Developmental and Neurologic Status of Children after Heart Surgery with Hypothermic Circulatory Arrest or Low-Flow Cardiopulmonary Bypass
David C. Bellinger, Ph.D., Richard A. Jonas, M.D., Leonard A. Rappaport, M.D., David Wypij, Ph.D., Gil Wernovsky, M.D., Karl C.K. Kuban, M.D., Patrick D. Barnes, M.D., Gregory L. Holmes, M.D., Paul R. Hickey, M.D., Roy D. Strand, M.D., Amy Z. Walsh, R.N., B.S.N., Sandra L. Helmers, M.D., Jules E. Constantinou, F.R.A.C.P., Enrique J. Carrazana, M.D., John E. Mayer, M.D., Frank L. Hanley, M.D., Aldo R. Castaneda, M.D., James H. Ware, Ph.D., and Jane W. Newburger, M.D., M.P.H.
Background Deep hypothermia with either total circulatory arrestor low-flow cardiopulmonary bypass is used to support vitalorgans during heart surgery in infants. We compared the developmentaland neurologic sequelae of these two strategies one year aftersurgery.
Methods Infants with D-transposition of the great arteries whounderwent an arterial-switch operation were randomly assignedto a method of support consisting predominantly of circulatoryarrest or a method consisting predominantly of low-flow bypass.Developmental and neurologic evaluations and magnetic resonanceimaging (MRI) were performed at one year of age.
Results Of the 171 patients enrolled in the study, 155 wereevaluated. After adjustment for the presence or absence of aventricular septal defect, the infants assigned to circulatoryarrest, as compared with those assigned to low-flow bypass,had a lower mean score on the Psychomotor Development Indexof the Bayley Scales of Infant Development (a 6.5-point deficit,P = 0.01) and a higher proportion had scores <80 (i.e., 2SD or more below the population mean) (27 percent vs. 12 percent,P = 0.02). The score on the Psychomotor Development Index wasinversely related to the duration of circulatory arrest (P =0.02). The risk of neurologic abnormalities increased with theduration of circulatory arrest (P = 0.04). The method of supportwas not associated with the prevalence of abnormalities on MRIscans of the brain, scores on the Mental Development Index ofthe Bayley Scale, or scores on a test of visual-recognitionmemory. Perioperative electroencephalographic seizure activitywas associated with lower scores on the Psychomotor DevelopmentIndex (P = 0.002) and an increased likelihood of abnormalitieson MRI scans of the brain (P<0.001).
Conclusions Heart surgery performed with circulatory arrestas the predominant support strategy is associated with a higherrisk of delayed motor development and neurologic abnormalitiesat the age of one year than is surgery with low-flow bypassas the predominant support strategy.
Deep hypothermia with total circulatory arrest is a method ofsupport for vital organs that is often used during the repairof complex congenital heart abnormalities in infants. The maximalduration of circulatory arrest that will not result in impairmentof the central nervous system is uncertain.1,2 Few data areavailable on the developmental and neurologic sequelae of themost important alternative support strategy, continuous low-flowcardiopulmonary bypass.3
In 1988 we began a randomized clinical trial to compare theincidence of brain injury in children with D-transposition ofthe great arteries undergoing an arterial-switch operation afterassignment to a strategy consisting predominantly of circulatoryarrest with that in children assigned to a strategy consistingpredominantly of low-flow cardiopulmonary bypass. In the earlypostoperative period, the infants assigned to circulatory arresthad a higher incidence of neurologic morbidity than those assignedto low-flow bypass, including a higher incidence of seizuresand ictal activity on continuous electroencephalographic (EEG)monitoring, a longer time to the reappearance of normal brainEEG activities, and release of greater amounts of the brainisoenzyme of creatine kinase.4 In this report we compare thedevelopmental and neurologic status of the children in the twogroups at one year.
