Impact of tight glycemic control and hypoglycemia after pediatric cardiac surgery on neurodevelopmental outcomes at three years of age: Findings from a randomized clinical trial.

BACKGROUND: Studies examining the impact of randomization As per standard instruction, city is required for affiliations; however, this information is missing in affiliation 6. Please check if the provided city is correct and amend if necessary. to tight glycemic control (TGC) and resultant hypoglycemia on later neurodevelopmental outcomes have produced mixed results. Our study examined this association in children undergoing cardiac surgery. METHODS: Participants who were enrolled in the Safe Pediatric Euglycemia after Cardiac Surgery (SPECS) trial returned for neurodevelopmental (ND) follow-up between 30 to 42.5 months of age. ND outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. ND scores were compared between the TGC and standard care treatment groups and between patients with moderate to severe and no to mild hypoglycemia. As a secondary analysis, to increase sample size and power, we combined the three-year-old assessments with previously collected assessments done at < 30 months of age to further examine differences between groups longitudinally. RESULTS: Among the 269 participants who completed neurodevelopmental evaluation (in-person testing or questionnaires) at three years of age (follow-up rate, 31%), there were no statistically significant differences in ND outcomes according to treatment group or hypoglycemia status. In the combined analysis of all evaluations (from 9 to 42.5 months of age), we found no treatment group differences. However, in these longitudinal analyses, children who experienced moderate to severe hypoglycemia had lower scores on the Bayley-III cognitive and motor domains compared to children with no to mild hypoglycemia. CONCLUSIONS: For infants undergoing cardiac surgery, there was no impact of tight glycemic control on neurodevelopmental outcomes. Moderate to severe hypoglycemia was associated with worse ND outcomes in longitudinal analyses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00443599. Registered: November 2016.

Early Neurodevelopmental Outcomes in Children Supported with ECMO for Cardiac Indications.

Extracorporeal membrane oxygenation (ECMO) is lifesaving for many critically ill children with congenital heart disease (CHD). However, limited information is available about their ensuing neurodevelopmental (ND) outcomes. We describe early ND outcomes in a cohort of children supported with ECMO for cardiac indications. Twenty-eight patients supported with ECMO at age < 36 months underwent later ND testing at 12-42 months of age using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). ND scores were compared with normative means and with ND outcomes of a matched cohort of 79 children with CHD undergoing cardiac surgery but not requiring ECMO support. Risk factors for worse ND outcomes were identified using multivariable linear regression models. Cardiac ECMO patients had ND scores at least one standard deviation below the normative mean in the gross motor (61%), language (43%), and cognitive (29%) domains of the Bayley-III. Cardiac ECMO patients had lower scores on the motor, language, and cognitive domains as compared to the matched non-ECMO group and clinically important (1/2 SD) differences in the motor domain persisted after controlling for primary caregiver education and number of cardiac catheterizations. Risk factors of worse ND outcomes among cardiac ECMO patients in more than one developmental domain included older age at first cannulation and more cardiac catheterization and cardiac surgical procedures prior to ND assessment. Overall, children supported on ECMO for cardiac indications have significant developmental delays and warrant close ND follow-up.

Neurodevelopmental assessment of infants with congenital heart disease in the early postoperative period.

OBJECTIVE: Mortality rates for children with congenital heart disease (CHD) have significantly declined, resulting in a growing population with associated neurodevelopmental disabilities. American Heart Association guidelines recommend systematic developmental screening for children with CHD. The present study describes results of inpatient newborn neurodevelopmental assessment of infants after open heart surgery. OUTCOME MEASURES: We evaluated the neurodevelopment of a convenience sample of high-risk infants following cardiac surgery but before hospital discharge using an adaptation of the Newborn Behavioral Observation. Factor analysis examined relationships among assessment items and consolidated them into domains of development. RESULTS: We assessed 237 infants at a median of 11 days (interquartile range [IQR]: 7-19 days) after cardiac surgery and median corrected age of 21 days (IQR: 13-33 days). Autonomic regulation was minimally stressed or well organized in 14% of infants. Upper and lower muscle tone was appropriate in 33% and 35%, respectively. Appropriate response to social stimulation ranged between 7% and 12% depending on task, and state regulation was well organized in 14%. The vast majority (87%) required enhanced examiner facilitation for participation. Factor analyses of assessment items aligned into four domains of development (autonomic, motor, oral motor, and attention organization). CONCLUSION: At discharge, postoperative infants with CHD had impairments in autonomic, motor, attention, and state regulation following cardiac surgery. Findings highlight the challenges faced by children with CHD relative to healthy peers, suggesting that neurodevelopmental follow-up and intervention should begin early in infancy.

