Publications

Abstract

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.  More 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.

 Less 

Download

Abstract

Background: Early life stress has enduring effects on physical and mental health. Hair cortisol concentrations (HCCs) reflect exposures to contextual stressors in early life, but are understudied in preschool children. More 

Methods: Hair samples from children (N = 693) during clinic visits (CVs) scheduled at 1-4 years (CV1-CV4) were measured using validated assay methods for HCC.

Results: HCCs were highest at CV1 and decreased at CV2-CV4, with no sex differences. Black children had higher HCC than White/other children; these differences persisted even after adjusting for socioeconomic factors. Bivariable analyses showed significant effects on HCC for Black race, with specific demographic and psychosocial factors at different ages. Multivariable analyses showed that higher HCC at CV1 were associated with Black race and male sex; at CV2 with Black race, lower maternal self-esteem, socioeconomic adversity, and the child's risk for developmental delay; at CV3 with Black race; at CV4 with maternal depression and the child's prior HCC values.

Conclusions: HCCs were higher in Black children than White/other races; differences were related to maternal factors, socioeconomic adversity, and the child's risk for developmental delay. Public health measures to reduce disparities between Blacks and other races must also consider the long-term effects of chronic stress in early life.

 Less 

Abstract

The link between socioeconomic deprivation and adverse health outcomes is widely recognised. In the UK, many reports have shown socioeconomic gradients in measures of poor health at birth (such as preterm birth or low birth weight), adverse health outcomes in childhood (such as asthma, obesity or tooth decay) and poorer educational and More  social outcomes 1, 2. Similar patterns are observed in other high‐income countries. Despite numerous studies linking the socioeconomic circumstances of families and child health, evidence is still needed to determine which policies aimed at improving child health should be prioritised, and how to best monitor the effectiveness of policies already introduced. In the current issue of Acta Paediatrica , Anand et al. 3 present a new measure of socioeconomic adversity in the population, the Socioeconomic Adversity Index (SAI) which can be used to describe inequalities in child health. What other measures are commonly used for research and how does SAI compare?

 Less 

Abstract

Aim: Early life adversity leads to enduring effects on physical and mental health, school performance and other outcomes. We sought to identify potentially modifiable factors associated with socioeconomic adversity in early life. More 

Methods: We enrolled 1503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial and economic variables were analysed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state and national levels.

Results: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education and health insurance. Significantly worse health and social outcomes occurred in the lower versus higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles.

Conclusion: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes.

 Less 

Comment on

Measuring socioeconomic adversity in early life.

Anand KJS, Rigdon J, Rovnaghi CR, Qin F, Tembulkar S, Bush N, LeWinn K, Tylavsky FA, Davis R, Barr DA, Gotlib IH.Acta Paediatr. 2019 Jul;108(7):1267-1277. doi: 10.1111/apa.14715. Epub 2019 Jan 25.PMID: 30614554 More 

The price of inequality-Inequality in wealth and health.

Meyer S.Acta Paediatr. 2019 Jul;108(7):1361. doi: 10.1111/apa.14748. Epub 2019 Feb 28.PMID: 30735584 No abstract available.

 Less 

Abstract

Randomised Trial of Fentanyl Anesthesia in Preterm Babies Undergoing Surgery: Effects on the Stress Response. By Anand KJ, Sippell WG, and Aynsley-Green A. Lancet 1987; 1:243-8. Reprinted with permission.In a randomised controlled trial, preterm babies undergoing ligation of a patent ductus arteriosus were given nitrous oxide and D- More tubocurarine, with (n = 8) or without (n = 8) the addition of fentanyl (10 μg/kg intravenously) to the anesthetic regimen. Major hormonal responses to surgery, as indicated by changes in plasma adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11-deoxycorticosterone, and 11-deoxycortisol levels, in the insulin/glucagon molar ratio, and in blood glucose, lactate, and pyruvate concentrations were significantly greater in the nonfentanyl than in the fentanyl group. The urinary 3-methylhistidine/creatinine ratios were significantly greater in the nonfentanyl group on the second and third postoperative days. Compared with the fentanyl group, the nonfentanyl group had circulatory and metabolic complications postoperatively. The findings indicate that preterm babies mount a substantial stress response to surgery under anesthesia with nitrous oxide and curare and that prevention of this response by fentanyl anesthesia may be associated with an improved postoperative outcome.

 Less 

Abstract

Background and objective: Maternal trauma can have intergenerational consequences but little is known about whether maternal traumas affect key biological domains associated with mental health in their offspring. The objective of this study was to examine maternal lifetime history of traumatic events through mid-gestation in More  relation to offspring cortisol production in early childhood.

Methods: The sample was comprised of 660 children (49.9% Black, 44.4% White) from a longitudinal study of mother-offspring dyads in Shelby County, Tennessee, followed from mid-gestation to child age 4 years (enrolled 2006-2011). Maternal lifetime history of traumatic life events were assessed mid-gestation using the Traumatic Life Events Questionnaire. Total cortisol output among offspring was measured using hair cortisol concentrations at ages 1 to 4 years.