Methods
Between April 1988 and February 1992, we enrolled 171 patientsin a prospective, randomized, single-center trial. The eligibilitycriteria included a diagnosis of d-transposition of the greatarteries with either an intact ventricular septum or a ventricularseptal defect, a scheduled repair to be performed by three monthsof age, and coronary-artery anatomy considered suitable forthe arterial-switch operation. Exclusion criteria included abirth weight below 2.5 kg, a recognizable syndrome of congenitalanomalies, associated extracardiac anomalies that were moderateor severe, previous cardiac surgery, or associated cardiovascularanomalies requiring reconstruction of the aortic arch or additionalopen surgical procedures. Informed consent was obtained fromthe parents of all the infants. Additional information aboutthe study design, perfusion methods, surgical techniques, andanesthetic management was presented previously.4
Information on family characteristics5,6 was obtained from interviewswith the parents. Prenatal and perinatal data were also recorded.Examination of the children at the age of one year was performedby investigators who were unaware of the treatment assignmentor clinical course.
Developmental Testing
All assessments were conducted at 8 a.m. Two examiners administeredthe Bayley Scales of Infant Development,7 which yield scoreson two indexes: the Psychomotor Development Index and the MentalDevelopment Index. We also calculated the proportion of childrenwhose scores were less than or equal to 80 (approximately 2SD below the current mean scores on the 1969 version of thistest8). An evaluation of interexaminer reliability (13 infants)showed that the examiners were in agreement for 99 percent ofthe individual items, and correlations between the raw scoreswere higher than 0.99.
The Fagan Test of Infant Intelligence,9 which assesses visual-recognitionmemory, was also administered. The mean novelty-preference score(percentage of time spent looking at a novel stimulus) was computed,and children with scores lower than 53 percent were consideredto have failed the test.9
Neurologic Examination
Neurologic examinations were performed by a pediatric neurologistusing the format derived from the National Collaborative PerinatalProject. Findings were classified as normal, possibly abnormal,or definitely abnormal. Abnormalities were subclassified accordingto type (cerebral palsy, tone alteration, ataxia or dysmetria,focal abnormalities, and abnormalities of the special senses).10,11,12,13Children who had cerebral palsy were excluded from classificationin other categories.
Magnetic Resonance Imaging
Patients underwent magnetic resonance imaging (MRI) of the brainwith a 1.5-tesla system (General Electric Medical, Milwaukee).We used conventional spin–echo techniques, including sagittalT1-weighted images (repetition time, 600 msec; echo time, 15msec; number of signals averaged [NSA], 2) and axial proton-density–weightedand T2-weighted images (repetition time, 2000 msec; echo time,90 msec; NSA, 2). A slice thickness of 5 mm was used with 1.0to 2.5 mm of spacing between slices and a 24-cm field of view.Gadolinium enhancement was not used.
Two pediatric neuroradiologists independently assessed structuraland intensity abnormalities. The findings were classified asnormal, possibly abnormal, or definitely abnormal (mild, moderate,or severe). Abnormalities were subclassified as diffuse (ventriculardilatation, delayed myelination or maturation, or periventricularleukomalacia), focal or multifocal (atrophy or intensity abnormalityof gray or white matter), or developmental (incidental). Incases of conflicting assessments (14 percent of the studies,with 4 percent frank disagreement), the two examiners reachedan agreement.
Statistical Analysis
The two treatment groups were compared in intention-to-treatanalyses. Secondary analyses examined the effect of the duration(in minutes) of total circulatory arrest on the outcome. Alltests of hypotheses and regression analyses of outcome variableswere adjusted for the diagnosis (i.e., intact ventricular septumor ventricular septal defect). Adjustment for the surgeon orfor an interaction between the surgeon and the treatment didnot alter the results.
The outcomes at one year included both continuous and categoricalvariables. Multiple linear-regression methods and Wilcoxon rank-sumtests were used to analyze continuous variables. Stratifiedexact tests14 and multiple logistic-regression methods wereused to analyze categorical variables.
Scores on the Bayley Scales were expressed in two ways. First,the standard scores on the Psychomotor Development Index andthe Mental Development Index were derived.7 Second, for eachscale, the numbers of items passed were totaled and adjustedfor age at the time of examination by means of an analysis ofcovariance. This approach adjusts for imbalances between treatmentand diagnostic groups in the assignment of children to the ageintervals used to derive standard scores.
