6 weeks gestation. Pain responses were measured using the composite Premature Infant Pain Profile Revised (PIPP-R) scale, the NIPE index, and skin conductance responses (SCR). Outcome measures were correlations between the NIPE index, the PIPP-R score, and the SCR. Sensitivity/specificity analyses tested the accuracy of the NIPE index and SCR. RESULTS: Two hundred and fifty-four procedures were recorded in 90 preterm infants. No significant correlation was found between PIPP-R and the NIPE index. PIPP-R and SCR were positively correlated (r = 0.27, P < 0.001), with stronger correlations for painful procedures (r = 0.68, P < 0.001) and especially for skin-breaking procedures (r = 0.82, P < 0.001). The NIPE index and SCR had high sensitivity and high negative predictive values to predict PIPP-R > 10, especially for skin-breaking painful procedures. CONCLUSIONS: We found no significant correlation between the NIPE index and PIPP-R during routine painful or stressful procedures in preterm infants. IMPACT: Exposure to repetitive pain can lead to neurodevelopmental sequelae. Behavior-based pain scales have limited clinical utility, especially for preterm infants. New devices for monitoring physiological responses to pain have not been validated sufficiently in preterm infants. This study found that the NIPE index was not significantly correlated to the validated PIPP-R scale during acute procedural pain. Secondary analysis of this study showed that NIPE index and SCRs may help to exclude severe pain in preterm infants. In clinical practice, measurements of physiological parameters should be combined with behavior-based scales for multidimensional pain assessments.

COVID-19 PICU guidelines: for high- and limited-resource settings.

BACKGROUND: Fewer children than adults have been affected by the COVID-19 pandemic, and the clinical manifestations are distinct from those of adults. Some children particularly those with acute or chronic co-morbidities are likely to develop critical illness. Recently, a multisystem inflammatory syndrome (MIS-C) has been described in children with some of these patients requiring care in the pediatric ICU. METHODS: An international collaboration was formed to review the available evidence and develop evidence-based guidelines for the care of critically ill children with SARS-CoV-2 infection. Where the evidence was lacking, those gaps were replaced with consensus-based guidelines. RESULTS: This process has generated 44 recommendations related to pediatric COVID-19 patients presenting with respiratory distress or failure, sepsis or septic shock, cardiopulmonary arrest, MIS-C, those requiring adjuvant therapies, or ECMO. Evidence to explain the milder disease patterns in children and the potential to use repurposed anti-viral drugs, anti-inflammatory or anti-thrombotic therapies are also described. CONCLUSION: Brief summaries of pediatric SARS-CoV-2 infection in different regions of the world are included since few registries are capturing this data globally. These guidelines seek to harmonize the standards and strategies for intensive care that critically ill children with COVID-19 receive across the world. IMPACT: At the time of publication, this is the latest evidence for managing critically ill children infected with SARS-CoV-2. Referring to these guidelines can decrease the morbidity and potentially the mortality of children effected by COVID-19 and its sequalae. These guidelines can be adapted to both high- and limited-resource settings.

Historical roots of pain management in infants: A bibliometric analysis using reference publication year spectroscopy.

Retrospective evaluations of the historical role of previously published research are often fraught with subjective bias and misrepresentation, which leads to contested scientific claims. This paper investigates the historical roots of infant pain management using novel quantitative methods to identify the published literature and evaluate its relative importance. A bibliometric analysis named "reference publication year spectroscopy" (RPYS), was performed using the program CitedReferencesExplorer (CRExplorer) to avoid the subjectivity associated with comparative evaluations of individual research studies. Web of Science (WoS) search queries on infant-related synonyms, pain-related synonyms, and analgesia or anesthesia-related synonyms were combined using the Boolean operator "AND," to identify all publications related to pain management in infants. The RPYS analyses were based on 8697 papers in our publication set containing the citations for 86268 references. Selected cited publications were associated with peak citation years in 1951, 1954, 1957, 1965, 1987, 1990, 1997, 1999, and 2000. Subsequent analyses suggested that research on infant pain management made rapid progress during 1982-1992. Landmark publications were defined as those belonging to the top 10% of the most frequently referenced publications for longer than 25 years. Through this analysis, we identified and ranked 24 landmark publications to illustrate the historical background and early research on infant pain management. From the first-ever application of RPYS (an objective, reproducible approach to study the early history of any scholarly activity) to pain research, infant pain management appears rooted in the scientific rationale for neonatal pain perception, randomized trials of opioid anesthesia/analgesia, and studies describing the facial expressions and crying activity following heel-lance procedures in newborns.