Results: Associations of maternal trauma history with child hair cortisol varied by child's age. No association was observed at age 1 or 2. In adjusted regression models, at ages 3 and 4, offspring of mothers in the third (β = 0.99, P < .01), fourth (β=0.72, P < .05), and fifth (β=0.83, P < .01) quintiles of trauma exposure history had elevated (natural log) hair cortisol concentrations, relative to mothers in the lowest quintile (P-trend = 0.003). The associations were not attenuated after adjustment for theorized pathways, including premature birth, maternal postpartum depression, and maternal parenting stress.

Conclusions: Maternal lifetime trauma exposures are associated with offspring hair cortisol concentrations. Future research is needed to determine intermediary mechanisms and functional significance of elevated hair cortisol concentration in young children.

 Less 

Abstract

The type, timing, duration, and frequency of exposures to adverse childhood experiences (ACEs) or early life stress (prenatal/postnatal) are likely antecedents of nervous system dysregulation manifesting across multiple systems. These are mediated through multiple neuroendocrine axes (hypothalamicpituitary-adrenal, More  hypothalamic-pituitary-thyroid, pituitary-growth hormone/insulin-like growth factor-1 (IGF), hypothalamicpituitary-gonadal) and the autonomic system (sympathetic or parasympathetic), but they also affect neuro-immune interactions (innate and adaptive immunity) and the neuroenteric system (gastric, intestinal, and hepato-pancreatic). Even in the absence of abuse or neglect, children are increasingly exposed to three overarching trends: 1) parental use of psychotropic drugs and substances; 2) inconsistent or distracted parenting; and 3) deprivation from natural environments, social engagements, and unstructured play (that is not technology-dependent). Thus, children may fail to acquire developmentally appropriate selfregulation, coping skills, or peer engagement skills; they often receive pharmaceuticals for behavioral compliance, as opposed to mindfulness, self-reflection, or cognitive-behavioral therapy to guide self-development. Children presenting with clinically unexplained symptoms across multiple domains (executive dysfunction, sleep disturbances, autonomic dysregulation, somatization, digestive symptoms, emotional dysregulation) are susceptible to permanent reductions in grey matter volume, cognitive/behavioral problems, and poorer physical and mental health. Early life stress disrupts their first-time learning experiences; acclimatizes them toward pathways of negative (fearmotivated, anxiety-inducing) reinforcement of affiliated experiences, with atypical internalizing or externalizing behaviors, and impaired self-regulation. Positive experiences in the presence of supportive, nurturing parents with consistent parenting styles/practices can reverse this trend and avoid the long-term consequences of nervous system dysregulation.

 Less 

Abstract

Background: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs). More 

Methods: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients.

Results: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001).

Conclusions: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study.

 Less 

Abstract

A framework for defining pain terms such as acute, persistent, prolonged or chronic pain to newborns was derived from the scientific literature on neonatal pain assessments, previous attempts to define chronic pain and the clinical and neurophysiological features of neonatal pain. This novel framework incorporates the temporal features, localising More  characteristics, and secondary effects of the pain experienced, as well as the behavioural and physiological response patterns of newborns.

Conclusion: Although not evidence-based, this framework provides an initial starting point for defining commonly used neonatal pain terms. It will require future revision/refinement based on the accumulating evidence for non-acute pain.

 Less 

Abstract

Aim: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. More 

Methods: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission.

Results: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001).

Conclusion: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

 Less 

Abstract

Objective: A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, More  this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients.

Design: Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7.

Setting: Tertiary care children's hospital.

Patients: Children (0-18years) with ARDS undergoing mechanical ventilation.

Interventions: 35 children were randomized within 72h of mechanical ventilation. The glucocorticoid group received methylprednisolone 2mg/kg loading dose followed by 1mg/kg/day continuous infusion from days 1 to 7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7.

Results: At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson's correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity.

Conclusion: This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

 Less 

Abstract

Objective: Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering More  duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1).

Design: Double-blind, placebo-controlled randomized trial.

Setting: Tertiary-care pediatric intensive care unit (ICU).

Patients: Mechanically ventilated children (0-18 years) with early ARDS.

Interventions: Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge.

Results: No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7. On day 7, sRAGE levels were positively correlated with MPT group PaO2/FiO2 ratios on day 8 (r = 0.93, p = 0.024). O2 requirements at ICU transfer positively correlated with day 7 MMP-8 (r = 0.85, p = 0.016) and Ang-2 levels (r = 0.79, p = 0.036) in the placebo group and inversely correlated with day 7 sICAM-1 levels (r = -0.91, p = 0.005) in the MPT group.

Conclusion: Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation (⇓MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery (⇓sRAGE). Large ARDS clinical trials should develop similar frameworks.

 Less 

Abstract

Background: Developmental neurotoxicity of ketamine, an N-methyl-D-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone More  (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study.

Methods: Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex.

Results: Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg).

Conclusion: These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.

 Less 

Abstract

Background: Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs. More 

Objectives: To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure.

Design: EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study.

Setting: All 16 NICUs in the Paris region in France.

Participants: All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns.

Methods: Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first.

Results: The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia.

Conclusions: Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number.

