| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2001;71:881-888
© 2001 The Society of Thoracic Surgeons
a Department of Pediatric Cardiology, Aachen University of Technology, Aachen, Germany
b Department of Pediatric Neurology, Aachen University of Technology, Aachen, Germany
c Department of Medical Psychology and Sociology, Aachen University of Technology, Aachen, Germany
d Department of Biomedical Statistics, Aachen University of Technology, Aachen, Germany
e Department of Cardiothoracic Surgery, Aachen University of Technology, Aachen, Germany
Accepted for publication June 26, 2000.
Address reprint requests to Dr Hövels-Gürich, Department of Pediatric Cardiology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany
e-mail: hhoevels-guerich{at}post.klinikum.rwth-aachen.de
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. A group of 33 unselected children (3.0 to 4.6 years) operated on as neonates with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass and a control group of 32 age-matched healthy children (3.0 to 4.8 years) underwent evaluation of socioeconomic and clinical neurological status and a standardized test comprising all areas of child development. Results of patients were related to those of the control group, to population norms, and to preoperative, perioperative, and postoperative cerebral risk factors.
Results. Clinical neurological status was normal in 26 patients (78.8%) and reduced in 7 (21.2%). Complete developmental score and the subscores for motor function, visual perception, learning and memory, cognitive function, language, and socioemotional functions were not different compared to population norms. Compared to the patients, the children of the control group scored higher on tests of complete development, cognition, and language, but also on socioeconomic status. Complete developmental score and the scores for motor, cognitive, and language functions were weakly inversely related to the duration of circulatory arrest, but not to the duration of bypass. Cerebral risk factors such as serum levels of the neuron-specific enolase, perinatal acidosis, perinatal asphyxia, peri- and postoperative cardiocirculatory insufficiency, or clinical seizures were not correlated to the test results.
Conclusions. Neonatal arterial switch operation with combined circulatory arrest and low flow bypass is associated with neurological impairment, but not with reduced development as assessed by formal testing of motor, cognitive, language, and behavioral functions. Perioperative serum level of the neuron-specific enolase is not a valid marker for later developmental impairment.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
The purpose of the present prospective study was: (1) to compare neurodevelopmental status of children 3 to 4 years after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA) to published normal values and to an age-matched control group of healthy children; (2) to correlate neurodevelopmental outcome to prospectively evaluated preoperative, perioperative, and postoperative cerebral risk factors including the duration of CPB and DHCA, as well as to blood levels of the biochemical marker enzyme neuron-specific enolase (NSE), indicative of neuronal cell damage.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
This prospective study was a case series with a control group as well as published control data and prognostic factor analyses. The study group comprised 33 unselected children (75% of the survivors). Participation in the study was determined mainly by the distance of the family’s residence from our institution. Written reports from the parents and the treating pediatricians of the nonparticipating 11 patients revealed that 5 (45.5%) of them were normally developed, although one of them suffered from preoperative hydrocephalus e vacuo, and another from postoperative hydrocephalus with shunt after signs of postoperative intracerebral hemorrhage. One of the 11 patients suffered from severe global neurodevelopmental delay of unknown origin without obvious peri- or postoperative complications. The remaining 5 patients were alive and in good health, but no specific data concerning their present developmental status were available.
In the study group, 24 patients (72.8%) had a simple transposition of the great arteries, 4 (12.1%) had, in addition, an unimportant ventricular septal defect, 4 (12.1%) a ventricular septal defect closed during the ASO, and 1 (3%) had a coarctation of the aorta corrected at the age of 1 month. Twenty (60.6%) of the neonates had undergone atrial balloon septostomy, and all 33 had been treated with prostaglandin E1 before operation.
Twenty-six patients (78.8%) were male and 7 (21.2%) were female. Age at the time of neurological and developmental examination ranged from 3.0 to 4.6 years (3.6 ± 0.5 years, mean ± standard deviation [SD]).
Control group
The control group for developmental examination consisted of 32 age-matched healthy children without perinatal complications and with a normal neurodevelopmental status according to their parents’ and treating pediatricians’ written reports.
