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Ann Thorac Surg 2006;81:958-966
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Long-Term Neurodevelopmental Outcome and Exercise Capacity After Corrective Surgery for Tetralogy of Fallot or Ventricular Septal Defect in Infancy

Hedwig H. Hövels-Gürich, MD a , * , Kerstin Konrad, PhD b , Daniela Skorzenski a , Claudia Nacken, MD a , Ralf Minkenberg, Dipl Phys d , Bruno J. Messmer, MD c , Marie-Christine Seghaye, MD a

a Department of Pediatric Cardiology, Aachen University of Technology, Aachen, Germany
b Department of Child and Adolescent Psychiatry, Aachen University of Technology, Aachen, Germany
c Department of Thoracic and Cardiovascular Surgery, Aachen University of Technology, Aachen, Germany
d Institute for Medical Research and Information Processing, Aachen, Germany

Accepted for publication September 6, 2005.

* Address correspondence to Dr Hövels-Gürich, Department of Pediatric Cardiology, University Hospital, Aachen University of Technology, Pauwelsstrasse 30, Aachen D-52057, Germany (Email: hhoevels-guerich{at}ukaachen.de).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The purpose of this prospective study was to assess whether neurodevelopmental status and exercise capacity of children 5 to 10 years after corrective surgery for tetralogy of Fallot or ventricular septal defect in infancy was different compared with normal children and influenced by the preoperative condition of hypoxemia or cardiac insufficiency.

METHODS: Forty unselected children, 20 with tetralogy of Fallot and hypoxemia and 20 with ventricular septal defect and cardiac insufficiency, operated on with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass at a mean age of 0.7 ± 0.3 years (mean ± SD), underwent, at mean age 7.4 ± 1.6 years, standardized evaluation of neurologic status, gross motor function, intelligence, academic achievement, language, and exercise capacity. Results were compared between the groups and related to preoperative, perioperative, and postoperative status and management.

RESULTS: Rate of mild neurologic dysfunction was increased compared with normal children, but not different between the groups. Exercise capacity and socioeconomic status were not different compared with normal children and between the groups. Compared with the normal population, motor function, formal intelligence, academic achievement, and expressive and receptive language were significantly reduced (p < 0.01 to p < 0.001) in the whole group and in the subgroups, except for normal intelligence in ventricular septal defect patients. Motor dysfunction was significantly higher in the Fallot group compared with the ventricular septal defect group (p < 0.01) and correlated with neurologic dysfunction, lower intelligence, and reduced expressive language (p < 0.05 each). Reduced New York Heart Association functional class was correlated with lower exercise capacity and longer duration of cardiopulmonary bypass (p < 0.05 each). Reduced socioeconomic status significantly influenced dysfunction in formal intelligence (p < 0.01) and academic achievement (p < 0.05). Preoperative risk factors such as prenatal hypoxia, perinatal asphyxia, and preterm birth, factors of perioperative management such as cardiac arrest, lowest nasopharyngeal temperature, and age at surgery, and postoperative risk factors as postoperative cardiocirculatory insufficiency and duration of mechanical ventilation were not different between the groups and had no influence on outcome. Degree of hypoxemia in Fallot patients and degree of cardiac insufficiency in ventricular septal defect patients did not influence the outcome within the subgroups.

CONCLUSIONS: Children with preoperative hypoxemia in infancy are at higher risk for motor dysfunction than children with cardiac insufficiency. Corrective surgery in infancy for tetralogy of Fallot or ventricular septal defect with combined circulatory arrest and low flow bypass is associated with reduced neurodevelopmental outcome, but not with reduced exercise capacity in childhood. In our experience, the general risk of long-term neurodevelopmental impairment is related to unfavorable effects of the global perioperative management. Socioeconomic status influences cognitive capabilities.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Children after cardiac operations for congenital heart defects with cardiopulmonary bypass with or without hypothermic cardiac arrest are at known risk of later neurodevelopmental impairment in the domains of motor functions, intelligence, academic achievement, and language [1–12]. Reduced exercise capacity has been found associated with increased developmental disorders [13]. However, the impact of the different bypass strategies and their concomitant modalites, the possible contribution of genetic polymorphisms [14], as well as of preoperative and postoperative risk parameters on final developmental status after corrective cardiac surgery in infancy remain to be clarified.

