Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial).

BACKGROUND: The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multisite, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at 5 years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension. METHODS: A total of 722 infants ≤60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine regional anesthesia (RA) or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born at <26 weeks of gestation. Moderate hypotension was defined as mean arterial pressure measurement of <35 mm Hg. Any hypotension was defined as mean arterial pressure of <45 mm Hg. Epochs were defined as 5-minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol. RESULTS: The relative risk of GA compared with RA predicting any measured hypotension of <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (confidence interval [CI], 2.0-4.1; P < .001) by ITT analysis and 4.5 (CI, 2.7-7.4, P < .001) as per protocol analysis. In the GA group, 87% and 49%, and in the RA group, 41% and 16%, exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA versus RA), weight at the time of surgery, and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (relative risk, 2.8, 95% CI, 1.7-4.4 by ITT). CONCLUSIONS: RA reduces the incidence of hypotension and the chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.

Blood lead level among Palestinian schoolchildren: a pilot study.

In Palestine, chronic exposure to lead has not been adequately addressed as a problem for children. To assess the exposure of Palestinian schoolchildren, we surveyed blood lead levels in 3 schools in Nablus city and collected demographic and clinical data. Blood samples were collected from 178 children (140 boys, 38 girls), age range 6-8 years. The overall mean blood lead level was 3.2 (SD 2.4) microg/dL, and 4.5% of children had levels above 10 microg/dL. Blood lead levels were significantly higher among children living in refugee camps near industrial/high traffic regions than among children living in residential areas of the city. Blood lead levels were positively correlated with family size (r = 0.15) and negatively correlated with household area (r = -0.18). Blood lead levels among these Palestinian schoolchildren were higher than those of other countries where leaded gasoline has been banned and seemed to be higher in more economically deprived children.

Blood lead level among Palestinian schoolchildren: a pilot study

In Palestine, chronic exposure to lead has not been adequately addressed as a problem for children. To assess the exposure of Palestinian school children, we surveyed blood lead levels in 3 schools in Nablus city and collected demographic and clinical data. Blood samples were collected from 173 children [140 boys/38 girls], age range 6-8 years. The overall mean blood lead level was 3.2 [SD 2.4] microg/dL, and 4.5% of children had levels above 10 microg/dL Blood lead levels were significantly higher among children living in refugee camps near industrial high traffic regions than among children living in residential areas of the city. Blood lead levels were positively correlated with family size [r = 0.15] and negatively correlated with household area [r =0.18]. Blood lead levels among these Palestinian schoolchildren were higher than those of other countries where leaded gasoline has been banned and seemed to be higher in more economically deprived children

Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity.

This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age.

Dental amalgam and psychosocial status: the New England Children's Amalgam Trial.

High-dose exposures to elemental mercury vapor cause emotional dysfunction, but it is uncertain whether the levels of exposure that result from having dental amalgam restorations do so. As part of the New England Children's Amalgam Trial, a randomized trial involving 6- to 10-year-old children, we evaluated the hypothesis that restoration of caries using dental amalgam resulted in worse psychosocial outcomes than restoration using mercury-free composite resin. The primary outcome was the parent-completed Child Behavior Checklist. The secondary outcome was children's self-reports using the Behavior Assessment System for Children. Children's psychosocial status was evaluated in relation to three indices of mercury exposure: treatment assignment, surface-years of amalgam, and urinary mercury excretion. All significant associations favored the amalgam group. No evidence was found that exposure to mercury from dental amalgams was associated with adverse psychosocial outcomes over the five-year period following initial placement of amalgams.

What is an adverse effect? A possible resolution of clinical and epidemiological perspectives on neurobehavioral toxicity.

The sizes of the effects observed in studies that rely on neurobehavioral endpoints are often small. Because the mean deficits implied are more modest in magnitude than are those that correspond to the clinical criteria used to diagnose "disease," some observers dismiss them as inconsequential. Other observers argue that the mean deficits take on greater import when viewed as effects on a population rather than on individual members of the population. Several considerations germane to an effort to reconcile these perspectives are discussed: (1) the relative sensitivity of clinical diagnoses and continuously distributed scores on neurobehavioral tests as indices of adverse effect, (2) the syndromal nature of many diagnoses in pediatric neurology and neuropsychology and the implications of shifting nosology, (3) neurobehavioral test-score changes as surrogates or as prodromes for clinically significant deficits, (4) the distinction between individual risk and population risk, and (5) the tendency of the distribution of a risk factor in a population to move up and down as a whole. The clinical and epidemiological perspectives are complementary rather than incompatible.

