Biomedical subjects
Publications and source records attributed to D C Bellinger.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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.
BACKGROUND: Deep hypothermia with either total circulatory arrest or low-flow cardiopulmonary bypass is used to support vital organs during heart surgery in infants. We compared the developmental and neurologic sequelae of these two strategies one year after surgery. METHODS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a method of support consisting predominantly of circulatory arrest or a method consisting predominantly of low-flow bypass. Developmental and neurologic evaluations and magnetic resonance imaging (MRI) were performed at one year of age. RESULTS: Of the 171 patients enrolled in the study, 155 were evaluated. After adjustment for the presence or absence of a ventricular septal defect, the infants assigned to circulatory arrest, as compared with those assigned to low-flow bypass, had a lower mean score on the Psychomotor Development Index of the Bayley Scales of Infant Development (a 6.5-point deficit, P = 0.01) and a higher proportion had scores < or = 80 (i.e., 2 SD or more below the population mean) (27 percent vs. 12 percent, P = 0.02). The score on the Psychomotor Development Index was inversely related to the duration of circulatory arrest (P = 0.02). The risk of neurologic abnormalities increased with the duration of circulatory arrest (P = 0.04). The method of support was not associated with the prevalence of abnormalities on MRI scans of the brain, scores on the Mental Development Index of the Bayley Scale, or scores on a test of visual-recognition memory. Perioperative electroencephalographic seizure activity was associated with lower scores on the Psychomotor Development Index (P = 0.002) and an increased likelihood of abnormalities on MRI scans of the brain (P < 0.001). CONCLUSIONS: Heart surgery performed with circulatory arrest as the predominant support strategy is associated with a higher risk of delayed motor development and neurologic abnormalities at the age of one year than is surgery with low-flow bypass as the predominant support strategy.
To examine whether pH management during core cooling is a risk factor for adverse developmental outcome, we studied 16 children with transposition of the great arteries and intact ventricular septum who underwent a Senning procedure in infancy (median age 32 days, range 2 to 154 days) between 1983 and 1988. Information was collected retrospectively on many aspects of perfusion, including lowest carbon dioxide tension during core cooling, duration of core cooling, and duration of circulatory arrest. The pH strategy changed from pH-stat to alpha-stat in 1985, resulting in a wide range of pH values and carbon dioxide tension (34 to 76 mm Hg) during the study period. All children had rapid core cooling to a rectal temperature of 19.8 degrees +/- 2.7 degrees C (mean +/- standard deviation) and a tympanic temperature of 16.6 degrees +/- 3.0 degrees C. Development was assessed at median age 48.0 (11 to 79) months with the Bayley Scales (n = 4, children younger than 30 months) or the McCarthy Scales (n = 12, children older than 30 months). The mean core-cooling duration was 14.5 +/- 6.2 minutes, circulatory arrest time was 43.4 +/- 6.6 minutes, and total bypass plus circulatory arrest time was 89.7 +/- 12.7 minutes. Lower carbon dioxide tension (alpha-stat) before onset of circulatory arrest was associated with worse developmental outcome (r = 0.71, p = 0.002). This relationship remained highly significant when we controlled for sociodemographic and intraoperative variables. including core-cooling time, circulatory arrest time, and total elapsed time. Duration of circulatory arrest was not associated with developmental outcome. We conclude that when relatively rapid core cooling is used to achieve hypothermia before circulatory arrest in young infants, a more alkaline pH strategy such as alpha-stat may result in less effective cerebral protection.
The implications of low-level lead exposure for children's intellectual and academic performance at school age are uncertain. This issue was investigated in a prospective study of middle-class and upper-middle-class children with low lifetime exposures to lead. A battery of neuropsychological tests was administered at age 10 years to 148 children whose lead exposure and cognitive function had been previously assessed at ages 6, 12, 18, 24, and 57 months. Primary endpoints were Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Kaufman Test of Educational Achievement (K-TEA). Higher levels of blood lead at age 24 months, but not at other ages, were significantly associated with lower global scores on both the WISC-R and the K-TEA after adjustment for potential confounders. Over the range of approximately 0 to 25 micrograms/dL, a 0.48-mumol/L (10 micrograms/dL) increase in blood lead at 24 months was associated with a 5.8-point decline in WISC-R Full-Scale IQ (95% confidence interval: 1.7 to 9.9, P = .007) and an 8.9-point decline in K-TEA Battery Composite score (95% confidence interval: 4.2 to 13.6, P = .0003). Mean blood lead level at age 24 months was 0.31 mumol/L (6.5 micrograms/dL; SD: 4.9, 90% percentile: 12.5). Slightly elevated blood lead levels around the age of 24 months are associated with intellectual and academic performance deficits at age 10 years.
Twenty-eight children who underwent corrective cardiac surgery in early infancy had developmental evaluations to explore whether cardiopulmonary bypass perfusion variables are associated with later cognitive function. All had transposition of the great arteries repaired by the arterial switch operation using deep hypothermic circulatory arrest. The mean duration of deep hypothermic circulatory arrest was 64 +/- 10 minutes (mean +/- SD). Median age at repair was 4 days (range 1 to 125 days). Tests of development were administered at age 7 to 53 months: Bayley Scales for children younger than 30 months of age (n = 18) and McCarthy Scales for older children (n = 10). Overall cognitive development score was 101.2 +/- 11.1. Duration of deep hypothermic circulatory arrest was not associated with performance. However, for core cooling periods of less than 20 minutes' duration, shorter cooling periods were associated with lower scores (r = .85, n = 11, P less than .001). These data suggest that patients undergoing relatively long periods of deep hypothermic circulatory arrest may require some minimum time of cardiopulmonary bypass cooling to avoid central nervous system injury.
This study investigates the impact of infantile colic on subsequent development. Infants with a history of colic scored significantly lower on the Mental and Psychomotor scales of the Bayley Scales of Infant Development at age 6 months but there was no significant effect of colic on test performance at later ages. The data suggest that this temporary delay in development may be due in part to less favorable patterns of caregiver-infant interaction as a result of the history of colic.