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Ann Thorac Surg 2007;84:2052-2058. doi:10.1016/j.athoracsur.2007.06.099
© 2007 The Society of Thoracic Surgeons
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Original Articles: Cardiovascular

Hyperglycemia After Infant Cardiac Surgery Does Not Adversely Impact Neurodevelopmental Outcome

Jean A. Ballweg, MDa,*, Gil Wernovsky, MDa, Richard F. Ittenbach, PhDb, Judy Bernbaum, MDc, Marsha Gerdes, PhDd, Paul R. Gallagher, MAb, Troy E. Dominguez, MDg, Elaine Zackai, MDe, Robert R. Clancy, MDf, Susan C. Nicolson, MDg, Thomas L. Spray, MDh, J. William Gaynor, MDh

a Division of Pediatric Cardiology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
c Division of General Pediatrics, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
d Division of Psychology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
e Division of Genetics, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
f Division of Neurology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
g Division of Cardiothoracic Anesthesiology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
h Division of Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
b Division of Biostatistics and Data Management Core, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Accepted for publication June 5, 2007.

* Address correspondence to Dr Ballweg, Division of Pediatric Cardiology, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd, Suite 6121, Philadelphia, PA 19104 (Email: ballweg{at}email.chop.edu).

Presented at the Poster Session of the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Hyperglycemia has been associated with worse outcome after traumatic brain injury and cardiac surgery in adults. It is not known whether postoperative hyperglycemia results in worse neurodevelopmental outcome after infant cardiac surgery.

Methods: Secondary analysis of postoperative glucose levels was performed in infants younger than 6 months of age enrolled in a prospective study of genetic polymorphisms and neurodevelopmental outcomes who were undergoing repair of two-ventricle cardiac defects. Neurodevelopmental outcomes at 1 year of age were assessed with the Bayley Scales of Infant Development-II, yielding two indices: Mental Developmental Index and Psychomotor Developmental Index.

Results: Surgical repair was performed in 247 infants with 1 in-hospital and 3 late deaths. Neurodevelopmental evaluation was performed in 188 of 243 (77%) survivors. Glucose levels at cardiac intensive care unit admission and during the first 48 postoperative hours were available for 180 of 188 patients. Mean admission glucose was 328 ± 106 mg/dL; maximum glucose was 340 ± 109 mg/dL. At least one glucose was greater than 200 mg/dL in 160 of 180 patients, and 49 of 180 patients (27%) had a glucose greater than 400 mg/dL. Only 1 patient had a glucose less than 50 mg/dL. Female sex (p = 0.02), but no other patient or operative variable, was associated with higher glucose levels. Mean Mental Developmental Index and Psychomotor Developmental Index were 90.6 ± 14.9 and 81.6 ± 17.2, respectively. Hyperglycemia was not associated with lower Mental Developmental Index and Psychomotor Developmental Index scores for the entire cohort or for neonates alone.

Conclusions: Hyperglycemia is common early after infant cardiac surgery, but is not associated with worse neurodevelopmental outcome at 1 year of age.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
There has been increasing recognition of adverse neurodevelopmental outcomes in some survivors of neonatal and infant cardiac surgery. Many observational and neuroprotective trials have focused on potentially modifiable intraoperative risk factors, such as use of deep hypothermic circulatory arrest (DHCA) versus low-flow cardiopulmonary bypass, blood gas management strategy, degree of hypothermia, and use of hemodilution [1–6]. However, patient-specific risk factors such as presence of a genetic syndrome, lower birth weight, and ethnicity are also important determinants of neurodevelopmental outcome [7]. There is increasing evidence that brain injury may occur preoperatively, perhaps in utero [8]. In addition, events in the early postoperative period such as hypoxemia and hypotension may also be risk factors for a worse outcome [9]. Prolonged hospital length of stay, a marker of postoperative morbidity, is predictive of a worse outcome [5]. Importantly, even when considered together, previously described risk factors (particularly intraoperative factors such as use and duration of DHCA), explain little of the variability in outcome. To improve neurodevelopmental outcomes, it will be important to identify additional, potentially modifiable, factors that may impact on the risk of brain injury.

