Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest.

OBJECTIVE: This pharmacologic protection trial was conducted to test the hypothesis that allopurinol, a scavenger and inhibitor of oxygen free radical production, could reduce death, seizures, coma, and cardiac events in infants who underwent heart surgery using deep hypothermic circulatory arrest (DHCA). DESIGN: This was a single center, randomized, placebo-controlled, blinded trial of allopurinol in infant heart surgery using DHCA. Enrolled infants were stratified as having hypoplastic left heart syndrome (HLHS) and all other forms of congenital heart disease (non-HLHS). Drug was administered before, during, and after surgery. Adverse events and the clinical efficacy endpoints death, seizures, coma, and cardiac events were monitored until infants were discharged from the intensive care unit or 6 weeks, whichever came first. RESULTS: Between July 1992 and September 1997, 350 infants were enrolled and 348 subsequently randomized. A total of 318 infants (131 HLHS and 187 non-HLHS) underwent heart surgery using DHCA. There was a nonsignificant treatment effect for the primary efficacy endpoint analysis (death, seizures, and coma), which was consistent over the 2 strata. The addition of cardiac events to the primary endpoint resulted in a lack of consistency of treatment effect over strata, with the allopurinol treatment group experiencing fewer events (38% vs 60%) in the entire HLHS stratum, compared with the non-HLHS stratum (30% vs 27%). In HLHS surgical survivors, 40 of 47 (85%) allopurinol-treated infants did not experience any endpoint event, compared with 27 of 49 (55%) controls. There were fewer seizures-only and cardiac-only events in the allopurinol versus placebo groups. Allopurinol did not reduce efficacy endpoint events in non-HLHS infants. Treated and control infants did not differ in adverse events. CONCLUSIONS: Allopurinol provided significant neurocardiac protection in higher-risk HLHS infants who underwent cardiac surgery using DHCA. No benefits were demonstrated in lower risk, non-HLHS infants, and no significant adverse events were associated with allopurinol treatment.congenital heart defects, hypoplastic left heart syndrome, induced hypothermia, ischemia-reperfusion injury, neuroprotective agents, allopurinol, xanthine oxidase, free radicals, seizures, coma.

Late cognitive effects of early treatment with phenobarbital.

We previously reported that IQ was significantly lowered in a group of toddler-aged children randomly assigned to receive phenobarbital or placebo for febrile seizures and there was no difference in the febrile seizure recurrence rate. We retested these children 3-5 years later, after they had entered school, to determine whether those effects persisted over the longer term and whether later school performance might be affected. On follow-up testing of 139 (of the original n = 217) Western Washington children who had experienced febrile seizures, we found that the phenobarbital group scored significantly lower than the placebo group on the Wide Range Achievement Test (WRAT-R) reading achievement standard score (87.6 vs 95.6; p = 0.007). There was a nonsignificant mean difference of 3.71 IQ points on the Stanford-Binet, with the phenobarbital-treated group scoring lower (102.2 vs 105.7; p = 0.09). There were five children in our sample with afebrile seizures during the 5-year period after the end of the medication trial. Two had been assigned to phenobarbital, and three had been in the placebo group. We conclude there may be a long-term adverse cognitive effect of phenobarbital on the developmental skills (language/verbal) being acquired during the period of treatment and no beneficial effect on the rate of febrile seizure recurrences or later nonfebrile seizures.

Magnesium sulfate and cerebral palsy in premature infants.

This article reviews clinical and experimental evidence as to whether magnesium sulfate, administered soon before premature birth, can reduce the high rate of cerebral palsy in tiny infants. Three observational studies have reported an association of magnesium sulfate with lower rate of cerebral palsy, whether treatment was for maternal preeclampsia or for tocolysis. One of these studies also noted a significant reduction in cognitive disability. In another study, no significant protective effect was seen except in a small subset of infants. Magnesium was neuroprotective in many but not all of a variety of experimental studies and has a variety of biologic effects that might account for benefit. All existing clinical studies had relatively small numbers of very premature infants. Although all attempted to control for possible confounders, such studies cannot provide definitive answers as to possible benefits or risks of magnesium therapy. Only randomized clinical trials are likely to resolve the question of whether a brief exposure to an agent which, in the American experience, is considered safe if administered with appropriate supervision, can reduce longterm neurologic disability in premature infants.