 Less 

Abstract

Aim: Noninvasive electrical stimulation at acupuncture points (NESAP) for analgesia is used in children, but has not been widely studied in neonates. The purpose of this study was to determine whether NESAP alone or in combination with sucrose relieved heelstick pain in neonates. More 

Methods: Term neonates (n = 162) receiving routine heelsticks for newborn screening were enrolled following parental consent. All infants received facilitated tucking and non-nutritive sucking. Neonates were randomised to standard care, sucrose, NESAP or sucrose plus NESAP. NESAP (3.5 mA, 10 Hz) or sham was administered over four acupuncture points. The Premature Infant Pain Profile (PIPP), heart rate variability (HRV) and salivary cortisol were used to measure heelstick pain.

Results: PIPP scores among all four treatment groups increased during heelstick, F (9,119) = 1.95, p = 0.05 and NESAP therapy had no significant effect on PIPP scores. However, PIPP scores from baseline to heelstick increased the most in the two groups not receiving sucrose (p < 0.01). Mean PIPP scores remained below five during the heelstick in all four groups, indicating minimal or no pain. Differences in HRV and salivary cortisol among groups were insignificant.

Conclusion: NESAP at 3.5 mA, 10 Hz is not effective in relieving pain during heelsticks in neonates.

 Less 

Abstract

Background: Hair cortisol levels are used increasingly as a measure for chronic stress in young children. We propose modifications to the current methods used for hair cortisol analysis to more accurately determine reference ranges for hair cortisol across different populations and age groups. More 

Methods: The authors compared standard (finely cutting hair) versus milled methods for hair processing (n = 16), developed a 4-step extraction process for hair protein and cortisol (n = 16), and compared liquid chromatography-mass spectrometry (LC-MS) versus enzyme-linked immunosorbent assays (ELISAs) for measuring hair cortisol (n = 28). The extraction process included sequential incubations in methanol and acetone, repeated twice. Hair protein was measured through spectrophotometric ratios at 260/280 nm to indicate the hair dissolution state using a BioTek plate reader and dedicated software. Hair cortisol was measured using an ELISA assay kit. Individual (n = 13), pooled hair samples (n = 12) with high, intermediate, and low cortisol values, and the ELISA assay internal standards (n = 3) were also evaluated by LC-MS.

Results: Milled and standard methods showed highly correlated hair cortisol (rs = 0.951, P < 0.0001) and protein values (rs = 0.902, P = 0.0002), although higher yields of cortisol and protein were obtained from the standard method in 13 of 16 and 14 of 16 samples, respectively (P < 0.05). Four sequential extractions yielded additional amounts of protein (36.5%, 27.5%, 30.5%, 3.1%) and cortisol (45.4%, 31.1%, 15.1%, 0.04%) from hair samples. Cortisol values measured by LC-MS and ELISA were correlated (rs = 0.737; P < 0.0001), although cortisol levels [median (interquartile range)] detected in the same samples by LC-MS [38.7 (14.4-136) ng/mL] were lower than that by ELISA [172.2 (67.9-1051) ng/mL]. LC-MS also detected cortisone, which comprised of 13.4% (3.7%-25.9%) of the steroids detected.

Conclusions: Methodological studies suggest that finely cutting hair with sequential incubations in methanol and acetone, repeated twice, extracts greater yields of cortisol than does milled hair. Based on these findings, at least 3 incubations may be required to extract most of the cortisol in human hair samples. In addition, ELISA-based assays showed greater sensitivity for measuring hair cortisol levels than LC-MS-based assays.

 Less 

Abstract

Importance: Research on health equity has focused on documenting health care disparities or understanding factors leading to disparities, but limited efforts have focused on reducing health care disparities in children. Latino children have increased prevalence of acute and chronic conditions; they have limited access and other barriers to More  high-quality health care, including intensive care.

Objective: To determine whether pediatric intensive care unit mortality can be reduced by a multilevel health care delivery intervention.

Design, setting, and participants: Observational study of factors associated with pediatric intensive care unit mortality at a tertiary care metropolitan children's hospital in Memphis, Tennessee. Participants were children younger than 18 years discharged from the pediatric intensive care unit during the 3-year preintervention period of 2007 to 2009 (n = 3891) and 3-year postintervention period of 2010 to 2012 (n = 4179).

Interventions: Multilevel health care intervention to address the increased odds of mortality among Latino children.

Main outcomes and measures: The odds of mortality were analyzed over the 3-year preintervention period (2007-2009) using multivariable logistic regressions to control for age, sex, race/ethnicity, severity of illness, major diagnostic categories, diagnosed infections, and insurance status. Data from the postintervention period (2010-2012) were analyzed similarly to measure the effect of changes in health care delivery.

