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Aims: To investigate the pharmacokinetics and safety of prolonged paracetamol use (>72 h) for neonatal pain. Methods: Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed‐effects model. Results: Forty‐eight neonates were enrolled (38 received paracetamol for >72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable >30 h after dose. There was no significant difference (P >.05) between alanine aminotransferase and bilirubin measures at <72 h or >72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81‐kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady‐state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half‐life was 3.55 h (range 2.41–5.65). Conclusion: Our study did not provide evidence of paracetamol‐induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between morphine exposure in the neonatal period and neurodevelopment at 2 and 5 years of age while controlling for potential confounders. Method: We performed a retrospective, single‐centre cohort study on 106 infants (60 males, 46 females; mean gestational age 26 weeks [SD 1]) born extremely preterm (gestational age < 28 weeks). Morphine administration was expressed as cumulative dose (mg/kg) until term‐equivalent age. Neurodevelopmental outcome was assessed at 2 years with the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version and at 5 years with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, Dutch version. Multiple linear regression analysis was used to assess the association between morphine exposure and outcome. Results: Sixty‐four out of 106 (60.4%) infants included in the study received morphine. Morphine exposure was not associated with poorer motor, cognitive, and language subscores of the Bayley Scales of Infant and Toddler Development, Third Edition, Dutch version at 2 years. Morphine exposure was associated with lower Full‐Scale IQ scores (p = 0.008, B = −9.3, 95% confidence interval [CI] = −15.6 to −3.1) and Performance IQ scores (p = 0.005, B = −17.5, 95% CI = −27.9 to −7) at 5 years of age. Interpretation: Morphine exposure in infants born preterm is associated with poorer Full‐Scale IQ and Performance IQ at 5 years. Individualized morphine administration is advised in infants born extremely preterm. What this paper adds: A significant association between morphine exposure and neurodevelopmental impairment at 5 years was observed.Higher exposure to painful and stressful procedures during the neonatal period was associated with poorer abilities at 5 years of age.Differently from previous studies on morphine, this association was also considered in the statistical analysis.A more individualized morphine administration is advised in infants born extremely preterm to counteract the negative effects of high stress without affecting neurodevelopment. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disease also known as hereditary sensory and autonomic neuropathy. CIPA is characterized by a lack of pain sensitivity and impaired development of sweat glands. Surgery is required for patients with self‐mutilation and skeletal developmental disorders. Due to the disease's rarity and intricacy, anesthesia poses its challenges. Although there have been a few cases of CIPA patients receiving surgery and anesthesia, the number is very limited. Here, we report a case of a child with CIPA who underwent open‐heart surgery and discuss the anesthetic considerations. We conclude that patients with CIPA undergoing open‐heart surgery require some opioids, that muscle relaxants and volatile anesthetics should be used with extreme caution, and that airway management and temperature control require special attention. [ABSTRACT FROM AUTHOR]

We aimed to compare ratings of self‐reported and parent‐reported pain sensitivity between early preterm (EP), moderately‐late preterm (MLP), and full‐term (FT) adolescents. For EP adolescents, we aimed to determine whether pain sensitivity was associated with early‐life events. EP (n = 68, response rate 47.4%), MLP (n = 128, response rate 33.0%), and FT (n = 78, response rate 31.1%) adolescents and their parents (n = 277) answered an author‐generated question on pain sensitivity at 14‐15 years of age within a community‐based cohort study. Differences between groups were determined using the chi‐square test for trends. For EP adolescents, we assessed associations of treatment modalities (inotrope treatment, mechanical ventilation, and C‐section) and neonatal morbidities (sepsis/necrotizing enterocolitis, small‐for‐gestational age status, asphyxia, and cerebral pathologies) with adolescent pain sensitivity using logistic regression analyses. Increased pain sensitivity was reported by 18% of EP adolescents, compared with 12% of MLP adolescents, and 7% of FT adolescents (P = 0.033). Parent‐reported pain sensitivity did not differ by gestational age group. For EP adolescents, inotrope treatment was associated with increased pain sensitivity (odds ratio, 5.00, 95% confidence interval, 1.23‐20.4, P = 0.025). No other neonatal treatment modalities or morbidities were associated with pain sensitivity in adolescence. In conclusion, we observed higher proportions of increased pain sensitivity for EP and MLP adolescents. Physicians treating preterm adolescents should be aware of altered pain sensitivity. [ABSTRACT FROM AUTHOR]