Twenty-two (68.8%) of them were male and 10 (31.2%) were female. Age at time of examination ranged from 3.0 to 4.8 years (3.8 ± 0.6 years, mean ± SD).
Surgical management and perfusion methods
According to a standardized technique including the Lecompte modification with DHCA and combined low-flow CPB, ASO was performed in our institution by two surgeons. At induction of anesthesia, dexamethasone (3 mg/m2 body surface area) was given to prevent cerebral edema. Cardiopulmonary bypass was instituted to reach an esophageal temperature of 15°C to 16°C. The priming solution had a temperature of 20°C to 22°C. It consisted of a pH-balanced crystalloid solution containing 5% glucose and packed red cells to achieve a hematocrit value of the circulating volume of 0.25. Single dose cardioplegia was applied by means of a 4°C cold Bretschneider solution (30 mL/kg of body weight). Duration of DHCA ranged from 45 to 99 minutes (59.1 ± 8.6 minutes). Patients with ventricular septal defect closed during ASO did not have prolonged periods of DHCA. Total duration of CPB comprised 34 to 134 minutes (50.8 ± 19.4 minutes). Low-flow perfusion rate was 0.7 L/m2 body surface area per minute. 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. At the beginning of CPB, sodium nitroprusside was added for vasodilation.
The age at repair of TGA ranged from 3 to 28 days (7.0 ± 4.7 days). One patient was older than 12 days.
Evaluation of preoperative, perioperative, and postoperative cerebral risk factors for neurodevelopmental outcome
For the analysis of the influence of risk factors on later outcome, a list of prospectively evaluated variables was considered (Table 1). For the determination of NSE, venous blood samples were collected before, immediately after, and 4 and 24 hours after CPB. Blood was taken in tubes containing ethylenediaminetetraacetic acid. The samples were immediately centrifuged for 3 minutes (3,000 rpm) and the plasma was stored at -70°C until analysis. Serum levels of NSE were determined by a commercially available ELISA kit (Pharmacia AB, Uppsala, Sweden) and expressed in micrograms per liter. Values more than 11.4 µg/L were considered elevated in healthy neonates [8]. Serum levels of the lactate dehydrogenase were determined as marker of hemolysis by a commercially available UV-test (optimized standard method by Boehringer Mannheim SA, Mannheim, Germany) and expressed in units per liter.
|
|
|
Developmental testing
All assessments in the patients as well as in the control population were conducted by the same psychologist during the morning hours. The patients were evaluated in our institution, whereas the controls were tested in their kindergarten or at home. Some assessments were not performed in all children because of lack of cooperation, mainly in younger children. Two patients with normal neurological status, borderline aged 3.0 and 3.1 years, were not yet able to meet the requirements of the test methods.
The Vienna Developmental Test [10], a recently developed German-speaking test battery standardized for children 3.0 to 6.0 years of age, comprises all areas of child development and was administered in 31 patients and 32 controls. It consists of a complete developmental score including six subscores consisting of 14 subscales in total (Table 3) to evaluate standard values of motor function, visual perception and visual motor integration, learning and memory, cognitive function, language (speech and comprehension), and socioemotional behavior. A complete developmental score can be evaluated if at least 50% of the subscales belonging to each subscore can be assessed; a subscore, however, can only be evaluated if all the subscales belonging to that subscore can be assessed. The test is normalized for age to have a mean of 100 and a SD of 10. Dysfunction was diagnosed when standard scores were below the simple SD (less than -1 SD, standard scores < 90). Developmental test results of the patient group as well as those of the control group were compared with the published results in an age-matched normal German-speaking population on whom the test is based (standardization sample consisting of 274 children [10]). The incidence of abnormal results in a normal population is by definition 15.5% (-1 SD > 13.5% > -2 SD and 2% < -2 SD). Moreover, developmental test results of the patient group were compared with the test results of the control group.
|
The Fisher’s exact test was used to analyze categoric variables. Wilcoxon rank sum tests and correlation analyses (Pearson’s correlation coefficients, t tests) were used to analyze continuous variables. Multivariate analysis of covariance was carried out to look for clinically relevant influencing factors associated with later developmental impairment. Variables were selected by a general linear models procedure.