One potentially modifiable factor that has been identified in critically ill patients and adults undergoing cardiac surgery is hyperglycemia. Hyperglycemia and impaired glucose control have been associated with worsened outcomes after myocardial infarction and acute coronary syndromes [10–14], stroke [15, 16], postoperative wound infections [17], and severe head injury [18]. Insulin protocols and use of a glucose-insulin-potassium solution to ensure tight glucose control after cardiac surgery in adults have been associated with lower mortality, improved hemodynamics, and decreased need for reoperations, as well as less renal failure [19–22]. Less is currently known about the impact of hyperglycemia after neonatal and infant cardiac surgery. In the Boston Circulatory Arrest Study [23], intraoperative hyperglycemia was not predictive of worse neurodevelopmental outcome after the arterial switch operation. However, a recent study in postoperative congenital heart disease surgical patients of varying ages reported that hyperglycemia in the postoperative period was associated with increased early morbidity and mortality [24]. The current study was undertaken to determine whether early postoperative hyperglycemia after cardiac surgery in infants is associated with a worse neurodevelopmental outcome at 1 year of age.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
This study constitutes a secondary analysis of a subgroup of patients enrolled in a prospective trial assessing the effects of polymorphisms of the apolipoprotein E (APOE) gene on neurodevelopmental disabilities [25]. The study was approved by the Institutional Review Board at The Children’s Hospital of Philadelphia. Informed consent was obtained from the parent or legal guardian.

Patient Population
Patients younger than 6 months of age who were undergoing repair of congenital cardiac defects using cardiopulmonary bypass, with or without DHCA, were eligible for the original study. Exclusion criteria at the time of surgical intervention included (1) multiple congenital anomalies, (2) recognizable genetic or phenotypic syndrome other than chromosome 22q11 microdeletions at birth, or (3) language other than English spoken in the home. Patients undergoing more than one operation with cardiopulmonary bypass or more than one episode of DHCA were excluded from the secondary analysis. Secondary analysis involved patients without arch obstruction. Preoperative and intraoperative characteristics of the patients have been previously published and are summarized in Table 1. The strongest predictors of a worse neurodevelopmental outcome at 1 year of age were patient-specific factors including the presence of a genetic syndrome, low birth weight, and the presence of the APOE {varepsilon}2 allele. Patient-specific factors eclipsed the use and duration of DHCA as predictors of worse neurodevelopmental outcomes.


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  		Table 1 Single Covariate Risk Factor Models for MDI and PDI Scores a
 
Five surgeons, with a dedicated team of cardiac anesthesiologists, performed the operations. Alpha-stat blood gas management was used. Methylprednisolone (30 mg/kg) was added to the pump priming solution. Glucose-containing fluids were administered in the perioperative period. Deep hypothermic circulatory arrest was used at the discretion of the surgeon. Modified ultrafiltration was performed in all patients. Postoperatively, patients were managed by a dedicated team of cardiologists and intensivists in the cardiac intensive care unit. Inotropic drugs were used as clinically indicated to support cardiac output in the immediate postoperative period. Insulin was not given to manage any level of hyperglycemia. Neonates were maintained on a 10% dextrose solution and infants were maintained on a 5% dextrose solution until they were able to tolerate enteral feeding. Total fluids were limited to 100 mL/kg per day for the first 24 hours postoperatively and then advanced appropriately. Parental nutrition was not routinely started until after the sampling period.

Glucose Measurements
Blood glucose values included both whole blood bedside glucometer (SureStep Flexx; Lifescan, Milpitas, CA) and chemistry laboratory serum glucose values (Vitros 950; Ortho-Clinical Diagnostics, Rochester, NY). These measurements were obtained as part of the clinical care of the patient and not as a part of a predesigned protocol. Blood glucose values were retrieved from the electronic data warehouse at The Children’s Hospital of Philadelphia. Initial glucose measurement was defined as the first glucose obtained by either measurement instrument after arrival in the cardiac intensive care unit from the operating room. All glucose measurements during the first 48 hours postoperatively were recorded. The minimum and maximum glucose values within the first 48 postoperative hours were identified. Hypoglycemia was defined as a glucose measurement of less than 50 mg/dL. Hyperglycemia was defined as a glucose measurement of greater than 200 mg/dL. The mean glucose value was the average of all available values for a patient during the study period.

Neurodevelopmental Examination
The protocol for the neurodevelopmental examination has been previously described [25]. Briefly, children were evaluated at 12 months of age ±2 weeks, adjusted as necessary for prematurity. Development was assessed by the Bayley Scales of Infant Development-II, which yields scores in two areas: psychomotor and mental development. The Psychomotor Development Index (PDI) assesses control of gross motor function, fine motor skills, use of writing instruments, and imitation of hand movements. The Mental Development Index (MDI) evaluates memory, problem solving, early number concepts, generalization, vocalizations, language, and social skills. Both the PDI and MDI yield a standard score. Population mean scores for PDI and MDI are 100 with a standard deviation of 15. Evaluation also included a medical history, growth measurements, detailed neurologic examination, and evaluation by a genetic dysmorphologist. The ethnicity of the child and the familial socioeconomic status were also documented. Ethnicity was classified as Asian/Pacific, Black, Hispanic, Native American, Other, or White as reported by the parent. Socioeconomic status was assessed by parental report using the Hollingshead scale [26].

