PEDIATRICS Vol. 111 No. 3 March 2003, pp. 592-601
Risk of Seizures in Survivors of Newborn Heart Surgery Using Deep Hypothermic Circulatory Arrest
From the Division of Neurology and the Cardiac Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. To identify pre- and intraoperative variables associated with postoperative acute neurologic events (ANEs), including seizures and coma, in newborn survivors of congenital heart surgery undergoing deep hypothermic circulatory arrest (DHCA), and to risk-stratify this population on the basis of preoperative risk variables for the purpose of designing future neuroprotection trials.
Methods. Survivors of newborn heart surgery who were enrolled in a neuroprotection trial provided a comprehensive database for the evaluation of pre- and intraoperative variables that influence the postoperative occurrence of ANEs (seizures or coma). Patients with hypoplastic heart syndrome were excluded. After characterization of the study population, stepwise logistic regression, combined with clinical judgment, was used to identify variables that were most likely to be associated with an increased risk of seizures in the study sample and that were most likely to be generalized to other populations.
Results. Data were available on 164 nonhypoplastic left heart syndrome survivors who underwent newborn heart surgery using DHCA. ANEs occurred in 31 (18.9%) including "seizures alone" (n = 28), "coma alone" (n = 2) or "seizures and coma" (n = 1). A preoperative risk model was constructed demonstrating that infants with a genetic condition and aortic arch obstruction had a 47.8% risk of ANEs compared with all other remaining infants, who had a 9.9% risk. It was also found that prolonged DHCA time (
60 minutes) can be a significant risk for infants who have a preexisting genetic condition; however, infants who have genetic conditions and do not undergo prolonged DHCA time or have an aortic arch obstruction are not at increased risk of ANEs.
Conclusions. This study provides new information about the occurrence of ANEs after newborn heart surgery. Seizures or coma, which appeared in approximately 19% of all non–hypoplastic left heart syndrome survivors, were not random events but were significantly associated with specific types of congenital heart disease, the presence of genetic conditions, and prolonged DHCA time. The 3 identified variables permitted individual cases to be assigned to low-, intermediate-, or high-risk categories. Because neonatal seizures are a good surrogate marker of long-term neurologic outcome, these models provide useful information to stratify individual patients for risk of seizures in future neuroprotection trials.
Key Words: heart defects • congenital • hypothermia • induced • seizures • risk factors • statistical models
Abbreviations: ANE, acute neurologic event • CHD, congenital heart disease • TGA, transposition of the great arteries • DHCA, deep hypothermic circulatory arrest • CPB, cardiopulmonary bypass • HLHS, hypoplastic left heart syndrome • OR, odds ratio • CI, confidence interval
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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After newborn heart surgery, some infants demonstrate acute neurologic events (ANEs), including seizures or coma, that signify neurologic dysfunction and often brain injury.1,2 Furthermore, seizures may serve as an ideal early "surrogate" endpoint in neuroprotection trials. Although the occurrence of postoperative seizures and coma is well known, there is limited understanding of the pre- and intraoperative risk factors that may influence their occurrence in infants who undergo various types of congenital heart disease (CHD) surgery. The investigation by Newburger et al3 of postoperative seizures after repair of transposition of the great arteries (TGA) identified higher risk infants as those 1) with a ventricular septal defect, 2) undergoing deep hypothermic circulatory arrest (DHCA), compared with low-flow cardiopulmonary bypass (CPB), and 3) having longer duration of DHCA. It is unknown, however, whether the risk factors are consistent across all forms of CHD requiring neonatal surgical repair using DHCA.
The results of the Children’s Hospital of Philadelphia allopurinol neurocardiac protection trial were reported using 2 strata of infants who underwent newborn heart surgery using DHCA: 1) hypoplastic left heart syndrome (HLHS) and 2) all other forms of CHD (non-HLHS).4 Allopurinol was not associated with improved survival in either strata, but in the survivors of the HLHS strata, allopurinol administration was associated with a statistically significant reduction in the occurrence of "seizures" and "cardiac events." In the non-HLHS strata, no allopurinol-related reduction in morbidity was observed. Consequently, the surviving non-HLHS infants in that trial allow for an evaluation of pre- and intraoperative factors that are associated with ANEs. HLHS survivors were excluded from this analysis because, as a group, they were significantly different from the non-HLHS group with respect to their concurrent genetic conditions and their response to the neuroprotection agent. The purpose of this investigation was to identify the pre- and intraoperative factors that are associated with postoperative ANEs in an anatomically diverse population of survivors of newborn heart surgery using DHCA. Once identified, these factors could be used to risk-stratify infants in future newborn heart surgery neuroprotection trials.