Probability values less than 0.05 were considered significant and p values between 0.05 and 0.09 were considered to have a tendency toward significance. Statistical procedures were performed with the statistical analysis system, version 6.12 (SAS Institute Inc, Cary, NC).
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
Developmental outcome
Complete developmental score according to the Vienna Developmental Test was found normal in 87.9% and reduced below the SD in 6.5% of 31 patients as shown in Table 3. Of the subscores, motor score was found normal in 98.7%, visual perception and visual motor integration in 89.5%, learning and memory in 96.7%, cognitive score, language, and socioemotional score in 100% of the tested patients. All standardized developmental test results did not differ statistically from published age-matched normal children [10]. The 4 patients with associated ventricular septal defect closed during ASO did not have worse test results than those without associated defects.
Within the control group of 32 children, cognitive score was found significantly elevated compared to published age-matched normal children [10] (p = 0.00006), whereas complete developmental score and learning and memory were elevated in tendency, and motor score was found reduced in tendency as shown in Table 3.
Comparing the patient group to the control group, complete developmental score, cognitive score, and language were found significantly reduced in patients (p < 0.01).
Evaluation of the socioeconomic status in both the patient as well as the control group showed significant differences between the groups (p = 0.0001), as described in Table 2. There was an adequate distribution of socioeconomic status in the patients, but an inhomogeneous distribution in the controls with a strong tendency toward upper social class, compared to published normal values and to the patient group.
Evaluation and influences of cerebral risk factors on developmental outcome
Biochemical marker neuron-specific enolase
Before operation, the enzyme NSE in serum was found within the normal range as compared to published normals in 22 newborns and elevated above the 90th percentile in 9 infants [8]. At the end of CPB and 4 hours postoperatively, NSE was significantly elevated compared to the values before operation, as shown in Figure 1 and Table 4. Individual peak level (NSEmax) and highest individual gradient (NSEgrad) [NSEmax - NSE before operation (NSEpre)] within 24 hours after operation were not correlated to durations of CPB and DHCA (p > 0.1). In addition, NSEpre, NSEmax, as well as NSEgrad were not significantly correlated to developmental test results (p > 0.1), as demonstrated in Figure 2. The NSE levels were not correlated to lactate dehydrogenase values.
|
|
|
|
Multivariate analysis
In our model, seven independent covariables—perinatal acidosis, cardiocirculatory insufficiency, enhanced cerebral echogenicity in the choroid plexus and ventricular system, late clinical seizures, NSEmax, duration of CPB, and duration of DHCA—were considered. The dependent target variables were complete developmental and motor scores. The model was not able to confirm a significant correlation between the considered cerebral risk factors and the developmental outcome scores (p > 0.1).
|
Comment |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
Clinical neurological status was found reduced in 7 children. The incidence of mostly mild neurological impairment of 21.2% of our patients is higher than in our recent study [5], but similar to the Boston Circulatory Arrest Study in which, at age 4 years, 30% suffered from mostly mild definitive neurological abnormalities [4], or in the Baltimore–Washington Infant Study where 31% of 28 children after neonatal ASO had abnormal neurological findings [11].
Complete developmental status and the subscores for motor function, visual perception and visual motor integration, learning and memory, cognitive function, language, and socioemotional behavior after ASO were not statistically reduced in patients compared to published normal values [10]. In contrast, a recent report of the Boston Study, at age 4 years after ASO demonstrated decreased performance in several domains including intelligence quotient, expressive language, visual motor integration, motor function, and oromotor control, compared to population norms [4]. Compared to the control group, reduced results of our patient group concerning complete developmental score, cognitive score, and language might be related to the better socioeconomic status of the control group.