For some children, not all outcome scores were available. Analyseswere based on scores on the Psychomotor Development Index for142 children and on scores on the Mental Development Index for143 children. One child was too distressed for the administrationof any developmental tests. Testing of another child had tobe terminated before completion of the Psychomotor DevelopmentIndex. A third child, later found to be autistic, could notbe tested because of reduced social relatedness. In addition,before data analysis and without knowledge of the treatmentassignments, a decision was made to exclude the developmentalscores of the first 10 children who returned for examinationsat one year. We had enrolled these 10 children to demonstrateour ability to assign children randomly to treatment groupsat the time of surgery. At one year, these infants were evaluatedunder conditions that were not standardized in terms of time,location, and the children's condition. The National Institutesof Health Data and Safety Monitoring Committee for the trialapproved our decision not to include these children in analysesof developmental end points.
Analyses of the Fagan test are based on the scores of 107 children.Twenty children were excluded because they were not within theage range of 11 to 13 months at the time of examination. Seventeenchildren had incomplete tests because of their inability tocooperate. (The 10 children first enrolled and the autisticchild were also not included.)
Neurologic examinations were completed for 154 children, andMRI examinations for 142. The most common reason for the unavailabilityof MRI scans was parental refusal to grant consent. The percentagesof children for whom data were not available for the differentend points did not differ significantly according to whetherthey underwent surgery with circulatory arrest or low-flow bypass.
Results
Of the 171 infants enrolled in the trial, 168 were alive atone year of age, and 155 (92 percent) returned for evaluation.Seventy-six percent were boys, and 89 percent were white. Ofthe 13 infants who did not return for the one-year evaluation(7 assigned to circulatory arrest and 6 to low-flow bypass),9 did not return because their parents decided not to participate,2 could not be located, and 2 were living in other countries.The children who returned for evaluation did not differ significantlyfrom those who did not with respect to sociodemographic factors,intraoperative perfusion variables, or preoperative and postoperativeneurologic status. However, the children who did not returnhad a longer median period of intubation (3.4 vs. 2.9 days,P = 0.02 by the Wilcoxon test) and a longer median hospitalstay (11 vs. 9 days, P = 0.08 by the Wilcoxon test).
Of the children who returned for evaluation, 120 (77 percent)had an intact ventricular septum, and 35 (23 percent) had aventricular septal defect (Table 1). Treatment groups for eachdiagnosis were similar with respect to preoperative variables,sociodemographic variables, and interim medical history. However,the infants with a diagnosis of ventricular septal defect wereolder at the time of surgery, making it difficult to distinguishthe independent contributions of age at the time of surgeryand diagnosis to the status at one year. The treatment groupsdid not differ in terms of age-adjusted weight or length atone year.
Table 1. Characteristics of Infants with d-Transposition of the Great Arteries, According to Ventricular Septal Status and Treatment Group.
During the period between the neonatal arterial-switch operationand the one-year evaluation, 78 children (51 percent of thosefor whom data were available) underwent cardiac catheterization,and 1 child (who had an intact ventricular septum and was assignedto low-flow bypass) underwent additional cardiac surgery. Atthe time of the one-year evaluation, 11 children (7 percent)were receiving digoxin, and 2 (1 percent) were receiving diuretics.No child had nonfebrile seizures after hospital discharge. Twochildren (1 percent) had febrile seizures; neither had seizuresdetected clinically or by EEG monitoring in the perioperativeperiod.
Developmental Testing
Psychomotor Development Index
The mean (±SD) score on the Psychomotor Development Indexfor the two treatment groups combined was 95.1±15.5.Scores were significantly lower among the children assignedto circulatory arrest (mean difference between the two groups,6.5 points; 95 percent confidence interval, 1.6 to 11.5; P =0.01) (Table 2). Lower scores were also associated with a longerduration of circulatory arrest (P = 0.02) (Figure 1). None ofvarious nonlinear or piecewise linear models of this associationfit the data significantly better than did a linear model. Withadjustment for age at the time of examination, the number ofscale items passed was lower for children assigned to circulatoryarrest (P = 0.003) and was inversely related to the durationof circulatory arrest (P = 0.008). Twenty percent of the children(28 of 142) had a score less than or equal to 80. Lower scoreswere more prevalent among the children assigned to circulatoryarrest (27 percent vs. 12 percent; exact P = 0.02) and thosewith a longer duration of circulatory arrest (P = 0.03).
Figure 1. Score on the Psychomotor Development Index at One Year as a Function of the Duration of Total Circulatory Arrest.
Regression lines are shown for infants with an intact ventricular septum (IVS) and those with a ventricular septal defect (VSD). The P value shown was calculated by linear regression for the effect of the duration of total circulatory arrest on the score on the Psychomotor Development Index, with adjustment for diagnosis.