Results: Unadjusted mortality rates for white, African American, and Latino children in 2007 to 2009 were 3.3%, 3.3%, and 8.6%, respectively. After controlling for covariates, no differences in the odds of mortality were observed between white children and African American children (odds ratio [OR], 1.0; 95% CI, 0.6-1.7; P = .97), but Latino children had 3.7-fold (95% CI, 1.8-7.5; P < .001) higher odds of mortality. A multilevel and multidisciplinary intervention was launched to address these differences. In the postintervention period, unadjusted mortality rates for white, African American, and Latino children were 3.6%, 3.2%, and 4.0%, respectively, with no differences observed after adjustment for covariates (OR, 0.7; 95% CI, 0.2-2.1; P = .49). The odds of mortality decreased between the preintervention period and postintervention period for Latino children (OR, 0.24; 95% CI, 0.06-0.88; P = .03) but remained unchanged for white and African American children (OR, 1.02; 95% CI, 0.73-1.43; P = .90).

Conclusions and relevance: Latino children had higher odds of mortality, even after controlling for age, sex, severity of illness, insurance status, and other covariates. These differences disappeared after culturally and linguistically sensitive interventions at multiple levels. Local multilevel interventions can reduce the effect of health care inequities on clinical outcomes, without requiring major changes in health care policy.

 Less 

Abstract

Objective: Low-dose methylprednisolone therapy in adults with early acute respiratory distress syndrome reduces systemic inflammation, duration of mechanical ventilation, and ICU length of stay. We report a pilot randomized trial of glucocorticoid treatment in early pediatric acute respiratory distress syndrome. More 

Design: Double-blind, placebo-controlled randomized clinical trial.

Setting: Le Bonheur Children's Hospital, Memphis, TN.

Patients: Children (0-18 yr) with acute respiratory distress syndrome undergoing mechanical ventilation.

Interventions: Patients were randomly assigned to steroid or placebo groups within 72 hours of intubation. IV methylprednisolone administered as loading dose (2 mg/kg) and continuous infusions (1 mg/kg/d) on days 1-7 and then tapered over days 8-14. Both groups were ventilated according to the Acute Respiratory Distress Syndrome Network protocol modified for children. Daily surveillance was performed for adverse effects.

Measurements and main results: Thirty-five patients were randomized to the steroid (n = 17, no death) and placebo groups (n = 18, two deaths). No differences occurred in length of mechanical ventilation, ICU stay, hospital stay, or mortality between the two groups. At baseline, higher plateau pressures (p = 0.006) and lower Pediatric Logistic Organ Dysfunction scores (p = 0.04) occurred in the steroid group; other characteristics were similar. Despite higher plateau pressures on days 1 (p = 0.006) and 2 (p = 0.025) due to poorer lung compliance in the steroid group, they had lower PaCO2 values on days 2 (p = 0.009) and 3 (p = 0.014), higher pH values on day 2 (p = 0.018), and higher PaO2/FIO2 ratios on days 8 (p = 0.047) and 9 (p = 0.002) compared with the placebo group. Fewer patients in the steroid group required treatment for postextubation stridor (p = 0.04) or supplemental oxygen at ICU transfer (p = 0.012). Steroid therapy was not associated with detectable adverse effects.

Conclusion: This study demonstrates the feasibility of administering low-dose glucocorticoid therapy and measuring clinically relevant outcomes in pediatric acute respiratory distress syndrome. Changes in oxygenation and/or ventilation are consistent with early acute respiratory distress syndrome pathophysiology and results of similar clinical trials in adults. We propose and design a larger randomized trial to define the role of glucocorticoid therapy in pediatric acute respiratory distress syndrome.

 Less 

Abstract

Background: Identifying risk factors related to central venous line (CVL) placement could potentially minimize central line-associated venous thrombosis (CLAVT). We sought to identify the clinical factors associated with CLAVT in children. More 

Methods: Over a 3-year period, 3733 CVLs were placed at a tertiary-care children's hospital. Data were extracted from the electronic medical records of patients with clinical signs and symptoms of venous thromboembolism, diagnosed using Doppler ultrasonography and/or echocardiography. Statistical analyses examined differences in CLAVT occurrence between groups based on patient and CVL characteristics (type, brand, placement site, and hospital unit).

Results: Femoral CVL placement was associated with greater risk for developing CLAVT (OR 11.1, 95% CI 3.9-31.6, p < 0.0001). CVLs placed in the NICU were also associated with increased CLAVT occurrence (OR 5.3, 95% CI 2.1-13.2, p = 0.0003). CVL brand was also significantly associated with risk of CLAVT events.

Conclusion: Retrospective analyses identified femoral CVL placement and catheter type as independent risk factors for CLAVT, suggesting increased risks due to mechanical reasons. Placement of CVLs in the NICU also led to an increased risk of CLAVT, suggesting that small infants are at increased risk of thrombotic events. Alternative strategies for CVL placement, thromboprophylaxis, and earlier diagnosis may be important for reducing CLAVT events.

 Less 

Abstract

One-third of childbearing women take prescription opioids, previously occurring only in 6-7% of pregnant women. Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome (NAS). NAS incidence increased fourfold and length of stay increased from 13 to 19 days over 10 years (2004-2013), More  leading to sevenfold increases in NICU days due to NAS. Initial data suggest that recent NAS increases have resulted from increased use of prescription opioids rather than illicit drugs.

Conclusion: Paediatricians will have to manage the consequences of prenatal opioid exposures, as the offspring often have complex medical and social issues associated with these families.