Febrile seizures: is the EEG a useful predictor of recurrences?

We examined the predictive value of a paroxysmal EEG in children with febrile seizures seen at the University Pediatric Clinic, Skopje, Macedonia, between 1982 and 1984. This was the only facility providing EEG or neurologic consultation for children in Macedonia, and almost all children in the area who experienced a febrile seizure were referred to this facility. EEGs were classified as epileptiform if they contained spikes and sharp waves or spike wave complexes, which were either focal or generalized, and were considered abnormal for age and state. Nonspecifically abnormal was defined as focal or generalized slowing excessive for age and state. Follow-up visits were scheduled at 6-month intervals; mean follow-up time was approximately 23 months. In order to determine whether clearly abnormal EEG features would predict recurrences, we compared the recurrences in 170 children with initial normal-appearing EEGs with 99 children with initial paroxysmal EEGs. There was no significant difference in risk of recurrence of febrile seizures between the two groups; increase in recurrence risk was determined primarily by younger age. The EEG did not add information regarding the likelihood of recurrence of febrile seizures.

Does phenobarbital used for febrile seizures cause sleep disturbances?

The effect of phenobarbital on total sleep time, night awakenings, and lengthy awakenings was examined as part of a randomized trial of children with febrile seizures; information about sleep patterns was gathered by parental observation. Children were between ages 8-36 months at enrollment and were examined subsequently for 2 1/2 years. Night awakenings were not more common in children assigned to phenobarbital except for those who were poor sleepers at the beginning of the study. Total sleep time was no different in children assigned to phenobarbital than in those assigned to placebo. It is concluded that sleep problems reported in most young children with febrile seizures treated with phenobarbital did not exceed those reported in children treated with placebo, but a subset of predisposed children did experience an increase in night awakenings.

Febrile seizures: clinical characteristics and initial EEG.

We examined the relationship between clinical characteristics and EEG classification in all children with febrile seizures examined at the University Pediatric Clinic, Skopje, Yugoslavia between 1982 and 1984. This is the only facility in Macedonia providing EEG or neurologic consultation for children. EEGs were classified as paroxysmally abnormal if they contained spikes, sharp waves, or spike-wave complexes considered abnormal for age. In all, 22% of the 676 children had an abnormal initial EEG. The most common basis for classification as abnormal was spike-wave complexes greater than 3 Hz; the next most common basis was the presence of spikes. Birth weight, gender, accompanying illness, and family history of seizures, and whether the index seizure was single or multiple were not associated with differences in rate of abnormal EEG. Clinically focal index seizures and longer duration were associated with EEG abnormality. Number of previous febrile seizures was associated with an increasing rate of EEG abnormality, from 18% in children with no previous seizures to 63% in those with four or more previous seizures. Age at EEG was linearly related to likelihood of paroxysmal EEG abnormality, both for the total cohort and for the 376 children with no previous seizures. In the total cohort, logistic regression identified leading predictors of abnormal initial EEG to be older age, number of previous febrile seizures, preexisting motor abnormality, and focal seizures. For children with a first febrile seizure, leading predictors were focal seizure, older age, and preexisting motor abnormality.

Analysis of clinical trials by treatment actually received: is it really an option?

The primary analysis of a randomized clinical trial should compare patients in their randomly assigned treatment groups (intention to treat analysis). When a substantial number of subjects fail to take a prescribed medication or are switched to a different study medication, it is tempting to consider treatment comparisons using only those subjects with treatment as actually received rather than as prescribed. There are several arguments against this approach: the prognostic balance brought about by randomization is likely to be disturbed; sample size will be reduced; and the validity of the statistical test procedures will be undermined. Further, results of analysis by treatment actually received may suffer from a bias introduced by using compliance, a factor often related to outcome independently of the treatment received, to determine the groups for comparison. The extent and nature of this bias will be related to the definition of compliance in an as treated analysis, a definition which could be unintentionally self-serving. We have investigated the problem of the definition of actual treatment in the context of a recent clinical trial. We used several definitions to classify patients as having received or not received treatment as prescribed. These definitions, when used in as treated analyses, provided results that were at times inconsistent or counter-intuitive, and which neither helped to confirm nor further explain the intention to treat analysis.

Intelligence at six years in relation to neonatal bilirubin levels: follow-up of the National Institute of Child Health and Human Development Clinical Trial of Phototherapy.