The present prospective study was therefore designed to test the hypothesis that (1) the preoperative condition of hypoxemia in infancy is associated with worse neurodevelopmental outcome in childhood, compared with the condition of preoperative cardiac insufficiency. Furthermore (2), influences of the preoperative, perioperative, and postoperative status and management on neurodevelopmental status and exercise capacity at age 5 to 11 years after corrective surgery in infancy should be evaluated in a uniform cohort of children with tetralogy of Fallot or ventricular septal defect.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Clinical Data
Between 1993 and 1999, 24 consecutive infants with a regular form of tetralogy of Fallot and hypoxemia and 26 consecutive infants with a ventricular septal defect and cardiac insufficiency had undergone primary corrective cardiac surgery in our institution at a mean age of 0.7 years with a standard deviation (SD) of 0.3. There was no early or late mortality. All patients with tetralogy of Fallot had normal chromosomal status (46, XY and XX, respectively), and microdeletion 22q11.2 had been excluded by fluorescence in situ hybridization analysis. There was no familial accumulation with respect to tetralogy of Fallot, and no sign of additional somatic malformation or phenotypic suspicion of syndrome. Patients with ventricular septal defect and Down's syndrome primarily had been excluded from the study.

In 2004, at a mean age of 7.4 years ± 1.6 (SD; range, 5.0 to 11.8), we evaluated 40 (80%) of them. The study group comprised two subgroups of unselected children. Group A consisted of 20 patients with tetralogy of Fallot (83.3% of the operated infants; 55% male; age at surgery, 0.7 ± 0.3 years; age at evaluation, 7.4 ± 1.4). All group A patients had suffered from preoperative cyanosis (arterial oxygen saturation <90%); 11 of them had presented with hypoxic spells, 9 of which had been treated with the ß-adrenergic blocker propranolol and 2 with morphine. Neurologic sequelae were not evident before surgery. Group B consisted of 20 patients with ventricular septal defect (76.9% of the operated infants; 45% male; age at surgery, 0.7 ± 0.2 years; age at evaluation, 7.4 ± 1.9). All group B patients had suffered from clinical signs of heart failure and pulmonary hypertension at cardiac catheterization owing to left-to-right shunt ranging from 50% to 80% and increased pulmonary flow; 18 of them had been treated with furosemide and digoxin. At the time of evaluation, all patients were in a good general and cardiac health status, and none of them received any cardiac-related medication. All patients had anatomically and functionally adequate repair of their defects.

The study was designed as a case series with published controls and prognostic factor analyses. Written informed consent of the parents was obtained.

Questionnaires for the 10 patients who did not participate in the study (4 with tetralogy of Fallot and 6 with ventricular septal defect) were completed by the parents as well as by the treating pediatricians and pediatric cardiologists; participation was determined mainly by the distance of the family's residence from our institution. The children who did not participate were not suggested to be different from the study patients concerning their socioeconomic background, neurodevelopmental outcome, and physical activity.

Surgical Procedure und Cardiopulmonary Bypass
Corrective surgery was performed in our institution by two surgeons following standardized techniques. All patients of group A underwent infundibulectomy; 18 of them had transpulmonary, 6 had subpulmonary patch enlargement. All patients of group B underwent transatrial ventricular septal defect repair.

Conventional general anesthesia and bypass protocol were uniform and described previously [1]. Dexamethasone (3 mg/m2 body surface area) was given before sternotomy.

During CPB, the pH-stat method was used, correcting arterial carbon dioxide tension to the patient's hypothermic temperature to maintain a pH value of 7.40. The aorta was crossclamped after deep hypothermia was reached (minimal nasopharyngeal temperature, 15.3°C ± 1.9°C). Cardiocirculatory arrest was instituted for 53.3 ± 8.4 minutes (Table 1). If necessary, the surgical procedure was continued under low-flow perfusion (25% of the calculated initial perfusion rate). Rewarming was achieved under full-flow conditions. The lungs of the patients were reventilated when core temperature reached 30°C. Neutralization of heparin was achieved with protamine-sulfate in a 1:1 ratio.