Cardiac surgery and the brain: differences between adult and paediatric studies.

Evidence is growing that patients with congenital heart disease who undergo surgery may be at increased risk of neurodevelopmental dysfunctions, particular paediatric survivors. However, paediatric studies involve different challenges from those conducted on adults.

Neurodevelopmental outcomes in children after the fontan operation.

BACKGROUND: Previous studies of patients after the Fontan operation have reported IQ scores lower than population norms. In the past decade, changes have occurred both in surgical methods used and in the patient population undergoing Fontan palliation. The present study examined the impact of these changes on neurodevelopmental outcomes after Fontan. METHODS AND RESULTS: Neuropsychological tests were administered to 27 five-year-old children after Fontan. Mean age at repair was 2 years 4 months. The present sample was compared with an earlier Fontan group (EFG) of 133 patients who underwent surgery in the 1970s and 1980s. Mean age at repair for the EFG was 7 years 3 months. Compared with EFG, the present study sample was younger at Fontan (P=0.0001) and more likely to have undergone a Norwood procedure (P=0.02), a pre-Fontan bidirectional cavopulmonary anastomosis (P<0.001), and Fontan fenestration (P=0.001). Although mean full-scale, verbal, and performance IQ scores were within 1 SD (15 points) of the population mean of 100 (93+/-16, 95+/-15, and 91+/-17, respectively), mean full-scale and performance IQ scores were significantly lower than this population mean (P=0.03 and P=0.01, respectively). CONCLUSIONS: Compared with a historical cohort of Fontan patients from this institution, a staged approach to Fontan earlier in life is not detrimental to neurodevelopmental outcome. Neurodevelopmental outcomes in children after Fontan are in the normal range, but performance remains lower than the general population.

General health status of children with D-transposition of the great arteries after the arterial switch operation.

BACKGROUND: To study the long-term impact on general health status of D-transposition of the great arteries (D-TGA) after the arterial switch operation (ASO) during infancy, we asked parents to complete the Child Health Questionnaire, Parent Form-50 when their children were 8 years old. METHODS AND RESULTS: Of 160 eligible patients, questionnaires were completed for 155 subjects (96%). Median age at surgery was 6 days (range 1 to 67 days), and median age at completion of the Child Health Questionnaire was 8.1 years (7.6 to 10.0 years). Subsequent to questionnaire completion, children underwent psychometric testing. Mean Physical Health Summary and Psychosocial Summary scores were 54.0+/-6.1 and 49.7+/-9.9, respectively, which were similar to those of normal subjects. Compared with the normative sample, parents of D-TGA patients reported more problems with attention, learning, and speech, as well as greater frequency of developmental delay (P<0.001 for each). Worse Psychosocial Summary scores were significantly associated with lower full-scale IQ (P=0.001) and lower achievement in reading (P=0.005) and math (P=0.007). Worse Physical Health Summary scores were associated with longer hospital stay after the ASO (P=0.02). General health status scores were not significantly related to presence of ventricular septal defect, age at surgery, perfusion variables during the ASO, sex, or history of cardiac reoperation. CONCLUSIONS: At age 8 years, children with D-TGA after ASO have an overall physical and psychosocial health status similar to that of the general population. Lower IQ and academic achievement are associated with worse psychosocial health status, whereas longer hospital course after initial surgery is associated with worse physical health status.

Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES: In a randomized single-center trial, we compared developmental and neurologic outcomes at 1 and 2 to 4 years of age in children who underwent reparative cardiac operations at less than 9 months of age after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS: Among 168 children eligible for follow-up, 1-year developmental evaluations were carried out on 111, neurologic evaluations on 110, and electroencephalographic evaluations on 102. Parents of 122 children completed questionnaires on behavior and development when children were 2 to 4 years of age. RESULTS: The Psychomotor Development Index scores of the alpha-stat and pH-stat groups did not differ significantly (P =.97). For Mental Development Index scores, the treatment group effect differed according to diagnosis (P =.007). In the D -transposition of the great arteries (n = 59) and tetralogy of Fallot (n = 36) subgroups, the pH-stat group had slightly higher Mental Development Index scores than the alpha-stat group, although these differences were not statistically significant. In the ventricular septal defect subgroup (n = 16), the alpha-stat group had significantly higher scores. Psychomotor Development Index and Mental Development Index scores were significantly higher in the group with D -transposition of the great arteries than in the other 2 groups (P =.03 and P =.01, respectively). Across all diagnoses, Mental Development Index scores were significantly higher than Psychomotor Development Index scores (P <.001). Treatment group assignment was not significantly associated with abnormalities on neurologic examination (P =.70) or electroencephalographic examination (P =.77) at 1 year or with parents' ratings of children's development (P =.99) or behavior (P =.27) at age 2 to 4 years. CONCLUSIONS: Use of alpha-stat versus pH-stat acid-base management strategy during reparative infant cardiac operations with deep hypothermic cardiopulmonary bypass was not consistently related to either improved or impaired early neurodevelopmental outcomes.

Future directions for neurobehavioral studies of environmental neurotoxicants.

Three proposals for enriching neurobehavioral toxicology studies are discussed. First, while IQ has proven useful as a primary endpoint, such apical measures are limited: they obscure important individual differences, tend to reflect the product rather than the process of learning, sample a limited range of intelligent behaviors, and are insensitive to critical outcomes such as learning disabilities. In terms of societal disease burden, behavioral and psychiatric morbidities might be even more important than cognitive morbidities. Such endpoints warrant careful attention. Second, the models of child development can be enriched, increasing our ability both to control for confounding bias and to evaluate potential modification of neurotoxicant effects by contextual factors. While the use of the Home Observation for Measurement of the Environment (HOME scale) and other measures of family-level proximal factors was an important advance, recent sociological work demonstrates the importance of broader conceptualizations of the ecology of child development (e.g. neighborhood and community characteristics). Third, much effort has been expended in attempts to identify the behavioral signature associated with exposure to a particular neurotoxicant. Given the limited success in identifying behavioral phenotypes even for well-characterized genetic disorders (e.g. Fragile-X, Williams, Velocardiofacial syndromes), the prospects seem grim for identifying specific and relatively invariant patterns in the expression of neurotoxicant effects across diverse dosing regimens and biological and cultural settings. In part this results from the likely influence of complex, but largely unknown, patterns of effect modification on the expressions of toxicity. Efforts to define the nature of these contingencies might be more productive than continued efforts to identify behavioral phenotypes.

Diminished motor timing control in children referred for diagnosis of learning problems.

Disabled readers exhibit motor timing control (MTC) deficits in bimanual coordination relative to average readers. This article evaluates to what extent poor MTC is specific to reading or if it is related to learning problems in general. Children (7 to 11 years of age) referred for learning impairment (LI; n = 100) and same-age children nonlearning impaired (NLI; n = 243) performed a paced finger-tapping task. Greater variability of interresponse intervals was associated with poorer reading, spelling, and arithmetic achievement. The LI group performed more poorly than the NLI group, a difference that persisted even after adjusting for reading skill. Poor MTC is associated with poor reading but may also be a characteristic of children referred for learning problems, possibly signaling increased vulnerability of underlying neural integrative processes relevant to the child's adaptation to academic demands, including reading.

Cognitive development after the Fontan operation.