 Less 

Abstract

Objective: To study whether new pharmacological and nonpharmacological guidelines lowered numbers of painful procedures in neonates and changed the amount and frequency of analgesic therapy as compared to the results of our previous study in 2001. More 

Design: A prospective observational study.

Setting: Level III NICU of the Erasmus MC-Sophia Children's Hospital, Rotterdam.

Participants: Neonates admitted at postnatal ages less than 3 days with length of stay at least 72 h.

Main outcome measures: Number of all potentially painful procedures and analgesic therapy recorded at the bedside during the first 14 days of NICU stay.

Results: A total number of 21,076 procedures were performed in the 175 neonates studied during 1,730 patient-days (mean 12.2). The mean number of painful procedures per neonate per day was 11.4 (SD 5.7), significantly lower than the number of 14.3 (SD 4.0) in 2001 (p < 0.001). The use of analgesics was 36.6% compared to 60.3% in 2001. Sixty-three percent of all peripheral arterial line insertions failed versus 37.5% in 2001 and 9.1% venipunctures failed versus 21% in 2001.

Conclusions: The mean number of painful procedures per NICU patient per day declined. Nonpharmacological pain- or stress-reducing strategies like NIDCAP and sucrose were fully embedded in our pain management. As further reduction of the number of painful procedures is unlikely, we should apply more nonpharmacological interventions and explore newer pharmacological agents.

 Less 

Abstract

Objective: To determine whether analgesic use for painful procedures performed in neonates in the neonatal intensive care unit (NICU) differs during nights and days and during each of the 6 h period of the day. More 

Design: Conducted as part of the prospective observational Epidemiology of Painful Procedures in Neonates study which was designed to collect in real time and around-the-clock bedside data on all painful or stressful procedures.

Setting: 13 NICUs and paediatric intensive care units in the Paris Region, France.

Participants: All 430 neonates admitted to the participating units during a 6-week period between September 2005 and January 2006.

Data collection: During the first 14 days of admission, data were collected on all painful procedures and analgesic therapy. The five most frequent procedures representing 38 012 of all 42 413 (90%) painful procedures were analysed.

Intervention: Observational study.

Main outcome assessment: We compared the use of specific analgesic for procedures performed during each of the 6 h period of a day: morning (7:00 to 12:59), afternoon, early night and late night and during daytime (morning+afternoon) and night-time (early night+late night).

Results: 7724 of 38 012 (20.3%) painful procedures were carried out with a specific analgesic treatment. For morning, afternoon, early night and late night, respectively, the use of analgesic was 25.8%, 18.9%, 18.3% and 18%. The relative reduction of analgesia was 18.3%, p<0.01, between daytime and night-time and 28.8%, p<0.001, between morning and the rest of the day. Parental presence, nurses on 8 h shifts and written protocols for analgesia were associated with a decrease in this difference.

Conclusions: The substantial differences in the use of analgesics around-the-clock may be questioned on quality of care grounds.

 Less 

Abstract

As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures More  and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns.

 Less 

Abstract

Ketamine is widely used as an anesthetic, analgesic, or sedative in pediatric patients. We reported that ketamine alters the normal neurogenesis of rat fetal neural stem progenitor cells (NSPCs) in the developing brain, but the underlying mechanisms remain unknown. The PI3K-PKB/Akt (phosphatidylinositide 3-kinase/protein kinase B) More  signaling pathway plays many important roles in cell survival, apoptosis, and proliferation. We hypothesized that PI3K-PKB/Akt signaling may be involved in ketamine-altered neurogenesis of cultured NSPCs in vitro. NSPCs were isolated from Sprague-Dawley rat fetuses on gestational day 17. 5-bromo-2'-deoxyuridine (BrdU) incorporation, Ki67 staining, and differentiation tests were utilized to identify primary cultured NSPCs. Immunofluorescent staining was used to detect Akt expression, whereas Western blots measured phosphorylated Akt and p27 expression in NSPCs exposed to different treatments. We report that cultured NSPCs had properties of neurogenesis: proliferation and neural differentiation. PKB/Akt was expressed in cultured rat fetal cortical NSPCs. Ketamine inhibited the phosphorylation of Akt and further enhanced p27 expression in cultured NSPCs. All ketamine-induced PI3K/Akt signaling changes could be recovered by N-methyl-d-aspartate (NMDA) receptor agonist, NMDA. These data suggest that the inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.

 Less 

Abstract

Objective: Chronic pain is poorly addressed in neonatal pain research. We aimed at contributing to define the concept of chronic pain in the newborn. More 

Method: We designed a Web-based, 3-round Delphi survey. We invited an international panel of experts (health care providers and parents) in the fields of neonatology and neonatal pain to participate.

Results: In the first round, participants (n=189) answered 3 open-ended questions: (1) define chronic pain in your own words, (2) what are the possible causes, and (3) which signs and symptoms are used to diagnose chronic pain? The answers were categorized and summarized into 437 statements, which were valued by the participants (n=189) on a 5-point Likert scale. In the second round, the remaining participants (n=72) were asked to reflect on 65 selected statements with a mode or median ≥4 or mean ≥3.75. These threshold values provided the opportunity to reach consensus in the following round. In the third round, the remaining participants (n=33) were provided with the group and individual responses. This process resulted in 23 statements with mode, mean, and median of ≥4, on which the participants reached consensus.