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  		Table 1. Preoperative, Perioperative, and Postoperative Course: Risk Factors for Neurodevelopmental Outcome
 
Postoperative Care
Postoperative monitoring included continuous registration of heart rate and rhythm, arterial blood pressure, central venous pressure, and diuresis. Target values for mean blood pressure, central venous pressure, and diuresis during the first 72 hours postoperatively were 50 mm Hg, 5 to 7 mm Hg, and more than 1.5 mL · kg-1 · h-1, respectively. Inotropic support consisted in all cases of dopamine (5 µg · kg-1 · min-1) and, if necessary, of epinephrine (0.05 to 0.2 µg · kg-1 · min-1) or dobutamine (5 to 7.5 µg · kg-1 · min-1) and vasodilatory treatment of sodium nitroprusside (0.5 to 2 µg · kg-1 · min-1). Diuretics (furosemide, single dosage 0.5 to 1 mg/kg) and volume substitution, which consisted of fresh frozen plasma or human albumin 5%, were administered according to the hemodynamic variables.

Risk Factors for Neurodevelopmental Outcome
The patients' data with respect to perioperative management as well as preoperative, perioperative, and postoperative complications were prospectively registered at time of surgery. For the analysis of the influence of cerebral risk factors on later outcome, a list of 15 definite variables was considered (Table 1). Socioeconomic status of the families [15] was not different from that of a normal population within the total group (p = 0.12 versus published controls).

Neurologic Examination
A complete clinical neurologic status was evaluated by an examiner experienced in neuropediatric examinations. Results were classified as normal or impaired. Impairment was categorized as mild (no functional impairment), moderate (functional impairment requiring therapy), or severe (dependence on continued assistance). Disorders were subclassified into seven types of dysfunction (more than one of which possible in one child), as follows: disorders of either head shape and growth or cranial nerves, motor dyspraxia, ataxia, sensory dysfunction, palsy, seizures (clinical or electroencephalographic) during the last 12 months (Table 2) [16–18]. Isolated nonparalytic strabism was not classified as neurologic disorder and was excluded from further analysis in this setting.


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  		Table 2. Neurologic Dysfunction After Corrective Surgery in Infancy
 
Developmental Testing
All assessments were conducted in the whole cohort by the same examiner during the morning hours. The applied tests are normalized for age to have a mean of 100 with SD of 15 (Table 3). Dysfunction was diagnosed when standard scores were below the simple SD (< -1 SD, standard scores < 85). At the time of assessment, all children had normal faculty of hearing as evaluated by tone threshold audiometry.


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  		Table 3. Developmental Outcome After Corrective Surgery in Infancy
 
The Kiphard and Schilling Body Coordination Test [19] was administered to assess standard scores of gross motor function (motor quotient [MQ]).

The Kaufman Assessment Battery for Children (K-ABC) [20] was performed to evaluate overall standard score of general intelligence (intelligence quotient [IQ]). Five children were tested with a speech-free version because of reduced knowledge of the German language. A second test block of the same battery was undertaken to evaluate acquired abilities (learning, academic knowledge). Seven children could not be tested because of reduced knowledge of the German language or lack of cooperation.

Language was assessed evaluating standard scores of expressive (combination of chosen items comprising subtests 4, 12, 14, 15 of the K-ABC) as well as receptive language (combination of chosen items comprising subtests 7, 13, 14, 16 of the K-ABC). Eight patients could not be tested because of reduced knowledge of the German language or lack of cooperation.

Developmental test results in the patients were compared with the published results in an age-matched normal German speaking population on which the tests or their German adaptations are based. The incidence of abnormal results in a normal population is by definition 16% (-1 SD > 14% > -2 SD and 2% < -2 SD).