Recent years have seen the increasing use of noninvasive respiratory support in preterm infants with the aim of minimizing the risk of mechanical ventilation and subsequent bronchopulmonary dysplasia. Respiratory distress syndrome is the most common respiratory diagnosis in preterm infants, and is best treated by administration of surfactant. Until recently, this has been performed via an endotracheal tube using premedication, which has often included opiate analgesia; subsequently, the infant has been ventilated. Avoidance of mechanical ventilation, however, does not negate the need for surfactant therapy. Less invasive surfactant administration (LISA) in spontaneously breathing infants is increasing in popularity, and appears to have beneficial effects. However, laryngoscopy is necessary, which carries adverse effects and is painful for the infant. Conventional methods of premedication for intubation tend to reduce respiratory drive, which increases the likelihood of ventilation being required. This has led to intense debate about the best strategy for providing appropriate treatment, taking into account both the respiratory needs of the infant and the need to alleviate procedural pain. Currently, clinical practice varies considerably and there is no consensus with respect to optimal management. This review seeks to summarize the benefits, risks, and challenges associated with this new approach. [ABSTRACT FROM AUTHOR]

Aim: Although not approved, the α‐adrenoceptor agonist clonidine is considered an option for long‐term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication. Methods: Relevant literature was systematically identified from PubMed and Embase. We included interventional and observational studies on paediatric patients admitted to intensive care units and systemically long‐term sedated with clonidine‐containing regimes. In duplicates, we conducted standardised and independent full‐text assessment and extraction of safety data. Results: Data from 11 studies with 909 patients were analysed. The studies were heterogeneous regarding patient characteristics (age groups, comorbidity, or comedication) and sedation regimes (dosage, route, duration, or concomitant sedatives). Just four randomised controlled trials (RCTs) and one observational study had comparison groups, using placebo or midazolam. For safety outcomes, our validity evaluation showed low risk of bias only in three studies. All studies focused on haemodynamic problems, particularly bradycardia and hypotension. Observed incidences or subsequent interventions never caused concerns. However, only two RCTs allowed meaningful comparisons with control groups. Odds ratios showed no significant difference between the groups, but small sample sizes (50 and 125 patients) must be considered; pooled analyses were not reasonable. Conclusion: All evaluated studies concluded that the use of clonidine in paediatric intensive care units is safe. However, a valid characterisation of the safety profile remains challenging due to limited, biased and heterogeneous data and missing investigation of long‐term effects. This evaluation demonstrates the lack of data, which prevents reliable conclusions on the safety of clonidine for long‐term sedation in critically ill children. For an evidence‐based use, further studies are needed. [ABSTRACT FROM AUTHOR]

Pediatric neuropathy attributed to metabolic dysfunction is a well‐known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth. [ABSTRACT FROM AUTHOR]

Infants in neonatal intensive care units frequently experience clinically necessary painful procedures, which elicit a range of behavioral, physiological, and neurophysiological responses. However, the measurement of pain in this population is a challenge and no gold standard exists. The aim of this study was to investigate how noxious‐evoked changes in facial expression, reflex withdrawal, brain activity, heart rate, and oxygen saturation are related and to examine their accuracy in discriminating between noxious and non‐noxious stimuli. In 109 infants who received a clinically required heel lance and a control non‐noxious stimulus, we investigated whether combining responses across each modality, or including multiple measures from within each modality improves our ability to discriminate the noxious and non‐noxious stimuli. A random forest algorithm was used to build data‐driven models to discriminate between the noxious and non‐noxious stimuli in a training set which were then validated in a test set of independent infants. Measures within each modality were highly correlated, while different modalities showed less association. The model combining information across all modalities had good discriminative ability (accuracy of 0.81 in identifying noxious and non‐noxious stimuli), which was higher than the discriminative power of the models built from individual modalities. This demonstrates the importance of including multiple modalities in the assessment of infant pain. [ABSTRACT FROM AUTHOR]