Results of the National Institute of Child Health and Human Development Randomized Controlled Trial of Phototherapy were examined for the relationship of neonatal bilirubin level to neurological and developmental outcome at 6-year follow-up. This analysis focused on 224 control children with birth weight of less than 2000 g. Bilirubin levels were maintained below previously specified levels by the use of exchange transfusion only (24%). Rates of cerebral palsy were not significantly higher for children with elevated maximum bilirubin level than for those whose level remained low. No association was evident between maximum bilirubin level and IQ (Full Scale, Verbal, or Performance) by simple correlation analysis (r = -.087, P = .2 for Full Scale) or by multiple linear regression adjusting for factors that covary with IQ (beta = -.15, P = .58). IQ was not associated with mean bilirubin level, time and duration of exposure to bilirubin, or measures of bilirubin-albumin binding. Thus, over the range of bilirubin levels permitted in this clinical trial, there was no evidence of bilirubin toxicity to the central nervous system. Measures used to control the level of bilirubin in low birth weight neonates appear to prevent effectively the risk of bilirubin-induced neurotoxicity.

Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial.

The National Institute of Child Health and Human Development Randomized, Controlled Trial of Phototherapy for Neonatal Hyperbilirubinemia was conducted to determine whether phototherapy used to control serum bilirubin is safe and is as effective in preventing brain injury as exchange transfusion. The study, conducted at six neonatal care centers, randomly assigned 1339 newborn infants to phototherapy or control groups by the following subgroups: (1) birth weight less than 2000 g; (2) birth weight 2000 to 2499 g and bilirubin level greater than 171 mumol/L (10 mg/dL); or (3) birth weight greater than or equal to 2500 g and bilirubin level greater than 222 mumol/L (13 mg/dL). Phototherapy was administered for 96 hours, and exchange transfusion was used to control hyperbilirubinemia at the same predetermined levels in both groups. Neurological and developmental examinations were conducted at 1 and 6 years of age, with follow-up rates of 83% and 62%, respectively. The two groups did not differ in mortality or diagnosed medical conditions. The phototherapy and control groups had similar rates of cerebral palsy (5.8% vs 5.9%), other motor abnormalities including clumsiness and hypotonia (11.1% vs 11.4%), and sensorineural hearing loss (1.8% vs 1.9%). The Wechsler Intelligence Scale for Children-Revised scores overall were not significantly different for the two groups (Verbal, 96.8 vs 94.8; Performance, 95.8 vs 95.1 for phototherapy and control groups, respectively). Phototherapy effectively controlled neonatal hyperbilirubinemia without evidence of adverse outcome at 6 years of age and was at least as effective as management with exchange transfusion alone.

Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence.

Phenobarbital is widely used in the treatment of children with febrile seizures, although there is concern about possible behavioral and cognitive side effects. In 217 children between 8 and 36 months of age who had had at least one febrile seizure and were at heightened risk of further seizures, we compared the intelligence quotients (IQs) of a group randomly assigned to daily doses of phenobarbital (4 to 5 mg per kilogram of body weight per day) with the IQs of a group randomly assigned to placebo. After two years, the mean IQ was 7.03 [corrected] points lower in the group assigned to phenobarbital than in the placebo group (95 percent confidence interval, -11.52 to -2.5, P = 0.0068 [corrected]). Six months later, after the medication had been tapered and discontinued, the mean IQ was 5.2 points lower in the group assigned to phenobarbital (95 percent confidence interval, -10.5 to 0.04, P = 0.052). The proportion of children remaining free of subsequent seizures did not differ significantly between the treatment groups. We conclude that phenobarbital depresses cognitive performance in children treated for febrile seizures and that this disadvantage, which may outlast the administration of the drug by several months, is not offset by the benefit of seizure prevention.

Generalized tonic-clonic and febrile seizures.

In general, children with febrile seizures have a good prognosis, and only a small minority of children go on to become epileptic. Most outgrow the tendency to have seizures, and the seizures do not appear to cause lasting intellectual or neurologic damage. Relatively few children need be exposed to daily anticonvulsant therapy, and these would be primarily children whose clinical picture is quite atypical.

Survey on the management of febrile seizures.