The effect of the treatment assignment on scores on the PsychomotorDevelopment Index could not be explained by any of the perioperativeor sociodemographic variables measured. In multiple-regressionmodels, scores were positively related to birth weight, butadjustment for this variable did not appreciably alter the treatment-groupeffect. A diagnosis of ventricular septal defect was an independentrisk factor for a lower score (mean difference between the twogroups, 6.6 points; 95 percent confidence interval, 0.7 to 12.6;P = 0.03).
Mental Development Index
The score on the Mental Development Index for the two treatmentgroups combined was 105.1±15.0. Scores tended to be loweramong children assigned to circulatory arrest (mean difference,4.1 points; 95 percent confidence interval, -0.7 to 8.8; P =0.10) (Table 2), although the scores did not decrease significantlywith an increased duration of circulatory arrest (P = 0.33).With adjustment for age at the time of examination, the numberof scale items passed was lower among children assigned to circulatoryarrest (P = 0.04) but was not significantly related to the durationof circulatory arrest (P = 0.16). Of the eight children withscores less than or equal to 80, six were assigned to circulatoryarrest (exact P = 0.27). In multiple-regression models, lowerscores on the Mental Development Index were significantly associatedwith a lower level of maternal education, but adjustment forthis variable did not appreciably alter the treatment-groupeffect. A diagnosis of ventricular septal defect was an independentrisk factor for a lower score (mean difference, 8.6 points;95 percent confidence interval, 2.8 to 14.4; P = 0.004).
Fagan Test of Infant Intelligence
The mean novelty-preference score for the two groups combinedwas 58.8±7.6 percent. Scores were not related to thetreatment assignment (Table 2) or the duration of circulatoryarrest. A diagnosis of ventricular septal defect was associatedwith lower scores (mean difference, 3.6 percent; 95 percentconfidence interval, 0.2 to 7.0; P = 0.04).
Although 21 percent of the children (23 of 107) had test scoresindicating failure (i.e., less than 53 percent), the percentageof such scores did not differ significantly according to thetreatment group (circulatory arrest, 25 percent; low-flow bypass,17 percent) or diagnosis (intact ventricular septum, 19 percent;ventricular septal defect, 29 percent). Inability to completethe test was not associated with the treatment assignment.
Neurologic Examination
Five of the 154 children who underwent neurologic examination(3 percent) had possible abnormalities, and 48 (31 percent)had definite abnormalities, all of which were judged to be mild.Neurologic abnormalities tended to be more common among thechildren assigned to circulatory arrest than among those assignedto low-flow bypass (41 percent vs. 28 percent; exact P = 0.09)(Table 3). Similarly, possible or definite neurologic abnormalitieswere associated with a longer duration of circulatory arrest(P = 0.04) (Figure 2). A low Apgar score at five minutes anda young gestational age were both independent risk factors forneurologic abnormalities, but adjustment for these factors didnot appreciably affect the estimate of the increased risk associatedwith assignment to circulatory arrest. A total of 28 children(18 percent) had hypotonia, 12 (8 percent) had hypertonia, 7(5 percent) had cerebral palsy, 4 (3 percent) had focal abnormalities,and 2 (1 percent) had abnormalities of special senses. The occurrenceof specific abnormalities was not associated with the treatmentassignment or the duration of circulatory arrest.
Figure 2. Estimated Probability of a Possible or Definite Neurologic Abnormality at One Year as a Function of the Duration of Total Circulatory Arrest.
Logistic-regression lines are shown for children with an intact ventricular septum (IVS) and those with a ventricular septal defect (VSD). Point estimates and exact 95 percent confidence intervals for outcome probabilities are plotted for the means of each quartile for the duration of circulatory arrest. The P value was calculated by logistic regression for the effect of the duration of circulatory arrest on the neurologic outcome, with adjustment for diagnosis.
Magnetic Resonance Imaging
Eleven of the 142 children (8 percent) who underwent MRI hadpossible abnormalities, and 22 (15 percent) had definite abnormalities,which were judged to be mild in 86 percent of these children.The abnormalities were classified as focal or multifocal in20 children, diffuse in 16, and developmental or incidentalin 3 (i.e., left temporal lobar hypoplasia, Chiari type I malformation,or a small arachnoid cyst in the left sylvian fissure).