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METHODS |
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Study Population
Newborn infants who were admitted to the Cardiac Center of the Children’s Hospital of Philadelphia from July 1992 to September 1997 for evaluation of CHD were screened for enrollment into the allopurinol neurocardiac protection trial, which provided the data used in this investigation. The protection trial was conducted as a single-center, stratified, randomized, blinded, placebo-controlled trial with study drug administered before, during, and after newborn heart surgery using DHCA. Infants were enrolled into the trial and underwent surgery, cardiac anesthesia, and clinical follow-up as previously described.4 The study protocol was approved by the Committee for the Protection of Human Subjects.
Data Collection
A comprehensive database was available, including clinical observations, laboratory values, and imaging examinations. The database was temporally organized into 3 periods: 1) preoperative, 2) intraoperative, and 3) postoperative. The data were further categorized to reflect preoperative sources of data.
Preoperative Data
Preoperative data evaluated are provided in Table 1. Preoperative data included demographic data and maternal/fetal characteristics of gestation, labor, and delivery. Demographic data included mother’s race, age, parity, and socioeconomic status (Hollingshead index5); the presence of maternal health conditions; and family history of epilepsy. Infants’ characteristics included gestational age, birth weight, gender, Apgar scores, and microcephaly (head circumference 
2nd percentile for age). The presence of a "genetic condition" was based on a clear constellation of clinical findings to name a specific genetic syndrome (eg, Goldenhar), an abnormal chromosomal analysis (eg, 22q11 deletion), or an isolated dysmorphic feature (eg, cleft palate).
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The infants’ CHDs were classified into standard anatomic categories on the basis of preoperative echocardiograms. Furthermore, each infant was classified in a simplified scheme by the presence or absence of aortic arch obstruction. Aortic arch obstruction was considered to be present for any hypoplasia or atresia of the ascending, transverse, or descending aorta of sufficient degree to require surgical repair.
Intraoperative Data
Data from the intraoperative period included the duration of surface cooling, lowest recorded nasopharyngeal temperature, duration of CPB cooling, DHCA time, duration of rewarming on CPB, the use of modified ultrafiltration, and the need for additional periods of CPB.
Postoperative ANEs
Clinical endpoints were recorded during the postoperative period in the intensive care unit, up to 6 weeks after surgery. Seizures were identified using established clinical criteria of tonic, clonic, or myoclonic activity of a limb, trunk, or cranial muscle that could not be aborted by restraining the area. All cardiac intensive care unit nurses were specifically trained in the recognition of clinical neonatal seizures by instructional videotapes, with pre- and posttest examinations. Coma was identified from clinical examination by a child neurologist (R.R.C.): comatose infants exhibited no spontaneous or responsive eye opening on repeated observations. Infants who were administered neuromuscular blocking drugs were not assessable for this endpoint.
Statistical Considerations
The study population is characterized using the number of infants available for each variable and presenting means, standard deviations, medians, ranges, and upper and lower quartiles for continuous data and frequencies and proportions (percentages) for categorical data. Means and standard deviations are presented in the text as mean ± standard deviation. The Kruskal-Wallis test was used to test for a significant association between the type of cardiac defect and DHCA time.
Model building was iterative, integrating clinical knowledge and results of statistical analyses to create models that are believed to be widely applicable for risk stratification in the population studied. Because 31 ANEs were available, it was determined a priori that a maximum of 3 independent variables (10:1 ratio) would be allowed in the final risk models. The logistic regression model6 was used for selecting variables and characterizing their strength of associations with ANEs, using the odds ratio (OR) and associated 95% confidence intervals (CIs). Logistic regression models the proportion of ANEs and how these proportions are influenced by independent model variables. Mean values were substituted for candidate independent variables with 5% or fewer missing values.