A survey regarding the management of the child with febrile seizures was mailed to 10 000 child neurologists, neurologists, pediatricians, and family and general practitioners. The response rate varied by specialty; overall, slightly more than half the physicians responded. One third or less of physicians prescribed anticonvulsive therapy only at the time of febrile illness, although this practice was much less common among recent graduates. If children had lengthy or focal seizures, the majority of physicians in all specialties either prescribed long-term treatment or referred for consultation. Long-term daily anticonvulsant therapy was prescribed most frequently by child neurologists and least often by general practitioners, who most often referred for consultation. Rate of hospitalization also differed according to specialty. The results of the survey indicate that the management of a child with febrile seizures may differ depending on the specialty of the attending physician.

Do seizures in children cause intellectual deterioration?

We studied whether the occurrence of seizures in childhood affected intellectual performance. We compared the full-scale IQs at seven years of age of children who had experienced one or more nonfebrile seizures with the IQs of their seizure-free siblings who were tested at the same age in a large longitudinal study. Among 98 children with seizures, the mean score on IQ tests at seven years was not significantly different from the mean score of their siblings. Mental retardation was more common among the children with seizures, but the excess was accounted for by children who had neurologic abnormalities before the first seizure. We also examined the IQ before and after the onset of seizures in 62 children whose first seizure occurred in the interval between psychometric examinations given at four and seven years of age. The IQ at seven years in the children with seizures did not differ significantly from that in controls matched for IQ (as determined at the four-year assessment), sex, race, and socioeconomic status. Thus, in both the sibling-control comparison and the comparisons made between controls and subjects before and after the onset of seizures, the occurrence of nonfebrile seizures was not associated with a significant change in full-scale IQ.

The risk of recurrence of nonfebrile seizures in children.

In a prospective study, the risk of recurrence after a first postneonatal nonfebrile seizure was 61% by age 7 years. The risk of recurrence for nonsymptomatic seizures was considerably higher than for seizures attributed to immediate precipitating factors. Focal motor seizures were more likely than generalized motor seizures to recur. Children who had prior neonatal seizures were at greater risk for nonfebrile recurrence than children with no prior seizure. Family history and neurodevelopmental status were not significantly related to recurrence risk. Almost 90% of recurrences took place within 1 year, and 96% within 2 years.

Age at onset of seizures in young children.

Age at onset of seizures in young children and its relationship to factors such as prior neurological status and neurological outcome were examined. Of 52,360 children, 39,270 of whom were followed for the full 7 years, a total of 2,635 experienced one or more seizures between birth and 7 years of age. The incidence of nonfebrile convulsions was highest in the first year of life, especially in the first month. Children with neonatal seizures who later developed nonfebrile seizures did so early, two-thirds by 6 months and three-quarters by 1 year of age. Children with neurological or developmental abnormality assessed in the first year of life did not have their first seizure earlier than children without abnormality. Neurological abnormality in the first year of life before any seizure, and the presence of minor motor seizures, were associated with an increased rate of mental retardation and cerebral palsy at age 7, but early age at onset appeared to have little prognostic value regarding intellectual function, cerebral palsy, and epilepsy.

The natural history of febrile seizures.

Febrile seizures are a common occurrence in early childhood and most children who experience them do well. This article reviews the clinical characteristics of febrile seizures, and summarizes the relevant clinical and laboratory research. The natural history of febrile seizures, the recurrence rate, and frequency of later epilepsy or intellectual handicap is presented, and controversies in evaluation and treatment are discussed.

Seizures following childhood immunizations.

In 1.4% of children who experienced a seizure during the first seven years of life, the seizure followed within two weeks of an immunization procedure. We report 40 postimmunization seizures in 39 children enrolled in the Collaborative Perinatal Project. Ten seizures followed diphtheria-pertussis-tetanus (DPT) immunization, and 10 followed measles immunization. All but one of the seizures were associated with fever, often high. Thirty-seven seizures lasted less than 30 minutes. More than half of the children had a personal or immediate-family history of febrile seizures. One of the children had a right focal seizure lasting six hours after DPT immunization and had a significant speech deficit on long-term follow-up. No child developed epilepsy, and results in all children with brief seizures were normal on neurologic and cognitive examination at 7 years of age. Both in clinical presentation and generally benign outcome, these immunization-related seizures closely resemble febrile seizures, which are common in early childhood.