Discussion: Although several etiologic factors were defined, no useful diagnostic criterion could be identified. The survey resulted in a description of chronic pain in the newborn. Identifying chronic pain is clinically relevant because it interferes with growth, prolongs hospitalization, leads to altered pain perception, and impairs cognitive and behavioral development.

 Less 

Abstract

Objective: To determine demographic, maternal, and child factors associated with socioemotional (SE) problems and chronic stress in 1-year-old children. More 

Study design: This was a prospective, longitudinal, community-based study, which followed mother-infant dyads (n = 1070; representative of race, education, and income status of Memphis/Shelby County, Tennessee) from midgestation into early childhood. Child SE development was measured using the Brief Infant-Toddler Social and Emotional Assessment in all 1097 1-year-olds. Chronic stress was assessed by hair cortisol in a subsample of 1-year-olds (n = 297). Multivariate regression models were developed to predict SE problems and hair cortisol levels.

Results: More black mothers than white mothers reported SE problems in their 1-year-olds (32.9% vs 10.2%; P < .001). In multivariate regression, SE problems in blacks were predicted by lower maternal education, greater parenting stress and maternal psychological distress, and higher cyclothymic personality score. In whites, predictors of SE problems were Medicaid insurance, higher maternal depression score at 1 year, greater parenting stress and maternal psychological distress, higher dysthymic personality score, and male sex. SE problem scores were associated with higher hair cortisol levels (P = .01). Blacks had higher hair cortisol levels than whites (P < .001). In the entire subsample, increased hair cortisol levels were associated with higher parenting stress (P = .001), lower maternal depression score (P = .01), lower birth length (P < .001), and greater length at 1 year of age (P = .003).

Conclusion: Differences in maternal education, insurance, mental health, and early stress may disrupt SE development in children. Complex relationships between hair cortisol level in 1-year-olds and maternal parenting stress and depression symptoms suggest dysregulation of the child's hypothalamic-pituitary-adrenal axis.

Keywords: BITSEA; BSI; Brief Infant-Toddler Social and Emotional Assessment; Brief Symptom Inventory; CANDLE; Conditions Affecting Neurocognitive Development and Learning in Early Childhood; EPDS; Edinburgh Postnatal Depression Scale; HPA; Hypothalamic-pituitary-adrenal; SE; Socioemotional; TEMPS; Temperament Evaluation of Memphis, Pisa, Paris, and San Diego.

 Less 

Abstract

Objectives: An increasing prevalence of pediatric asthma has led to increasing burdens of critical illness in children with severe acute asthma exacerbations, often leading to respiratory distress, progressive hypoxia, and respiratory failure. We review the definitions, epidemiology, pathophysiology, and clinical manifestations of severe acute More  asthma, with a view to developing an evidence-based, stepwise approach for escalating therapy in these patients.

Methods: Subject headings related to asthma, status asthmaticus, critical asthma, and drug therapy were used in a MEDLINE search (1980-2012), supplemented by a manual search of personal files, references cited in the reviewed articles, and treatment algorithms developed within Le Bonheur Children's Hospital.

Results: Patients with asthma require continuous monitoring of their cardiorespiratory status via noninvasive or invasive devices, with serial clinical examinations, objective scoring of asthma severity (using an objective pediatric asthma score), and appropriate diagnostic tests. All patients are treated with β-agonists, ipratropium, and steroids (intravenous preferable over oral preparations). Patients with worsening clinical status should be progressively treated with continuous β-agonists, intravenous magnesium, helium-oxygen mixtures, intravenous terbutaline and/or aminophylline, coupled with high-flow oxygen and non-invasive ventilation to limit the work of breathing, hypoxemia, and possibly hypercarbia. Sedation with low-dose ketamine (with or without benzodiazepines) infusions may allow better toleration of non-invasive ventilation and may also prepare the patient for tracheal intubation and mechanical ventilation, if indicated by a worsening clinical status.

Conclusions: Severe asthma can be a devastating illness in children, but most patients can be managed by using serial objective assessments and the stepwise clinical approach outlined herein. Following multidisciplinary education and training, this approach was successfully implemented in a tertiary-care, metropolitan children's hospital.

 Less 

Abstract

Objective: To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit.

Design: Prospective, observational study with 100% accrual of eligible patients. More 

Setting: Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network.

Patients: Four hundred nineteen children treated with morphine or fentanyl infusions.

Interventions: None.

Measurements and main results: Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03).

Conclusions: Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Conflict of interest statement

Conflict of Interest Declaration: Authors have no conflicts of interest related to the data or concepts presented in this article.

 Less 

Comment on

• Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial.  More 

  Ceelie I, de Wildt SN, van Dijk M, van den Berg MM, van den Bosch GE, Duivenvoorden HJ, de Leeuw TG, Mathôt R, Knibbe CA, Tibboel D.JAMA. 2013 Jan 9;309(2):149-54. doi: 10.1001/jama.2012.148050.PMID: 23299606 Clinical Trial.