Evaluation of Exercise Capacity
A formalized questionnaire was completed to evaluate the subjective physical activity as reported by the parents. It comprised seven questions: (1) cardiac related symptoms; (2) physical limitations according to the New York Heart Association (NYHA) functional classification; (3) participation in school or preschool sports; (4) participation in leisure sports; (5) encouragement of the family on participation in sports; (6) satisfaction with the degree of physical activity; and (7) physical activity compared with healthy mates (Table 4).


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  		Table 4. Parents' Questionnaire for Evaluation of Subjective Physical Activity After Corrective Surgery in Infancy
 
To evaluate the objective exercise capacity, treadmill exercise testing was performed using the Bruce walking treadmill protocol to voluntary exhaustion on a Jaeger LE 300 C treadmill (Erich Jaeger, Höchberg, Germany). The standardized protocol according to the original Bruce walking protocol [21] consisted of seven 3-minute stages with increasing velocity (2.7 to 9.6 km/h) and slope (10% to 22%). None of the children had routine in using the treadmill. They were encouraged to push themselves to the limit, and the test was stopped when the children refused to continue the test despite encouragement. Electrocardiography was continuously monitored using leads I to III and V4 to V6 up to at least 10 minutes after end of the test. Heart rate was registered at rest, at the end of each exercise stage, at the end of maximal exercise, and after 2 and 5 minutes of the recovery period. Blood pressure at rest and at the end of maximal exercise was measured on the right arm using a sphygmomanometer (Dinamap 1846 XS; Critikon GmbH, Johnson & Johnson, Norderstedt, Germany) with cuffs of appropriate sizes. Endurance time and electrocardiographic changes with respect to conduction intervals, rhythm, and repolarization abnormalities were analyzed. Results were compared among the groups (Table 6) and with the published results in age- and sex-matched healthy nonathletic children (Table 6) [21, 22].


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  		Table 6. Bruce Treadmill Test Results After Corrective Surgery in Infancy
 
Statistical Analysis
Results were expressed by mean values and standard deviation (m ± SD), or as percentages. For comparison of mean values, t tests were applied; for comparison of frequencies, the {chi}2 test was used. For intergroup comparison of clinical variables, the nonparametric Mann-Whitney U test was administered. The Spearman rank-correlation coefficient was assessed for correlation of independent parameters and the Fisher exact test for the analysis of contingency tables. Alpha-adjustment for repeated measures was done according to Bonferroni- Holm.

One binary and 7 continuous outcome variables were compared with normal values as well as between the groups, and in univariate analyses, related to 7 binary and 8 continuous risk factors for neurodevelopmental outcome (Table 1).

Statistical analysis was performed with the SPSS for Windows software, version 12.0 (SPSS GmbH Software, München, Germany), and with the Statistical Analysis System, version 8.0 (SAS Institute, Cary, North Carolina). All statistical tests were performed at a significance level of 0.05. All p values between 0.05 and 0.09 were considered to have a tendency toward significance. The term "significant" was only used to indicate statistical, not clinical significance.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Neurologic Status
In the total group, 13 children (33.0%) had neurologic abnormalities, all of which were considered mild. Rate of dysfunction tended to be higher in group A versus group B patients (p = 0.09). Rate and type of dysfunctions are summarized in Table 2. Neurologic dysfunction was found associated with lower motor quotient (see below).

Developmental Evaluation
In the total group, gross motor (MQ) dysfunction was found in 50.0% (42.5% below the simple and 7.5% below the double SD) of the patients. Reduced formal intelligence (IQ) was diagnosed in 25.5% (22.5% < -1 SD; 2.5% < -2 SD), and dysfunction in academic knowledge (acquired abilities) in 30.0% (30.0% < -1 SD). Expressive language was found reduced in 34.4% (25.0% < -1 SD; 9.4% < -2 SD) and receptive language in 28.1% (25.0% < -1 SD; 3.1% < -2 SD). In all 5 test domains, rates of dysfunction were significantly higher compared with published normal values (p < 0.01 to p < 0.001) in the whole group as well as in groups A and B, except of normal intelligence in group B patients. Incidence of gross motor dysfunction was higher in group A versus group B patients (p < 0.01), whereas no differences between the groups were found in the other domains of assessment. Detailed results are described in Table 5.