Cognitive Effects of Adenotonsillectomy for Obstructive Sleep Apnea.

OBJECTIVE: Research reveals mixed evidence for the effects of adenotonsillectomy (AT) on cognitive tests in children with obstructive sleep apnea syndrome (OSAS). The primary aim of the study was to investigate effects of AT on cognitive test scores in the randomized Childhood Adenotonsillectomy Trial. METHODS: Children ages 5 to 9 years with OSAS without prolonged oxyhemoglobin desaturation were randomly assigned to watchful waiting with supportive care (n = 227) or early AT (eAT, n = 226). Neuropsychological tests were administered before the intervention and 7 months after the intervention. Mixed model analysis compared the groups on changes in test scores across follow-up, and regression analysis examined associations of these changes in the eAT group with changes in sleep measures. RESULTS: Mean test scores were within the average range for both groups. Scores improved significantly (P < .05) more across follow-up for the eAT group than for the watchful waiting group. These differences were found only on measures of nonverbal reasoning, fine motor skills, and selective attention and had small effects sizes (Cohen's d, 0.20-0.24). As additional evidence for AT-related effects on scores, gains in test scores for the eAT group were associated with improvements in sleep measures. CONCLUSIONS: Small and selective effects of AT were observed on cognitive tests in children with OSAS without prolonged desaturation. Relative to evidence from Childhood Adenotonsillectomy Trial for larger effects of surgery on sleep, behavior, and quality of life, AT may have limited benefits in reversing any cognitive effects of OSAS, or these benefits may require more extended follow-up to become manifest.

Impact of Tight Glycemic Control on Neurodevelopmental Outcomes at 1 Year of Age for Children with Congenital Heart Disease: A Randomized Controlled Trial.

OBJECTIVE: To assess the association of postoperative tight glycemic control and hypoglycemia in children undergoing cardiac surgery with neurodevelopmental outcomes at 1 year of age. STUDY DESIGN: A 2-center, prospective, randomized trial of postoperative tight glycemic control vs standard care was conducted in 980 children undergoing cardiac surgery. Neurodevelopmental outcomes were assessed at nine to 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Adaptive Behavior Assessment System, Second Edition, the Ages and Stages Questionnaire, Third Edition, and the Brief Infant Toddler Social-Emotional Assessment. RESULTS: Neurodevelopmental follow-up was performed on 237 patients with a mean age of 13 months. No significant treatment group differences were found in the Bayley-III and Adaptive Behavior Assessment System, Second Edition composite scores or percentage at risk based on the Ages and Stages Questionnaire, Third Edition and the Brief Infant Toddler Social-Emotional Assessment. Patients who experienced moderate to severe hypoglycemia (n = 8) had lower Bayley-III composite scores compared with patients with no to mild hypoglycemia, even after controlling for factors known to be associated with poorer neurodevelopmental outcomes. CONCLUSION: For infants undergoing cardiac surgery, tight glycemic control did not impact neurodevelopmental outcomes compared with standard care. These data suggest a possible association between moderate to severe hypoglycemia and poorer neurodevelopmental outcomes at 1 year of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00443599.

Antecedents of the child behavior checklist-dysregulation profile in children born extremely preterm.

OBJECTIVE: Extremely preterm newborns are at heightened risk for emotional and behavioral dysregulation later in childhood. Our goal was to systematically evaluate the antenatal and early postnatal antecedents that might mediate the association between extreme preterm birth and emotional and behavioral dysregulation at age 2 years (corrected age). METHOD: In a multi-site prospective study, the parents of 826 infants born before 28 weeks gestation completed a Child Behavior Checklist (CBCL) when the child was 2 years corrected age. We compared the maternal, pregnancy, placenta, delivery, and newborn characteristics, as well as early postnatal characteristics and exposures of those who satisfied criteria for the CBCL-Dysregulation Profile (CBCL-DP) to those of their peers. We then used time-oriented logistic regression models, starting first with antenatal variables that distinguished children with the CBCL-DP profile from their peers, and then added the distinguishing postnatal variables. RESULTS: Approximately 9% of the children had a CBCL-DP. In the time-oriented logistic regression model with antenatal variables only, low maternal education achievement, passive smoking, and recovery of Mycoplasma from the placenta were associated with increased risk, whereas histologic chorioamnionitis was associated with reduced risk. None of the postnatal variables added statistically significant discriminating information. CONCLUSION: Very preterm newborns who later manifest the CBCL-DP at age 2 years differ in multiple ways from their preterm peers who do not develop the CBCL-DP, raising the possibility that potentially modifiable antenatal and early postnatal phenomena contribute to the risk of developing emotional and behavioral dysregulation.

Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants.

BACKGROUND: Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 y. METHODS: In a cohort of 600 children born before 28 wk gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5) at 2 y of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least 2 d ~1 wk apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93 rd percentile. RESULTS: A single-day elevation of intercellular adhesion molecule-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of myeloperoxidase, interleukin-6, tumor necrosis factor-RI, interleukin-8, intercellular adhesion molecule-3, vascular endothelial growth factor-R1, and vascular endothelial growth factor-R2. These associations persisted among infants without white matter injury and cognitive impairment. CONCLUSION: Among children born extremely prematurely, recurrent, or persistent elevations of inflammation-related proteins in blood during in the first two postnatal weeks are associated with an attention problem at age 2 y.

Association between Technical Performance Scores and neurodevelopmental outcomes after congenital cardiac surgery.

OBJECTIVES: Technical Performance Score (TPS) has been shown to have a strong association with early and late outcomes after congenital cardiac surgery, with greater morbidity and reintervention in children with major residual lesions (TPS class 3). We sought to explore the effect of TPS on the neurodevelopmental outcomes. METHODS: All infants undergoing cardiac surgery, excluding those with trisomy 21, were offered neurodevelopmental testing at 1 year of age using the Bayley Scales of Infant Development, 3rd edition. TPSs from the discharge echocardiograms were graded as class 1 (optimal), class 2 (minor residual), or class 3 (major residual). Multivariate regression analysis was performed using patient characteristics and preoperative variables. RESULTS: Neurodevelopmental testing was performed in 140 patients at a median age of 16 months. Of these, 28 (20%) had single ventricle palliation; 39 (28%) were in Risk Adjustment for Congenital Heart Surgery category 4 to 6. Significant differences between the groups were found in the cognitive (P = .01) and motor (P = .05) domains, with subjects in TPS class 3 having significantly lower cognitive and motor composite scores. The scores did not vary significantly according to single ventricle versus biventricular repair or Risk Adjustment for Congenital Heart Surgery categorization. In multivariate modeling, class 3 TPS remained significantly associated with a lower Bayley cognitive score (P = .02), with a trend toward a lower Bayley motor score (P = .08). CONCLUSIONS: We found that TPS is an independent predictor of neurodevelopmental outcomes after infant heart surgery. Future research should explore whether a structured program of intraoperative recognition and intervention on residual lesions can improve the TPS and neurodevelopmental outcomes.

A randomized trial of adenotonsillectomy for childhood sleep apnea.

BACKGROUND: Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes. METHODS: We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months. RESULTS: The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD] improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%). CONCLUSIONS: As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.).

Design and rationale of safe pediatric euglycemia after cardiac surgery: a randomized controlled trial of tight glycemic control after pediatric cardiac surgery.

OBJECTIVES: To describe the design of a clinical trial testing the hypothesis that children randomized to tight glycemic control with intensive insulin therapy after cardiac surgery will have improved clinical outcomes compared to children randomized to conventional blood glucose management. DESIGN: Two-center, randomized controlled trial. SETTING: Cardiac ICUs at two large academic pediatric centers. PATIENTS: Children from birth to those aged 36 months recovering in the cardiac ICU after surgery with cardiopulmonary bypass. INTERVENTIONS: Subjects in the tight glycemic control (intervention) group receive an intravenous insulin infusion titrated to achieve normoglycemia (target blood glucose range of 80-110 mg/dL; 4.4-6.1 mmol/L). The intervention begins at admission to the cardiac ICU from the operating room and terminates when the patient is ready for discharge from the ICU. Continuous glucose monitoring is performed during insulin infusion to minimize the risks of hypoglycemia. The standard care group has no target blood glucose range. MEASUREMENTS AND MAIN RESULTS: The primary outcome is the development of any nosocomial infection (bloodstream, urinary tract, and surgical site infection or nosocomial pneumonia). Secondary outcomes include mortality, measures of cardiorespiratory function and recovery, laboratory indices of nutritional balance, immunologic, endocrinologic, and neurologic function, cardiac ICU and hospital length of stay, and neurodevelopmental outcome at 1 and 3 yrs of age. A total of 980 subjects will be enrolled (490 in each treatment arm) for sufficient power to show a 50% reduction in the prevalence of the primary outcome. CONCLUSIONS: Pediatric cardiac surgery patients may recognize great benefit from tight glycemic control in the postoperative period, particularly with regard to reduction of nosocomial infections. The Safe Pediatric Euglycemia after Cardiac Surgery trial is designed to provide an unbiased answer to the question of whether this therapy is indeed beneficial and to define the associated risks of therapy.