BACKGROUND: Patients with a single ventricle have multiple risk factors for central nervous system injury, both before and after the Fontan procedure. METHODS AND RESULTS: A geographically selected cohort was invited to undergo standardized testing, including age-appropriate measures of intelligence quotient (IQ) and achievement tests. Historical information was obtained by chart review and patient questionnaires. Of the 222 eligible patients, 133 (59.9%) participated. Median age at testing was 11.1 years (range, 3. 7 to 41.0 years), 6.0 years (range, 1.6 to 19.6 years) after surgery. Mean full-scale IQ was 95.7+/-17.4 (P<0.006 versus normal); 10 patients (7.8%) had full-scale IQ scores <70 (P=0.001). After adjustment for socioeconomic status, lower IQ was associated with the use of circulatory arrest before the Fontan operation (P=0.002), the anatomic diagnoses of hypoplastic left heart syndrome (P<0.001) and "other complex" (P=0.05), and prior placement of a pulmonary artery band (P=0.04). Mean composite achievement score was 91.6+/-15. 4 (P<0.001 versus normal); 14 patients (10.8%) scored <70 (P<0.001). After adjustment for socioeconomic status, independent risk factors for low achievement scores included the diagnoses of hypoplastic left heart syndrome (P=0.004) and "other complex" (P=0.003) or prior use of circulatory arrest (P=0.03), as well as a reoperation with cardiopulmonary bypass within 30 days of the Fontan (P=0.01). CONCLUSIONS: Most individual patients palliated with the Fontan procedure in the 1970s and 1980s have cognitive outcome and academic function within the normal range, but the performance of the cohort is lower than that of the general population.

Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes.

Little attention has been invested in exploring the possibility that the nature or magnitude of a neurotoxicant's health impact on children depends on host characteristics (e.g., sex, age) or contextual factors (e.g., socioeconomic status, other chemical exposures). Such effect modification is a property of a true association, and should be distinguished from confounding. In epidemiologic studies of children, most efforts to identify effect modification have been unsystematic, pursued as part of data analysis rather than of study design. As a result, most samples have insufficient statistical power to characterize effect modification with adequate precision. This may contribute to an inconsistency in results across studies. Failure to assess effect modification adequately may also lead to invalid inferences. If the magnitude of an association between a neurotoxicant exposure and a particular end point varies across strata of a third factor, an estimate that summarizes the association across strata of this factor will be inappropriate, overestimating the association in a stratum in which the association is absent, and underestimating it in a stratum in which it is present. Until such dependencies are identified, our understanding of the mechanism(s) of a compound's neurotoxicity will remain incomplete, as will the knowledge base required to formulate public policy that adequately protects the most sensitive subgroups of the population.

Processing speed in children with attention deficit/hyperactivity disorder, inattentive type.

Attention Deficit/Hyperactivity Disorder (ADHD) is among the most common and most often reconceptualized neurobehavioral disorders of childhood. In the most recent DSM-IV, a primarily inattentive subtype of ADHD (AD) has again been identified. This study explores the neuropsychological profile of this group of children. Eighty-two children referred for school-related problems participated. Twenty-five met criteria for AD; 52 met criteria for reading disability (RD); 9 were comorbid for RD and AD. AD children performed poorly on measures of information processing speed. Children with comorbid AD/RD were distinguishable from those with RD on speed of processing measures only. Vulnerability to information processing load may be at the root of many of the behavioral manifestations of AD.

Developmental outcome after surgical versus interventional closure of secundum atrial septal defect in children.

BACKGROUND: The assessment of the impact of cardiopulmonary bypass (CPB) on developmental outcomes in children who undergo open heart surgery is hampered by the absence of a suitable comparison group. The development of interventional catheterization techniques for the repair of certain types of congenital heart lesions provides the opportunity to study children who have not been exposed to CPB. METHODS AND RESULTS: We performed standardized neuropsychological testing on children after closure of a secundum atrial septal defect through the use of surgery (n=26) or a transcatheter device (n=19). Device patients, compared with surgical patients, were similar in age at defect closure (mean, 6 years) but older at follow-up testing (12.3 versus 10.6 years). The mean weight percentile at closure was greater and the defect size was smaller in the device patients. Families of device patients tended to have a higher parent IQ, higher level of maternal education, and higher level of maternal occupation. In general, however, children's IQ and achievement scores were in the normal range for both groups. In regression analyses with adjustment for age at testing and parent IQ, surgical repair was associated with a 9.5-point deficit in Full-Scale IQ (P=0. 03) and a 9.7-point deficit in Performance IQ (P=0.05). Block Design was the IQ subtest on which treatment groups differed the most (P=0. 01). Surgical patients achieved significantly better scores on errors of commission (P=0.05) and attentiveness index (P=0.03) on a continuous performance test of attention. Scores on tests of achievement and other neuropsychological domains did not differ significantly between the groups. Regression analyses within the surgical group failed to identify significant CPB-related risk factors. CONCLUSIONS: A prospective randomized trial or a study that includes prerepair and postrepair assessments is necessary to establish whether the observed advantages of device closure in neuropsychological outcome represent deleterious effects of CPB or a methodological artifact.

Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.

BACKGROUND: It is not known whether developmental and neurological outcomes in the preschool period differ depending on whether the predominant vital organ support strategy used in infant heart surgery was total circulatory arrest (CA) or low-flow cardiopulmonary bypass. METHODS AND RESULTS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a support method consisting predominantly of CA or low-flow cardiopulmonary bypass. Developmental and neurological status were evaluated blindly at 4 years of age in 158 of 163 eligible children (97%). Neither IQ scores nor overall neurological status were significantly associated with either treatment group or duration of CA. The CA group scored lower on tests of motor function (gross motor, P=0.01; fine motor, P=0.03) and had more severe speech abnormalities (oromotor apraxia, P=0.007). Seizures in the perioperative period, detected either clinically or by continuous electroencephalographic monitoring, were associated with lower mean IQ scores (12.6 and 7.7 points, respectively) and increased risk of neurological abnormalities (odds ratios, 8.4 and 5.6, respectively). The performance of the full cohort was below expectations in several domains, including IQ, expressive language, visual-motor integration, motor function, and oromotor control. CONCLUSIONS: Use of CA to support vital organs during open heart surgery in infancy is associated, at the age of 4 years, with worse motor coordination and planning but not with lower IQ or with worse overall neurological status.

Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Boston Circulatory Arrest Study Group.

BACKGROUND: The outcome of infants who have transient seizures after open heart surgery has not been studied. Using the database of the Boston Circulatory Arrest Study involving 171 children with D-transposition of the great arteries, we explored the relationship between early postoperative clinical and EEG seizures and neurodevelopmental outcomes at ages 1 and 2 1/2 years. METHODS AND RESULTS: At 1 year, children returned for developmental and neurological evaluations and MRI. Parent-completed developmental questionnaires were collected at 2 1/2 years of age. At 1 year, children with early postoperative seizures had lower Psychomotor Development Index (motor function) scores (clinical seizures: 12.9 mean difference [MD]; 95% confidence interval [CI], 2.2 to 23.6; P=.02; EEG seizures: 13.3 MD; 95% CI, 6.8 to 19.7; P<.001). Mental Developmental Index scores of children with clinical or EEG seizures were also lower, but the differences were not statistically significant. Infants with seizures were more likely to have an abnormal neurological examination (clinical seizures: 78% versus 31%; P=.008; EEG seizures: 58% versus 34%; P=.04). Children with EEG seizures were more likely to have MRI abnormalities (43% versus 13%, P=.002). At age 2 1/2, children with EEG seizures had lower scores in several areas of function. CONCLUSIONS: In infants undergoing the arterial switch operation for correction of D-transposition of the great arteries, transient postoperative clinical and EEG seizures were associated with worse neurodevelopmental outcomes at ages 1 and 2 1/2 years as well as neurological and MRI abnormalities at 1 year of age. The occurrence of such seizures may provide an early sign of brain injury with neurological and developmental sequelae.

Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries.

A randomized clinical trial was conducted to compare the early development of children with d-transposition of the great arteries (N = 171) repaired by an arterial switch operation that used either predominantly total circulatory arrest or predominantly continuous low-flow cardiopulmonary bypass. The children assigned to the circulatory arrest group scored lower than those assigned to low-flow bypass on the Bayley Scales of Infant Development at 1 year of age. Responses to parental questionnaires completed when the children were 2.5 years old indicated that the children in the circulatory arrest group, especially those with a ventricular septal defect, also manifested poorer expressive language and were considered to display more internalizing and externalizing problem behaviors. The use of circulatory arrest to protect vital organs during open heart surgery might place children at increased risk of early developmental difficulties, especially in the domains of motor and language function.