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  		Table 5. Bruce Treadmill Test Endurance Times After Corrective Surgery in Infancy Versus Controls
 
In the total group, motor dysfunction was significantly associated with neurologic dysfunction (p < 0.05). It was correlated with lower intelligence quotient (Spearman 0.35, p < 0.05) and with lower expressive language (Spearman: 0.39, p < 0.05), and tended to have a correlation to reduced acquired abilities (Spearman: 0.32, p < 0.1) and to endurance time in the Bruce walking test (Spearman: 0.29, p < 0.1). Correlations are summarized in Table 7.


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  		Table 7. Correlations Between Neurodevelopmental Outcomes After Corrective Surgery in Infancy
 
Evaluation of Exercise Capacity
The parents' questionnaire for evaluation of subjective physical activity documented overall good parental estimate with respect to all 7 questions of the inventory. No differences could be assessed between groups A and B. Detailed results are shown in Table 4.

All Fallot patients with transpulmonary patch enlargement had mild pulmonary insufficiency and no signs of right ventricular dysfunction as evaluated by transthoracic echocardiography. Patients with subpulmonary patch enlargement had trivial to mild pulmonary insufficiency.

During the Bruce treadmill test to evaluate objective exercise capacity, electrocardiogram at rest and during exercise were normal in all patients. All children remained asymptomatic, did not complain of chest pain, and pushed themselves to the limit of physical activity.

Endurance times were in the normal range in all patients, compared with healthy children [21] with respect to sex and age: between the 75th and 90th percentile in 7 (17.5%), between the 50th and 75th percentile in 15 (37.5%), between the 25th and 50th percentile in 11 (27.5%), and between the 10th and 25th percentile in 7 (17.5%). Endurance times were not different between groups A and B. Details are described in Tables 5 and 6. There was an inverse correlation between endurance time and NYHA classification (Spearman -0.32, p < 0.05; Table 7).

In the whole group, heart rate at rest was 81 ± 17 beats per minute and significantly increased to 189 ± 12 beats per minute at peak exercise. Values were not different compared with healthy children [21] and between groups A and B. Systolic and diastolic blood pressures rose significantly between rest and end of maximal exercise and were not different between groups A and B. Hemodynamic findings are summarized in Table 6.

Influence of Risk Factors on Outcome
Duration of cardiopulmonary bypass was correlated to NYHA functional classification (Spearman: 0.31, p < 0.05; Table 8). Duration of mechanical ventilation tended to correlate inversely to endurance times (Spearman: -0.30, p < 0.1). Socioeconomic status was correlated to standard scores of intelligence and acquired abilities (Spearman: 0.42, p < 0.01 and 0.43, p < 0.05, respectively) and tended to correlate to endurance times (Spearman: 0.29, p < 0.1). In univariate analyses, the additional 12 risk factors (Table 1) were not found significantly related to any outcome parameters (p > 0.1 each).


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  		Table 8. Correlations Between Cerebral Risk Factors and Neurodevelopmental Outcomes After Corrective Surgery in Infancy
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
Our data are based on two homogeneous groups of infants with preoperative hypoxemia caused by tetralogy of Fallot or with preoperative cardiac failure caused by a ventricular septal defect, respectively, in whom preoperative, perioperative, and postoperative care was conducted according to standardized protocols. Follow-up of developmental status and exercise capacity at a mean age of 7.4 years after corrective surgery in infancy were prospectively evaluated in the whole cohort; 80% of these patients were examined by an extensive test battery, the other 20% were considered by questionnaire. Similar percentages of impairment in both assessment procedures suggest the present status of our study group as representative for the outcome of the whole cohort. The outcome data were compared between the group with former hypoxemia and the group with former cardiac insufficiency to test whether the condition of preoperative hypoxemia led to a less favorable neurodevelopmental outcome.

Furthermore, the outcome data were correlated to prospectively assessed preoperative, perioperative and postoperative variables to evaluate whether neurodevelopmental status after corrective surgery in infancy was found reduced compared with published normal children.