Summary: Background: Temporomandibular disorder (TMD) is a multifactorial condition involving environmental, psychological and genetic factors. Objective: The aim of this case‐control study was to evaluate the influence of genetic polymorphisms in 5HTT and COMT on TMD and anxiety in adolescents. Methods: TMD was diagnosed and classified according to the RDC/TMD criteria. For case group, the following TMD categories were used: myofascial pain, disc displacement, arthralgia and painful TMD (myofascial and arthralgia). Anxiety levels were assessed according to the State‐Trait Anxiety Inventory. Genomic DNA was extracted, and genetic polymorphisms were genotyped by TaqMan chemistry and endpoint analysis. Logistic multivariate regression was used to analyse the associations between TMD types and genotypes, anxiety level and genotypes, using an adjusted odds ratio (ORa; CI 95%) that considered the gender. Results: In 5HTT, the rs1042173 was associated with painful TMD (arthralgia and myofascial pain) (ORc = 1.97; CI 95%: 1.02‐3.77; P = 0.04). Polymorphisms in COMT rs4818 were significantly associated with myofascial pain (ORc = 2.15; CI 95%: 1.08‐4.29; P = 0.02) and were borderline for painful TMD (ORc = 1.85; CI 95%: 0.97‐3.51; P = 0.06) and disc displacement (ORc = 2.42; CI 95%: 1.00‐5.87; P = 0.05). The rs6269 was borderline for myofascial pain (ORc = 1.82; CI 95%: 0.92‐3.59; P = 0.08) and disc displacement (ORc = 2.38; CI 95% 0.95‐5.97; P = 0.06) and also was associated with anxiety (ORa = 2.34; CI 95% 1.04‐5.25; P = 0.03). Conclusion: Polymorphisms in 5HTT and COMT are associated with TMD in adolescents. Moreover, polymorphism in COMT is associated with anxiety in adolescents. [ABSTRACT FROM AUTHOR]

Abstract: Inadequate pain and/or stress management in preterm‐ and term‐born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long‐term effects on the developing human brain and neuropsychological functioning are reviewed. [ABSTRACT FROM AUTHOR]

Aim: To examine the neurobiology of long-term neuropsychological deficits after neonatal extracorporeal membrane oxygenation (ECMO).Method: This cross-sectional study assessed white matter integrity and hippocampal volume of ECMO survivors (8-15y) and healthy children (8-17y) using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) respectively. Neuropsychological outcome was evaluated in ECMO survivors. Included clinical predictors of white matter integrity: age start ECMO, ECMO duration, highest oxygenation index before ECMO, highest mean airway pressure, and mechanical ventilation duration.Results: ECMO survivors (n=23) had lower global fractional anisotropy than healthy children (n=54) (patients=0.368; comparison group=0.381; p=0.018), but similar global mean diffusivity (p=0.410). ECMO survivors had lower fractional anisotropy in the left cingulum bundle (ECMO survivors=0.345; comparison group=0.399; p<0.001) and higher mean diffusivity in a region of the left parahippocampal cingulum (patients=0.916; comparison group=0.871; p<0.001). Higher global mean diffusivity predicted worse verbal memory in ECMO survivors (n=17) (β=-0.74, p=0.008). ECMO survivors (n=23) had smaller bilateral hippocampal volume than healthy children (n=43) (left, p<0.001; right, p<0.001) and this was related to worse verbal memory (left, β=0.65, p=0.018; right, β=0.71, p=0.006).Interpretation: Neonatal ECMO survivors are at risk for long-term brain alterations, which may partly explain long-term neuropsychological impairments. Neuroimaging may contribute to better risk stratification of long-term impairments. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various articles within the issue on topics including contemporary antibiotic drug therapy; probiotics and their use in fostering/supporting good health; and the state of individual vaccines.

Recent studies have demonstrated the working memory impairment in patients with amnestic mild cognitive impairment (aMCI). However, the neurophysiological basis of the working memory deficit in aMCI is poorly understood. The aim of this study was to explore the abnormal activity during encoding and recognition procedures, as well as the reorganization of the background network maintaining the working memory state in aMCI. Using event-related fMRI during a visuospatial working memory task with three recognition difficulty levels, the task-related activations and network efficiency of the background network in 17 aMCI patients and 19 matched controls were investigated. Compared with cognitively healthy controls, patients with aMCI showed significantly decreased activity in the frontal and visual cortices during the encoding phase, while during the recognition phase, decreased activity was detected in the frontal, parietal, and visual regions. In addition, increased local efficiency was also observed in the background network of patients with aMCI. The results suggest patients with aMCI showed impaired encoding and recognition functions during the visuospatial working memory task, and may pay more effort to maintain the cognitive state. This study extends our understanding of the impaired working memory function in aMCI and provides a new perspective to investigate the compensatory mechanism in aMCI. Hum Brain Mapp 36:3387-3403, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]