Statistical Analysis
Data analysis proceeded in two discrete steps. First, descriptive statistics for all variables in the data set were computed using both parametric and nonparametric measures of central tendency and variability for the group as a whole and for neonates specifically. Second, measures of association were computed among four measures of glucose (initial, minimum, maximum, and mean) and two primary outcomes (MDI score, PDI score). As indicated previously, the first glucose reading was obtained at the time of admission to the cardiac intensive care unit. Minimum and maximum glucose values represented the lowest and highest readings, respectively, during the first 48 hours postoperatively. Mean glucose values represented the average during the first 48 hours postoperatively. Secondary measures of association were also computed among the four glucose readings and the 10 different patient-specific and operative variables of interest. Spearman {rho} correlations were used as the test of choice for all computations described here owing to the continuous nature of the measures and the nonnormative nature of the distributions. Two dichotomous variables, sex and APOE {varepsilon}2, were handled similarly using point-biserial correlations. All analyses were computed using SPSS v14.0 (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Between October 1998 and April 2003, 247 patients enrolled in the primary study met inclusion criteria for the secondary analysis. Hospital mortality was 0.4% (1 of 247 patients), with 3 additional deaths after hospital discharge before 1 year of age. Neurodevelopmental evaluation was performed at 1 year of age in 77% (188 of 243 patients) of the surviving cohort. Glucose data could not be obtained for 8 patients, and was therefore available for 96% of the patients who had undergone neurodevelopmental evaluation. Comparative statistics for the preoperative and intraoperative characteristics for the 188 patients who returned and the 55 patients who did not return for 1-year follow up have been previously published [7].

For the entire cohort, the mean PDI was 81.6 ± 17.2 and the mean MDI was 90.6 ± 14.9. As previously reported, stepwise logistic regression for PDI had identified a model containing lower birth weight, presence of a confirmed or suspected genetic syndrome, the APOE {varepsilon}2 allele, lower nasopharyngeal temperature intraoperatively, and longer postoperative length of stay as significant predictors of a lower PDI score [7]. Similarly, stepwise logistic regression for MDI identified a model containing lower birth weight, presence of a confirmed or suspected genetic syndrome, and the presence of the APOE {varepsilon}2 allele as significant predictors of a lower MDI score [7]. Hyperglycemia was not evaluated in previous analysis.

Mean initial postoperative blood glucose for the entire cohort was 328 ± 106 mg/dL (range, 52 to 622 mg/dL). The mean glucose measurement during the 48-hour period was 185 ± 56 mg/dL. Maximum and minimum glucose measurements for the first 48 postoperative hours were 341 ± 109 mg/dL (range, 108 to 685 mg/dL) and 95 ± 23 mg/dL (range, 49 to 165 mg/dL), respectively. One patient had documented hypoglycemia. Glucose values varied widely but tended to decrease during the study period (Fig 1). There were no statistically significant correlations by nonparametric testing of first, mean, or maximum glucose measurements with baseline or operative characteristics, with the exception of female sex (p = 0.02), which was associated with higher maximum glucose measurements. Neonates constituted 26% (49 of 188 patients) of the entire study cohort. Subgroup analysis of the glucose data at time of surgery yielded findings similar to those of the entire cohort. Mean initial postoperative glucose was 314 ± 101 mg/dL (range, 124 to 562 mg/dL) for the neonates specifically. The mean glucose was 174 ± 50 mg/dL (range, 101 to 406 mg/dL). Neonatal maximum, and minimum glucose measurements for the first 48 postoperative hours were 327 ± 112 mg/dL (range, 136 to 685 mg/dL) and 95 ± 22 mg/dL (range, 49 to 149 mg/dL), respectively.


Figure 1
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  		Fig 1. Forty-eight–hour postoperative blood glucose values. Scatter plot of glucose values during the first 48 postoperative hours for the cohort is shown.

 
There were no statistically significant correlations between initial, mean, minimum, or maximum glucose measurements and PDI or MDI scores. Even when mean and maximum glucose measurements were polychotomized into quintiles, there were no statistically significant associations of higher glucose levels with lower scores on the PDI or MDI (Figs 2, 3). Go Postoperative glucose measurements for 17 patients were less than 200 mg/dL at all measured time intervals. The MDI and PDI scores for this subgroup were not statistically significantly different compared with patients with glucose levels greater than 200 mg/dL (p = 0.27).