The prevalence of possible or definite abnormalities was notrelated to the treatment assignment, the duration of circulatoryarrest, or an associated diagnosis of ventricular septal defect.Preoperative acidosis, however, was a significant risk factorfor abnormalities detected on MRI scanning.
Relation between Perioperative Seizure Activity and Status at One Year
During the first 48 hours after surgery, the infants assignedto circulatory arrest had a significantly higher risk of seizureactivity, detected by continuous EEG monitoring, than the infantsassigned to low-flow bypass.4 In regression analyses with adjustmentfor the treatment group and the presence or absence of a ventricularseptal defect, the occurrence of EEG seizure activity in theearly postoperative period was associated with a mean reductionof 11.2 points on the Psychomotor Development Index (P = 0.002)and with a significantly higher risk of possible or definiteabnormalities on MRI scanning (odds ratio, 9.4; 95 percent confidenceinterval, 2.7 to 32.3; P<0.001). The children assigned tocirculatory arrest also had an increased risk of clinical seizuresin the early postoperative period.4 Despite the limited statisticalpower of the analysis, the occurrence of clinical seizures wasassociated with an increased risk of possible or definite neurologicabnormalities at one year (P = 0.05).
Discussion
We found that a strategy of support consisting predominantlyof circulatory arrest during open-heart surgery in infants,as compared with a strategy consisting predominantly of low-flowcardiopulmonary bypass, was associated with worse performanceon tests of developmental and neurologic function at the ageof one year. Moreover, longer duration of circulatory arrestwas associated with increased risk of delayed psychomotor developmentand neurologic abnormalities at one year. The magnitude of theeffect was modest, since the difference between the scores onthe Psychomotor Development Index for the two treatment groupswas approximately 0.4 SD. However, trends toward a more favorableoutcome for children assigned to low-flow bypass were evidentfor many of the end points measured. These findings are consistentwith the higher risk of neurologic morbidity in the early postoperativeperiod previously reported for the children randomly assignedto circulatory arrest.4 In addition, seizure activity detectedon continuous EEG monitoring during the early postoperativeperiod and a diagnosis of ventricular septal defect were independentrisk factors for a poor outcome.
The duration of circulatory arrest that is safe (the periodduring which no irreversible central nervous system damage occurs)is unknown. Studies in animals suggest that periods of arrestthat are shorter than 30 minutes at brain temperatures of 15to 20°C do not result in permanent structural or functionaldamage.1,15 In follow-up studies of children who had undergoneopen-heart surgery,3,16,17,18,19,20,21,22,23 developmental impairmentwas associated with periods of arrest that were longer than60 minutes (at brain temperatures of 18 to 20°C) and possiblywith periods as short as 45 minutes. Modifying factors may includethe depth of hypothermia, the nature of the cooling process,cerebral blood flow during cooling and rewarming, and bloodpH values and arterial carbon dioxide tension during cooling.3,24
Although we were unable to determine a threshold for the durationof circulatory arrest below which no increase in risk was evident,the data are consistent with the hypothesis that a period shorterthan 35 minutes (at 18°C) has a minimal adverse effect onscores on the Psychomotor Development Index at one year. Substantialdeficits seemed to be most prevalent among the children withcirculatory-arrest periods longer than 45 minutes. Our abilityto establish a threshold was limited by the modest effect ofthe duration of circulatory arrest and the considerable degreeof scatter in the data.
Although this study was designed to compare treatment strategiesand did not include a normal control group, the scores of patientsin both treatment groups were considerably below average. Themean novelty-preference score was similar to that for otherinfants at risk for impaired cognitive development.9 The meanscores on the Bayley Scales were approximately 0.5 SD (for theMental Development Index) to 1 SD (for the Psychomotor DevelopmentIndex) lower than population norms.25 Apart from the durationof circulatory arrest, these low scores may be associated withpreoperative cyanosis or hemodynamic instability, the generallydeleterious effects of cardiopulmonary bypass on the centralnervous system (e.g., microembolism and hypoperfusion), or theadverse effects of hemodynamic conditions in the postoperativeperiod.