The safety and tolerability of galantamine in patients with epilepsy and memory difficulties.

Individuals with epilepsy commonly experience memory loss. We investigated the safety and tolerability of galantamine in treatment of memory loss in a pilot study of 28 patients with epilepsy, randomly assigned to galantamine (n=13) or placebo (n=15) and followed for a total of 12 weeks. Participants underwent blinded memory assessment at baseline and 12 weeks (Selective Reminding Test, 7/24 Spatial Recall). One participant in the galantamine group had a suspected recurrence of brain neoplasm and increased seizures; all other participants receiving galantamine showed no increase in seizure activity during the trial. Patients in both groups reported mild, tolerable side effects (headache, appetite suppression), with no difference between groups. No significant differences were observed on the memory measures when both groups were retested at Week 12. Galantamine appears to be safe and tolerable in patients with epilepsy. Further studies with larger samples and comparison with other cholinesterase inhibitors should be considered.

Approaches to neurodevelopmental assessment in congenital diaphragmatic hernia survivors.

BACKGROUND: Infants with congenital diaphragmatic hernia require complex surgical care and may have neurodevelopmental morbidity. We examined the performance of reports of motor functioning in 25 congenital diaphragmatic hernia survivors using the parent-completed Developmental Profile-II and a clinical evaluation by a neurodevelopmental pediatrician (MD) measured against the Bayley motor scale. METHODS: Bayley motor scores were dichotomized as normal or abnormal. Sensitivity and specificity were calculated for each test. RESULTS: The median age at assessment was 25 months. Bayley motor scores were abnormal in 77% of infants tested (10/13). The MD examinations detected motor problems in 92% (12/13). Sensitivity and specificity of the MD examination were 1.0 and 0.33, respectively. Developmental Profile-II physical scores were abnormal in 15% (2/13); sensitivity and specificity were 0.2 and 1.0, respectively. CONCLUSIONS: The high rate of abnormal motor findings in this study supports the need for ongoing screening and evaluation. The sensitivity of MD examinations was excellent, but hypotonia findings were not universally corroborated by the Bayley. Although specificity of parent-reported motor findings was high, parents underreported abnormal motor findings. Parental reports of neurodevelopmental problems should be heeded, and physicians should perform screening motor examinations. Bayley assessments may be warranted to determine the functional implications of observed abnormalities.

cAMP regulation of Cl(-) and HCO(-)(3) secretion across rat fetal distal lung epithelial cells.

We isolated and cultured fetal distal lung epithelial (FDLE) cells from 17- to 19-day rat fetuses and assayed for anion secretion in Ussing chambers. With symmetrical Ringer solutions, basal short-circuit currents (I(sc)) and transepithelial resistances were 7.9 +/- 0.5 microA/cm(2) and 1,018 +/- 73 Omega.cm(2), respectively (means +/- SE; n = 12). Apical amiloride (10 microM) inhibited basal I(sc) by approximately 50%. Subsequent addition of forskolin (10 microM) increased I(sc) from 3.9 +/- 0.63 microA/cm(2) to 7.51 +/- 0.2 microA/cm(2) (n = 12). Basolateral bumetanide (100 microM) decreased forskolin-stimulated I(sc) from 7.51 +/- 0.2 microA/cm(2) to 5.62 +/- 0.53, whereas basolateral 4,4'-dinitrostilbene-2,2'-disulfonate (5 mM), an inhibitor of HCO secretion, blocked the remaining I(sc). Forskolin addition evoked currents of similar fractional magnitudes in symmetrical Cl(-)- or HCO(-)(3)-free solutions; however, no response was seen using HCO(-)(3)- and Cl(-)-free solutions. The forskolin-stimulated I(sc) was inhibited by glibenclamide but not apical DIDS. Glibenclamide also blocked forskolin-induced I(sc) across monolayers having nystatin-permeablized basolateral membranes. Immunolocalization studies were consistent with the expression of cystic fibrosis transmembrane conductance regulator (CFTR) protein in FDLE cells. In aggregate, these findings indicate the presence of cAMP-activated Cl(-) and HCO(-)(3) secretion across rat FDLE cells mediated via CFTR.