Factors influencing neurological and developmental outcome after cardiac operation include preoperative illness as well as perioperative and postoperative measures [2, 5, 12–16]. Preoperative morbidity as measured by perinatal acidosis or perinatal asphyxia indicative of hypoxia or acidosis was low in our neonates. Incidence of reduced preoperative clinical status between birth and operation, however, was not sufficiently measurable and impractical for statistical correlations.
Operative support modalities to ensure optimum cerebral as well as cardiac outcome in neonates undergoing ASO include CPB with adequate pump flow rate to maintain sufficient cerebral blood flow [16, 17] and, if deemed necessary, circulatory arrest with cerebral cooling to deep hypothermic temperatures. More acidotic pH-stat strategy during cooling and rewarming before and after cardiac arrest, as always used in our institution, was found associated with lower postoperative morbidity and less adverse neurological effects than the use of the more alkaline 
-stat strategy [18–20].
The risks of CPB comprise the exposure to cerebral embolic injury, cerebral hypoperfusion, and global severe inflammatory response continuing into the postoperative period [15, 16, 21]. Longer duration of CPB did not increase the risk of neurological or developmental impairment in this series, whereas it had marginally increased the risk of intellectual impairment in a recently published study comprising another series of children after neonatal ASO in our institution [5]. In the present study, longer duration of DHCA marginally increased the risk of motor impairment, and, within a range of DHCA times of 45 to 60 minutes considered safe for the brain, weakly increased the risk of impaired complete developmental, cognitive, and language scores as based on formal test methods. Multivariable analysis was not able to confirm a significant correlation between the duration of the bypass modalities and developmental impairment.
The modest sample size results in a reduced statistical power; therefore, all univariable correlations have to be interpreted with caution. The limited number of patients as well as the rare incidence of reduced test results might have masked further significant correlations.
Recent results from the Boston Circulatory Arrest Study [4, 22], comparing the incidence of brain injury after assignment to either predominantly cardiac arrest or predominantly low-flow bypass in children 2.5 or 4 years, respectively, after neonatal ASO for TGA demonstrate markedly decreased performance in motor function and speech in the arrest group compared to the bypass group, whereas results in cognitive function and overall neurological status were similar between the groups. Children assigned to the arrest group having increased risk of clinical or electroencephalographic seizures in the early postoperative period [2], predicting increased risk of neurologic abnormalities at 1 year of age [3], showed, at age 4 years, continuing association between perioperative seizures and neurological and cognitive impairment [4]. Final conclusions about the impact of CPB and DHCA on long-term development after neonatal ASO cannot be drawn, but duration of DHCA should be minimized if ever possible.
The occurrence of postoperative seizures has been assumed to provide an early sign of brain injury with adverse effects on neurological and developmental outcome [23]. In this study, however, we were unable to find a correlation between early (within 24 hours after operation, 3%) or late (later than 24 hours after operation, 12%) clinical seizures on one hand and neurodevelopmental scores at age 3 to 4 years on the other hand. In contrast, the Boston study group demonstrated a significant association between postoperative clinical (6%) as well as electroencephalographic seizures (20%) and reduced motor development and neurologic function at age 1 and 2.5 years [23, 24]. At age 4, perioperative seizures in both groups were associated with lower mean intelligence quotient and increased risk of neurological dysfunction [4].
As the range of conditions and procedures is wide in current support strategies, monitoring the brain aiming to prevent potential neurological complications has become an increasing area of interest [16, 17]. Thus, several biochemical markers, such as the serum creatine phosphokinase isoenzyme BB, lactate, S-100 protein, and NSE have been measured perioperatively [25, 26]. Neuron-specific enolase is a glycolytic enzyme localized in neurons and regarded as brain specific. In high-risk newborns, a significant relationship between increased concentration of NSE in serum and intracerebral hemorrhage has been detected [27], but no significant correlation to further psychomotor development [8]. In our study, NSE serum levels 4 and 24 hours after CPB were found elevated compared to preoperative values, but neither durations of CPB and DHCA nor later developmental status were correlated to individual NSE peak values and highest individual NSE gradients within 24 hours after operation. The fact that we could not find a correlation between serum levels of the lactate dehydrogenase and serum NSE levels renders unlikely severe hemolysis [26] as the main cause of NSE elevation.