   

 Less 

Comment on

Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort. More 

Bailey D, Colantonio D, Kyriakopoulou L, Cohen AH, Chan MK, Armbruster D, Adeli K.Clin Chem. 2013 Sep;59(9):1393-405. doi: 10.1373/clinchem.2013.204222. Epub 2013 May 1.PMID: 23637247

 Less 

Abstract

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study More  indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

 Less 

Abstract

Ketamine is widely used as an anesthetic, analgesic, and sedative in pediatric clinical practice and it is also listed as an illicit drug by most countries. Recent in vivo and in vitro animal studies have confirmed that ketamine can induce neuronal cell death in the immature brain, resulting from widespread neuronal apoptosis. These effects can disturb More  normal development further altering the structure and functions of the brain. Our recent studies further indicate that ketamine can alter neurogenesis from neural stem progenitor cells in the developing brain. Taken together, these findings identify a novel complication associated with ketamine use in premature infants, term newborns, and pregnant women. Recent data on the developmental neurotoxicity of ketamine are reviewed with proposed future directions for evaluating the safety of ketamine in these patient populations.

 Less 

Abstract

Objectives: To test the comparative effectiveness of 2 nonpharmacologic pain-relieving interventions administered alone or in combination across time for repeated heel sticks in preterm infants. More 

Methods: A multicenter randomized controlled trial in 3 NICUs in Switzerland compared the effectiveness of oral sucrose, facilitated tucking (FT), and a combination of both interventions in preterm infants between 24 and 32 weeks of gestation. Data were collected during the first 14 days of their NICU stay. Three phases (baseline, heel stick, recovery) of 5 heel stick procedures were videotaped for each infant. Four independent experienced nurses blinded to the heel stick phase rated 1055 video sequences presented in random order by using the Bernese Pain Scale for Neonates, a validated pain tool.

Results: Seventy-one infants were included in the study. Interrater reliability was high for the total Bernese Pain Scale for Neonates score (Cronbach's α: 0.90-0.95). FT alone was significantly less effective in relieving repeated procedural pain (P < .002) than sucrose (0.2 mL/kg). FT in combination with sucrose seemed to have added value in the recovery phase with lower pain scores (P = .003) compared with both the single-treatment groups. There were no significant differences in pain responses across gestational ages.

Conclusions: Sucrose with and without FT had pain-relieving effects even in preterm infants of <32 weeks of gestation having repeated pain exposures. These interventions remained effective during repeated heel sticks across time. FT was not as effective and cannot be recommended as a nonpharmacologic pain relief intervention for repeated pain exposure.

 Less 

Abstract

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has More  ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

 Less 

Abstract

Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes More  and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These ex-preterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n=14) and placebo (n=5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohen'sd: 2.83, effect size large) and body weight was approximately 4% less (Cohen'sd: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86±0.33 and 2.71±0.24 s, respectively) (p<0.03) and completed approximately 27% less of the task than placebo children (Cohen'sd: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohen'sd: -0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes.

 Less 

Abstract

Objective: Infants are potentially more susceptible to cell death mediated via glutamate excitotoxicity attributed to cardiopulmonary bypass. We hypothesized that ketamine, via N-methyl D-aspartate receptor blockade and anti-inflammatory effects, would reduce central nervous system injury during cardiopulmonary bypass. More 

Methods: We randomized 24 infants, without chromosomal abnormalities, to receive ketamine (2 mg/kg, n = 13) or placebo (saline, n = 11) before cardiopulmonary bypass for repair of ventricular septal defects. Plasma markers of inflammation and central nervous system injury were compared at the end of surgery, and 6, 24, and 48 hrs after surgery. Magnetic resonance imaging and spectroscopy before cardiopulmonary bypass and at the time of hospital discharge were performed in a subset of cases and controls (n = 5 in each group). Cerebral hemodynamics were monitored postoperatively using near-infrared spectroscopy, and neurodevelopmental outcomes were assessed using Bayley Scales of Infant Development-II before and 2-3 wks after surgery.

Results: Statistically significant differences were noted in preoperative inspired oxygen levels, intraoperative cooling and postoperative temperature, respiratory rate, platelet count, and bicarbonate levels. The peak concentration of C-reactive protein was lower in cases compared to controls at 24 hrs (p = .048) and 48 hrs (p = .001). No significant differences were noted in the expression of various cytokines, chemokines, S100, and neuron-specific enolase between the cases and controls. Magnetic resonance imaging with spectroscopy studies showed that ketamine administration led to a significant decrease in choline and glutamate plus glutamine/creatine in frontal white matter. No statistically significant differences occurred between pre- and postoperative Bayley Scales of Infant Development-II scores.

Conclusions: We did not find any evidence for neuroprotection or neurotoxicity in our pilot study. A large, adequately powered randomized control trial is needed to discern the central nervous system effect of ketamine on the developing brain. brain.

 Less 

Abstract

Objective: High doses or prolonged exposure to ketamine increase neuronal apoptosis in the developing brain, although effects on neural stem progenitor cells remain unexplored. This study investigated dose- and time-dependent responses to ketamine on cell death and neurogenesis in cultured rat fetal cortical neural stem More  progenitor cells.