Categorical variables were formatted using customary dummy variables structure. Dichotomous variables were coded as 0 and 1, with 0 being the reference category. For exploring initial models, ordinal and continuous (interval scaled) scaled data (Table 1) were evaluated as collected or transformed using the natural logarithm for continuous data. Sums of binary variables representing maternal and infant infections; ischemic conditions; and cardiac, metabolic, and neurologic conditions (Table 1) were evaluated for their association with ANEs, as well as the individual binary variables. Stepwise logistic regression (entry P values of 0.25, P value to stay of 0.10) was used to facilitate model selection of variables; however, statistical knowledge gained through separate analyses and clinical knowledge guided the selection process. Continuous variables that were strongly considered for model selection were also evaluated based on quartiles. Strong statistical support and/or a clear clinical rationale for inclusion of variables into the final model were required.
After final selection of the independent variables to model risk of ANEs, exact logistic regression methods were used to derive the final models. Model fit was determined using the Hosmer and Lemeshow7 method and a rejection of the model at P < .05. ORs and associated exact 95% CIs are provided for each independent model variable. Risk stratification trees are displayed to help describe the relationships among the independent variables obtained from the logistic regression analysis and how these variables interrelate to influence ANE risk. All P values and 95% CIs are based on using exact 2-sided methods. Where the exact method was inapplicable, a Monte Carlo method was used to substitute for the exact procedure. SAS8 (SAS Institute, Cary, NC) and StatXact and LogXact (Cytel Software, Cambridge, MA) software was used for all statistical analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Sample Size
A total of 217 non-HLHS infants were enrolled in the neurocardiac protection study from June 1992 to September 1997. However, 30 infants did not undergo surgery or DHCA, and 6 who underwent DHCA <20 minutes were excluded. There were 17 deaths, with 41% (7 of 17) having ANEs. Consequently, 164 (76%) of 217 surviving infants’ data were available for statistical analyses.
Pre- and Intraoperative Population Characteristics
Demographics and selected preoperative characteristics are provided in Table 2. The study population was predominantly full term (38.6 ± 2.2 weeks), appropriate birth weight (3.2 ± 0.7 kg) for gestational age, male (54.3%), and white (79.3%), with age at admission to Children’s Hospital of Philadelphia of 6.3 ± 10.3 days. The Hollingshead scores were 40.5 ± 17.2. Although the 1- and 5-minute Apgar scores were 7.6 ± 1.4 and 8.5 ± 1.0, respectively; 46.3% underwent some form of delivery room resuscitation. Microcephaly occurred in 13 (7.9%). A genetic condition was recognized in 50 (30.5%) infants. The distribution of anatomic CHDs is provided in Table 3.
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Intraoperative characteristics are provided in Table 4. Duration of surface cooling (ambient room temperature, cooling blanket, and ice bags to the head) was 67.9 ± 18 minutes, CPB cooling time was 11.5 ± 6.9 minutes, DHCA time was 50.5 ± 14.1 minutes, and first CPB rewarming time was 26.2 ± 12.2 minutes. Additional periods of CPB and modified ultrafiltration were used in 5.5% and 32.3% of the infants, respectively.
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ANEs
ANEs were almost entirely composed of seizures and occurred in 31 (18.9%) infants, including "seizures alone" in 28, "seizures and coma" in 1, and "coma alone" in 2 infants. The time after heart surgery when the first observed ANE was identified is provided in Table 5. The first and second days after surgery accounted for 64.5% of all events. The proportion of patients with ANEs varied widely among various forms of CHD, ranging from 0% to 53.9% (Table 6).
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Logistic Regression Analysis
With the use of logistic regression, 3 variables were found to be associated with the occurrence of ANEs and could be justified by clinical judgment and existing scientific literature (Table 6). These variables were genetic conditions, cardiac anatomy, and DHCA time. Cardiac anatomy was analyzed by type of defect (P = .001) and classification of anatomy by the presence of aortic arch obstruction (P = .04). Genetic condition was evaluated by type of genetic condition (dysmorphism, specific genetic syndrome, and/or abnormal chromosomes; P = .01), and DHCA was evaluated by prolonged duration (DHCA
60 minutes, the longest quartile of DHCA duration in this study population; P = .07). DHCA time, measured as a continuous variable, was not significantly associated with ANEs. The exact logistic model analysis of DHCA time 60 minutes alone (ie, in the absence of a genetic condition or arch obstruction) yields a P = .13 with OR = 2.9 and 95% CI of 0.5 to 15.4. The presence of aortic arch obstruction or DHCA time 60 minutes was analyzed as a composite variable, which is referred to as "complex" in Table 6 (P = .003). The percentage of genetic condition, percentage of arch obstruction, percentage of DHCA time 60 minutes, and the percentage of "complex" are provided in Table 6.