In conclusion, the present study points out and confirms that neurological impairment in preschool-aged children after neonatal ASO is more frequent than in a normal population. Developmental status as based on formal testing of motor, cognitive, language, and socioemotional functions, however, has not been found different from a normal population. Better than normal results in our control group are probably related to differences in socioeconomic status between patients and controls. Duration of the support technique DHCA, but not CPB, slightly influenced complete developmental, motor, cognitive, and language dysfunctions. The NSE serum concentrations assumed to be indicative of neuronal cell damage are markedly elevated after cardiac operation in neonatal age, but in our experience, showed no predictive influence on later developmental outcome. The limited sample size of the present study, the rare incidence of abnormal perioperative cerebral risk factors, as well as of reduced neurodevelopmental test results might have masked significant correlations. Continuation of long-term neurodevelopmental assessment of children after neonatal ASO and further evaluation of causes for brain injury after cardiac operation remain mandatory.
|
Acknowledgments |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  G. Wernovsky Improving neurologic and quality-of-life outcomes in children with congenital heart disease: Past, present, and future J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 240 - 242. [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Corno Systemic venous drainage: can we help Newton? Eur. J. Cardiothorac. Surg., June 1, 2007; 31(6): 1044 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pouard, P. Mauriat, F. Ek, A. Haydar, S. Gioanni, N. Laquay, L. Vaccaroni, and P. R. Vouhe Normothermic cardiopulmonary bypass and myocardial cardioplegic protection for neonatal arterial switch operation Eur. J. Cardiothorac. Surg., November 1, 2006; 30(5): 695 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Hashmi, M. Hanif, and K. O'Reilly Electrographic seizure after neonatal and infant cardiac surgery. J. Thorac. Cardiovasc. Surg., August 1, 2006; 132(2): 441 - 441. [Full Text] [PDF]
|
|
|
|
 |
|
 H. H. Hovels-Gurich, K. Konrad, D. Skorzenski, C. Nacken, R. Minkenberg, B. J. Messmer, and M.-C. Seghaye Long-Term Neurodevelopmental Outcome and Exercise Capacity After Corrective Surgery for Tetralogy of Fallot or Ventricular Septal Defect in Infancy Ann. Thorac. Surg., March 1, 2006; 81(3): 958 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G Raja, A. Shauq, and M. Kaarne Outcomes after Arterial Switch Operation for Simple Transposition Asian Cardiovasc Thorac Ann, June 1, 2005; 13(2): 190 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Williams, B. W. McCrindle, D. A. Ashburn, R. A. Jonas, C. Mavroudis, E. H. Blackstone, and the members of the Congenital Heart Surgeon's Soci Outcomes of 829 neonates with complete transposition of the great arteries 12-17 years after repair Eur. J. Cardiothorac. Surg., July 1, 2003; 24(1): 1 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H H Hovels-Gurich, K Konrad, M Wiesner, R Minkenberg, B Herpertz-Dahlmann, B J Messmer, and G von Bernuth Long term behavioural outcome after neonatal arterial switch operation for transposition of the great arteries Arch. Dis. Child., December 1, 2002; 87(6): 506 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Hovels-Gurich, M.-C. Seghaye, R. Schnitker, M. Wiesner, W. Huber, R. Minkenberg, F. Kotlarek, B. J. Messmer, and G. von Bernuth Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation J. Thorac. Cardiovasc. Surg., September 1, 2002; 124(3): 448 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sigler, J. F. Vazquez-Jimenez, R. G. Grabitz, H. H. Hovels-Gurich, B. J. Messmer, G. von Bernuth, and M.-C. Seghaye Time course of cranial ultrasound abnormalities after arterial switch operation in neonates Ann. Thorac. Surg., March 1, 2001; 71(3): 877 - 880. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