Design: Laboratory-based study.

Setting: University research laboratory.

Subject: Sprague-Dawley rats.

Interventions: Neural stem progenitor cells were isolated from the cortex of Sprague-Dawley rat fetuses on embryonic day 17. In dose-response experiments, cultured neural stem progenitor cells were exposed to different concentrations of ketamine (0-100 µM) for 24 hrs. In time-course experiments, neural stem progenitor cells cultures were exposed to 10 µM ketamine for different durations (0-48 hrs).

Measurements and main results: Apoptosis and necrosis in neural stem progenitor cells were assessed using activated caspase-3 immunostaining and lactate dehydrogenase assays, respectively. Proliferative changes in neural stem progenitor cells were detected using bromo-deoxyuridine incorporation and Ki67 immunostaining. Neuronal differentiation was assessed using Tuj-1 immunostaining. Cultured neural stem progenitor cells were resistant to apoptosis and necrosis following all concentrations and durations of ketamine exposure tested. Ketamine inhibited proliferation with decreased numbers of bromo-deoxyuridine-positive cells following ketamine exposure to 100 µM for 24 hrs (p<.005) or 10 µM for 48 hrs (p< .01), and reduced numbers of Ki67-positive cells following exposure to ketamine concentration>10 µM for 24 hrs (p<.001) or at 10 µM for 48 hrs (p<.01). Ketamine enhanced neuronal differentiation, with all ketamine concentrations increasing Tuj-1-positive neurons (p<.001) after 24-hrs of exposure. This also occurred with all exposures to 10 µM ketamine for >8 hrs (p<.001).

Conclusions: Clinically relevant concentrations of ketamine do not induce cell death in neural stem progenitor cells via apoptosis or necrosis. Ketamine alters the proliferation and increases the neuronal differentiation of neural stem progenitor cells isolated from the rat neocortex. These studies imply that ketamine exposure during fetal or neonatal life may alter neurogenesis and subsequent brain development.

 Less 

Abstract

Objectives: To estimate federal dollars spent on critical care research, the cost of providing critical care, and to determine whether the percentage of federal research dollars spent on critical care research is commensurate with the financial burden of critical care. More 

Design and data sources: The National Institutes of Health Computer Retrieval of Information on Scientific Projects database was queried to identify funded grants whose title or abstract contained a key word potentially related to critical care. Each grant identified was analyzed by two reviewers (three if the analysis was discordant) to subjectively determine whether it was definitely, possibly, or definitely not related to critical care. Hospital and total costs of critical care were estimated from the Premier Database, state discharge data, and Medicare data. To estimate healthcare expenditures associated with caring for critically ill patients, total costs were calculated as the combination of hospitalization costs that included critical illness as well as additional costs in the year after hospital discharge.

Measurements and main results: Of 19,257 grants funded by the National Institutes of Health, 332 (1.7%) were definitely related to critical care and a maximum of 1212 (6.3%) grants were possibly related to critical care. Between 17.4% and 39.0% of total hospital costs were spent on critical care, and a total of between $121 and $263 billion was estimated to be spent on patients who required intensive care. This represents 5.2% to 11.2%, respectively, of total U.S. healthcare spending.

Conclusions: The proportion of research dollars spent on critical care is lower than the percentage of healthcare expenditures related to critical illness.

 Less 

Abstract

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal More  period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.

 Less 

Abstract

Background: The "golden-hour" concept has led to emphasis on speed of patient delivery during pediatric interfacility transport. Timely intervention, in addition to enhanced monitoring during transport, is the key to improved outcomes in critically ill patients. Taking the ICU to the patient may be more beneficial than rapid delivery to a tertiary care center. More 

Methods: The Improved Monitoring During Pediatric Interfacility Transport trial was the first randomized controlled trial in the out-of-hospital pediatric transport environment. It was designed to determine the impact of improved blood pressure monitoring during pediatric interfacility transport and the effect on clinical outcomes in patients with systemic inflammatory response syndrome and moderate-to-severe head trauma. Patients in the control group had their blood pressure monitored intermittently with an oscillometric device; those in the intervention group had their blood pressure monitored every 12 to 15 cardiac contractions with a near-continuous, noninvasive device.

Results: Between May 2006 and June 2007, 1995, consecutive transport patients were screened, and 94 were enrolled (48 control, 46 intervention). Patients in the intervention group received more intravenous fluid (19.8 ± 22.2 vs 9.9 ± 9.9 mL/kg; P = .01), had a shorter hospital stay (6.8 ± 7.8 vs 10.9 ± 13.4 days; P = .04), and had less organ dysfunction (18 of 206 vs 32 of 202 PICU days; P = .03).

Conclusions: Improved monitoring during pediatric transport has the potential to improve outcomes of critically ill children. Clinical trials, including randomized controlled trials, can be accomplished during pediatric transport. Future studies should evaluate optimal equipment, protocols, procedures, and interventions during pediatric transport, aimed at improving the clinical and functional outcomes of critically ill patients.

 Less