The preoperative logistic regression analysis, which includes genetic condition and aortic arch obstruction, yields ORs of 2.9 (95% CI: 1.2–7.1; P = .02) and 2.1 (95% CI: 0.9–5.1; P = .10), respectively (Table 7). In the first operative model, DHCA time 60 minutes is added to the preoperative model and results in an OR of 2.1 (95% CI: 0.8–5.4; P = .13). A second operative model was applied using the presence of a genetic condition and the composite variable "complex," resulting in an OR of 3.1 (95% CI: 1.2–7.8; P = .01) and 3.9 (95% CI: 1.5–11.6; P = .004), respectively. The model fit with all 3 models was acceptable, ranging from P = .29 to P = .63.
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Risk Stratification Trees
Risk stratification trees were generated using the results of the logistic regression modeling and clinical judgment. A risk stratification tree using genetic condition, aortic arch obstruction, and prolonged DHCA time is provided in Fig 1. The tree can be used to provide preoperative risk stratification, which is high risk (47.8%; 95% CI: 26.8%–69.4%) for infants with a genetic condition and aortic arch obstruction and low risk (9.9%; 95% CI: 5.5%–16.1%) for all other infants. This tree can provide intraoperative risk stratification by collapsing into the tree provided in Fig 2, which corresponds to logistic regression model 2 (Table 7). Three categories of risk are observed (Fig 2). The risk of ANEs was low (9%; 95% CI: 3.7%–17.6%) when there was no aortic arch obstruction and the DHCA time was <60 minutes, regardless of genetic status. In those without a genetic condition, the risk of ANEs was intermediate (17.2%; 95% CI: 8.6%–29.4%) when there was an aortic arch obstruction or DHCA
60 minutes. The risk of ANEs was highest (50.0%; 95% CI: 30.7%–69.4%) in those who had a genetic condition and aortic arch obstruction or DHCA time 60 minutes. Although these 3 groups show increasing percentage of ANEs, the first 2 groups, although distinguishable on clinical grounds, cannot be separated on statistical grounds (Fig 3). The relationships among postoperative ANEs and cardiac anatomy, prolonged DHCA duration, and genetic conditions can be observed in Figs 4 and 5 (Table 6). These plots indicate a higher association between risk of ANEs and presence of a genetic condition (OR: 2.9; P = .02; Table 7) than between ANEs’ risk and prolonged DHCA duration (OR: 2.1; P = .13; Table 7).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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It has long been recognized that acute postoperative seizures occur after heart surgery at any age. However, in this study, seizures can occur in up to 50% in certain groups of newborn infants after surgery for repair of congenital heart defects. It is generally considered that seizures in the newborn infant not only signify a transient neurologic dysfunction but also often indicate lasting physical injury to the brain.9–12 Consequently, neonatal seizures are a clinical sign that is associated with developing chronic encephalopathy, including developmental delay, mental retardation, cerebral palsy, and epilepsy. The presence of clinical seizures after surgery for repair of transposition of TGA in the Boston circulatory arrest trial was significantly associated with subsequent adverse neurodevelopmental outcome and abnormalities of brain magnetic resonance imaging studies.13 For these reasons, neonatal seizures serve as an important surrogate endpoint in neuroprotection trials of the CHD population.
In the newborn CHD population, factors that contribute to the risk of postoperative neurologic events are incompletely understood. In the Boston circulatory arrest TGA trial,3 infants with coexisting ventricular septal defects, the use of DHCA, and prolonged DHCA duration were associated with increased risk of seizures. However, it is unknown whether these factors apply to the broader CHD population. In this investigation, the overall proportion of infants with ANEs was 19%, with low-, intermediate-, and high-risk groups being identified on the basis of genetic conditions, specific cardiac anatomy, and prolonged DHCA duration.