Nearly one quarter of the patients had possible or definiteabnormalities on MRI scans, a finding that is relatively commonafter open-heart surgery in children and adults.26,27 Theseabnormalities included both diffuse global or watershed (border-zone)injuries related to hypoperfusion or to hypoxia or ischemiaand focal or multifocal lesions presumed to be macroembolic.Periventricular leukomalacia, selective neuronal necrosis, focalor multifocal ischemic brain necrosis, and parasagittal cerebrallesions have been reported in infants with congenital heartdisease.28,29,30,31 White-matter injury, reported in infantsafter cardiac surgery,28,29 could account for the observed motordeficits. The topography of both neuronal and white-matter injuryafter heart surgery in infants is consistent with ischemia asan important pathogenetic factor.32
EEG evidence of seizures during the first 48 hours after surgerywas common in the study cohort, and infants with seizures hadworse outcomes at one year of age than infants without postoperativeseizures. Indeed, ictal activity on EEG monitoring in the first48 hours after surgery was one of the strongest predictors ofoutcome, which is consistent with the findings in studies ofneonates with other conditions.33 At a developmental stage similarto that of the human infant at birth, the infant rat brain ishighly vulnerable to postischemic seizures; this epileptic activityis correlated with the degree of neuronal injury and neurologicsequelae.34,35,36 It is not clear whether the occurrence ofseizures reflects an underlying brain injury or contributesindependently to the injury.37
Several limitations inherent in the use of infant developmentaltesting at one year of age warrant comment. Although tests suchas the Bayley Scales have satisfactory concurrent validity,the scores of one-year-old children have limited predictivevalidity.38,39 The relative deficits of the children assignedto circulatory arrest were most prominent in the domain of motorfunction, but assessments at older ages may reveal treatmenteffects in other domains, such as language or visual–motorintegration, that are not easily tested in very young children.40
In summary, at one year of age the developmental and neurologicstatus of children randomly assigned to a strategy consistingpredominantly of total circulatory arrest as a method of supportingvital organs during heart surgery was worse than that of childrenrandomly assigned to a strategy consisting predominantly oflow-flow bypass. Assessments of the children as they approachschool age will clarify whether these findings portend clinicallyimportant differences in academic functioning. In treating individualinfants, cardiovascular surgeons must balance the technicaladvantages of total circulatory arrest with its potential disadvantages.
Supported by grants (HL41786, RR02172, and P30-HD18655) fromthe National Institutes of Health.
We are indebted to the members of the Safety and Data MonitoringCommittee — Julien I.E. Hoffman, M.D. (chairman), JohnW. Kirklin, M.D., Barry M. Lester, Ph.D., Robert J. Levine,M.D., Eli M. Mizrahi, M.D., Joseph G. Reves, M.D., George W.Williams, Ph.D., and Joel I. Verter, Ph.D.; to the perfusionists— David M. Farrell, M.A., C.C.P., Willis G. Gieser, C.C.P.,Robert A. LaPierre, B.S., C.C.P., Robert J. Howe, B.S., C.C.P.,and Bettina Archilla, B.S.; to the electroencephalographers— Lewis Kull, Sheila A. McPeck, Susan M. Hegarty, andWayne A. Cote; to Ludmila Kyn for data-base and statisticalprogramming; to the nursing staff for assistance with adherenceto the protocol; to Donna M. Donati, Donna M. Duva, and Lisa-JeanBuckley for data management; to Kathleen M. O'Brien for projectcoordination; and to Edward Z. Tronick, Ph.D., for the use ofa testing suite in the Child Development Unit, Children's Hospital.
Source Information
From the Departments of Neurology (D.C.B., K.C.K.K., G.L.H., S.L.H., J.E.C., E.J.C.), Cardiovascular Surgery (R.A.J., J.E.M., F.L.H., A.R.C.), Medicine (L.A.R.), Cardiology (G.W., A.Z.W., J.W.N.), Anesthesia (P.R.H.), and Radiology (P.D.B., R.D.S.), Children's Hospital; the Departments of Neurology (D.C.B., K.C.K.K., G.L.H., S.L.H., J.E.C., E.J.C.), Surgery (R.A.J., J.E.M., F.L.H., A.R.C.), Pediatrics (L.A.R., G.W., J.W.N.), and Radiology (P.D.B., R.D.S.), Harvard Medical School; and the Department of Biostatistics, Harvard School of Public Health (D.W., J.H.W.) — all in Boston.
Address reprint requests to Dr. Newburger at the Department of Cardiology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
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