Neurodevelopmental Outcome Related to Condition of Preoperative Hypoxemia
The present results confirm our hypothesis that children with a state of chronic preoperative hypoxemia that has been found to be associated with a lower preoperative and perioperative anti-inflammatory cytokine balance and a higher risk of morbitity in the early postoperative period [1] are also at increased risk for worse neurodevelopmental outcome at school age. Our data show that, on the base of nearly identical conditions in the preoperative, perioperative, and postoperative management, motor dysfunction was significantly more prevalent and neurologic impairment due to motor coordination disorders tended to be higher in the Fallot group. This difference was not negatively influenced by a reduced exercise capacity, which was assessed normal in both groups, as it has also been demonstrated in recent studies [23, 24]. With respect to neurodevelopmental impairment in Fallot patients with genetic or phenotypic syndromes [25–27], it must be emphasized that these patients had been excluded from the study.

Neurodevelopmental impairment is well known in children after palliative or corrective surgery for cyanotic heart disease beyond infancy, especially for tetralogy of Fallot [12, 28–30]. Impairment mostly has been related to a combination of preoperative, perioperative, and postoperative damage. Preoperative impairment, however, due to prolonged chronic cyanosis with thromboembolic or septic brain damage, should be markedly reduced in Fallot patients without preoperative complications and operated on during infancy, as evaluted in our study. Our data may evoke the question whether influences of the preoperative and perioperative conditions with elevated circulating levels of proinflammatory cytokines in hypoxemic patients versus patients with heart failure [1, 31–33], perhaps responsible for the enhanced inflammatory response to cardiac surgery seen in those patients, might be also in part responsible for damage to the brain and consecutive unfavorable neurodevelopmental outcome.

Neurodevelopmental Outcome Compared With Published Normal Children and Risk Factors for Impairment
We found, at age 5 to 11 years after corrective cardiac surgery in infancy, marked developmental impairment compared with normal children, as well in patients with preoperative hypoxemia as in those with preoperative heart failure. Although the subjective and objective exercise capacities known as a basic influencing factor for developmental and behavioral outcome in childhood [12] were normal in both groups, compared with healthy children, the increase of neurologic impairment due to a higher incidence of patients with developmental motor coordination disorders, a higher rate of reduced intelligence and academic achievement as well as an increased rate of language dysfunctions are of specific concern. These results are the more remarkable as children after neonatal arterial switch operation for transposition of the great arteries, who had been assessed with an identical test battery at comparable age [2, 3], had a significantly better outcome in all domains of evaluation. The conditions of perioperative management, for example, durations of deep hypothermic cardiac arrest [9–11, 34, 35], and cardiopulmonary bypass [8, 36–39], duration of cooling and temperature at initiation of cardiac arrest, pH- or hemodilution strategies [40–43]—all widely discussed and well known to be potentially responsible for adverse later developmental outcome—had not been different between both patient groups of our present study, compared with the arterial switch cohort. So it may be assumed that the bypass modalities in cardiac surgery are generally associated with a higher risk of unfavorable sequelae for the brain beyond surgical intervention after neonatal age. Especially times of deep hypothermic cardiac arrest beyond 40 minutes [9, 35] have been demonstrated to be potentially bad. In our study, it was not unexpected that specific perioperative risk factors could not be identified to significantly influence neurodevelopmental outcome as the conditions of perioperative management were very uniform, and the total number of patients was limited. Consistent with similar associations observed in former studies [3, 11, 44], socioeconomic status predicted poorer outcome in cognition-related domains of evaluation as intelligence and academic achievement.

In conclusion, chronic preoperative hypoxemia rather than chronic preoperative heart failure is associated with unfavorable neurodevelopmental outcome with respect to motor functions. Primary corrective surgery in infancy for tetralogy of Fallot or ventricular septal defect with combined circulatory arrest and low flow bypass is associated with reduced neurodevelopmental outcome, but not with reduced exercise capacity in childhood. Perioperative management should avoid prolonged durations of cardiac arrest, especially in the condition of surgery beyond neonatal age.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
The study was supported by Grants from "Bundesverband Herzkranke Kinder e.V." and "Herzkrankes Kind Aachen e.V.," Aachen, Germany.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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