Genetic Conditions
Higher postoperative mortality has been associated with the presence of genetic conditions,14,15 but its association with an increased risk of seizures has not been previously reported. In the Boston circulatory arrest trial,3 infants were excluded when a genetic condition was present, and, consequently, the role of genetics could not be evaluated in that study. This is an important consideration in the general CHD population because a significant proportion harbor genetic conditions. In our study, 30% (50 of 164) were classified as having some form of a genetic condition, other than a heart defect. Older individuals with genetic conditions such as Down syndrome and 22q11.2 deletion have an inherently lowered seizure threshold. Various forms of chronic epilepsy occur in these individuals far more commonly than in the general population in whom the lifetime prevalence of epilepsy is estimated to be 0.84% to 1.5%. Approximately 7.3% of 344 older children followed at this institution for 22q11.2 deletion have spontaneous recurrent seizures, unprovoked by hypocalcemia, fever, or postoperative status (unpublished data). It is also estimated that 10% to 20% of those with Down syndrome also experience seizures. The observation that acute postoperative seizures occur significantly more often in those with genetic conditions (P = .02; Table 6) is consistent with the hypothesis that genetic-mediated lowering of the seizure threshold is present early on, although the mechanism of that effect is unknown.
Cardiac Anatomy
The type of CHD defect was found to be significantly associated with an increased risk of ANEs when evaluated by individual defects (P = .001; Table 6) or by a simplified classification on the basis of the presence or absence of aortic arch obstruction (P = .04; Table 6). The results presented suggest that the risk of ANEs varies considerably over the various types of cardiac defects (Table 6). Aortic arch obstruction was clearly associated with an increased risk of ANEs; however, this classification is oversimplified because it assumes that all other differences of congenital heart defect anatomies are unimportant.
Duration of DHCA
DHCA time 60 minutes resulted in a higher risk of ANEs (29%) compared with briefer durations (15%). However, the relationship between prolonged DHCA duration and ANEs must be interpreted with caution. Figure 4 shows a plot of ANEs’ percentages versus percentages of prolonged DHCA times (60 minutes) for various types of CHDs. Clearly, there are anatomic groups (eg, TGA/intact ventricular septum, TGA/ventricular septal defect) with low (10%) ANE risks despite longer DHCA times and others (eg, ventricular septal defect/coarctation, heterotaxy) with higher ANE risk but shorter DHCA times.
Relationships Among Risk Factors
First, there seems to be complex relationships among the risk variables: prolonged DHCA time, genetic conditions, and aortic arch obstruction. In those without a genetic condition, prolonged DHCA produced only an intermediate ANE risk (19%; Fig 1), whereas those with a genetic condition and prolonged DHCA times had a substantially higher risk (50%; Fig 1). Second, there is a likely relation between cardiac anatomy and prolonged DHCA time. With the use of a Kruskal-Wallis test (analysis of variance using ranks), the association between the different types of cardiac defects and DHCA time was significant (P < .001). Prolonged DHCA time occurred in 35% (22 of 63) of those with aortic arch obstruction but in only 23% (23 of 101) of those without aortic arch obstruction (Fisher exact P = .11; Fig 1). Finally, there may be increased risk of ANEs by combining genetic conditions and aortic arch obstruction (Fig 1). ANEs occurred in 47.8% (11 of 23) of those with both a genetic condition and aortic arch obstruction compared with 14.1% (20 of 141; P = .001) of all others.
Limitations
There are several important limitations to the results reported here. The seizures were identified on clinical grounds, which are subject to errors of over- and underdiagnosis. However, all nurse observers were specifically trained in clinical seizure recognition. No systematic bias should exist in their ability to recognize clinical seizures among the various forms of CHDs. The database for performing the analysis was obtained from a randomized pharmacological protection trial using selected patients, as previously described.4 Because ANEs before surgery were an exclusion criteria, the results do not apply to these infants. Although the results seem internally consistent, the risk-of-seizures models are exploratory and require validation on an independent contemporary population. At the Children’s Hospital of Philadelphia, we now conduct 48-hour continuous video-electroencephalogram monitoring for electrographic seizures in selected newborn infants after heart surgery to characterize the present seizure rate. This risk model may reflect the results at a single institution and the skills of a relatively small group of cardiac surgeons and anesthesiologists. Nevertheless, these analyses suggest that several important variables should be used to perform preoperative risk stratification in randomized CHD surgery neuroprotection trials and that the evaluation of the consistency of the results should be verified on the basis of prolonged DHCA time. Routine formal genetics evaluation of this population might be considered because dysmorphism may be unappreciated by casual inspection and the presence of a genetic condition is associated with both increased risk of mortality and postoperative ANEs. The occurrence of postoperative ANEs will likely continue to serve as an important early surrogate endpoint of newborn neurologic status in future neuroprotection trials. The design of such trials is exceedingly complex and must be controlled and carefully analyzed to allow clinically beneficial interventions to be identified.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This study provides important new information about risk factors associated with postoperative seizures, an ideal surrogate marker for breach of neurologic integrity. The overall occurrence of ANEs was 19% in this diverse population of newborn heart surgery survivors. However, low-, intermediate-, and high-risk groups can be recognized on the basis of the 3 risk variables identified: cardiac anatomy, genetic conditions, and prolonged DHCA time. The design of future neuroprotection studies in this population might concentrate on those infants with the highest anticipated occurrence of ANEs, stratified by the specific type of congenital heart defects and the presence of genetic conditions.
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ACKNOWLEDGMENTS |
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This study was performed under contract with the National Institute of Neurologic Disorders and Stroke, National Institutes of Health, NS-N01-2315. General Clinical Research Center nursing support was provided by NIH MO1-RR00240.
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FOOTNOTES |
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Received for publication Jan 18, 2002; Accepted Jul 23, 2002.
Reprint requests to (R.C.) Division of Neurology, Children’s Hospital of Philadelphia, 324 South 34th St, Philadelphia, PA 19104. E-mail: clancy{at}email.chop.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
- Ferry P. Neurologic sequelae of open-heart surgery in children: an irritating question.
Am J Dis Child.1990; 144
:369
–373
[Abstract/Free Full Text] - Miller G, Eggli K, Contant C, Baylen B, Myers J. Postoperative neurologic complications after open heart surgery on young infants.
Arch Pediatr Adolesc Med.1995; 149
:764
–768
[Abstract/Free Full Text] - Newburger J, Jonas R, Wernovsky G. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery.
N Engl J Med.1993; 329
:1057
–1064
[Abstract/Free Full Text] - Clancy RR, McGaurn SA, Goin JE, et al. Allopurinol neuro-cardiac protection trial in infants undergoing heart surgery utilizing deep hypothermic circulatory arrest.
Pediatrics.2001; 107
:61
–70
[Abstract/Free Full Text] - Hollingshead A. Four Factor Index of Social Status. New Haven, CT: Department of Sociology, Yale University; 1975
- Hosmer D, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley; 1989
- Hosmer D, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley; 1989:135–173
- SAS II. SAS/STAT Software: Changes and Enhancements Through Release 6.12. Cary, NC: SAS Institute; 1997:461
- Mizrahi E, Clancy R, Dunn J, et al. Neurologic impairment, developmental delay and post-natal seizures two-years after video-EEG documented seizures in near-term and full-term neonates: report of the Clinical Research Centers for Neonatal Seizures. Epilepsia.2001; 42(suppl 7) :102 –103
- Mizrahi E, Clancy R. Neonatal seizures: early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev.2000; 6 :229 –241[CrossRef][Web of Science][Medline]
- Nelson K, Broman S. Perinatal risk factors in children with serious motor and mental handicaps. Ann Neurol.1977; 2 :371 –377[CrossRef][Web of Science][Medline]
- Ellenberg J, Nelson K. Cluster of perinatal events identifying infants at high risk for death or disability. J Pediatr.1988; 113 :546 –552[CrossRef][Web of Science][Medline]
- Rappaport LA, Wypij D, Bellinger DC, et al. Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Boston Circulatory Arrest Study Group.
Circulation.1998; 97
:773
–779
[Abstract/Free Full Text] - Bove E. Current status of staged reconstruction for hypoplastic left heart syndrome. Pediatr Cardiol.1998; 19 :308 –315[CrossRef][Web of Science][Medline]
- Clancy R, McGaurn S, Wernovsky G, et al. Preoperative risk-of-death prediction model in heart surgery with deep hypothermic circulatory arrest in the neonate.
J Thoracic Cardiovascular Surgery.2000; 119
:347
–357
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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