Figure 2
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  		Fig 2. Box plot of Mental Developmental Index (MDI; A) and Psychomotor Developmental Index (PDI; B) according to quintile of mean glucose in the first 48 postoperative hours. Solid line within box represents the median value. The upper boundary of the box is the 75th percentile; the lower boundary of the box is the 25th percentile. Vertical lines represent the 10th and 90th percentiles. Open circles are values outside of the 10th and 90th percentiles.

 

Figure 3
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  		Fig 3. Box plot of Mental Developmental Index (MDI; A) and Psychomotor Developmental Index (PDI; B) according to quintile of maximum glucose (Max Glucose Quintiles) in the first 48 postoperative hours. Solid line within box represents the median value. The upper boundary of the box is the 75th percentile; the lower boundary of the box is the 25th percentile. Vertical lines represent the 10th and 90th percentiles. Open circles are values outside of the 10th and 90th percentiles.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
In this analysis of neonates and infants undergoing congenital heart surgery, we found no adverse effect of early postoperative hyperglycemia on neurodevelopmental outcome, as assessed by the Bayley Scales of Infant Development-II, at 1 year of age. Neither higher maximum glucose nor higher mean glucose in the first 48 hours after surgery was predictive of lower scores on the Bayley Scales of Infant Development-II. Our findings are in contrast to previous studies in pediatric patients that have demonstrated an association of hyperglycemia with increased in-hospital mortality and longer lengths of stay [27, 28]. In addition to the presence of hyperglycemia, maximum glucose level and the duration of hyperglycemia in multivariate modeling have been demonstrated to have independent association with mortality in the pediatric intensive care setting [29]. A recent study demonstrated that hyperglycemia was associated with increased early morbidity and mortality in postoperative pediatric cardiac patients [24]. Higher initial glucose levels and higher peak glucose levels as well as a longer duration of hyperglycemia were associated with increased morbidity [24]. In contrast to our data, that study included patients with a wide range of ages and assessed only short-term outcomes.

Possible mechanisms of hyperglycemia in the postoperative period include the physiologic stress response, insulin resistance, a disruption of glucoregulation, and a response to administered steroids, as well as fluid management in the perioperative period. There is evidence that withholding administration of dextrose-containing intravenous fluids to children undergoing cardiac surgery in the perioperative period does not negatively impact immediate neurologic outcome and does not increase the risk of hyperglycemia intraoperatively, but may increase the risk of hypoglycemia [30, 31].

Adult cardiac surgical studies have demonstrated that hyperglycemia in the perioperative period may be deleterious. Ouattara and colleagues [32] demonstrated an increased incidence of cardiovascular, infectious, neurologic, renal, and respiratory in-hospital morbidity after cardiac surgery in diabetic patients. Cognitive deficits have been reported in 50% of adults after coronary artery bypass grafting, and hyperglycemia has been shown to worsen the neurologic outcome [33].

Only one study has investigated the impact of intraoperative hyperglycemia on neurodevelopmental outcomes after infant cardiac surgery [23]. Glucose concentrations were measured at seven perioperative times beginning after the induction of anesthesia to 90 minutes after the end of DHCA or low-flow cardiopulmonary bypass. Lower glucose concentrations at 10 and 90 minutes after separation from cardiopulmonary bypass tended to have a higher probability of electroencephalographic seizure activity; however, there was no correlation between glucose concentrations and an abnormal or possibly abnormal neurologic examination [23]. Categorical glucose evaluation (glucose <150 mg/dL or >150 mg/dL) did not demonstrate any relationship of hypoglycemia or hyperglycemia to short-term neurologic evaluation or midterm neurodevelopmental testing at 1, 4, and 8 years of age [23].

The mechanisms by which blood glucose levels modulate the risk of brain injury after hypoxic ischemia have not been fully elucidated. There is convincing evidence that hyperglycemia worsens outcome after brain injury in adults [18]. The current study and others suggest that hyperglycemia has no adverse effect after hypoxic ischemia of the immature brain, and in some cases may be neuroprotective [34]. Maturational changes in glucose metabolism by the brain may explain some of the divergent findings [35]. In adults, hyperglycemia leads to lactic acid production and subsequent neuronal death secondary to metabolic acidosis. In the immature brain, lactic acid production during hyperglycemia is less and lactic acid clearance may be enhanced, decreasing the severity of the metabolic acidosis [36]. However, the experimental data are not completely consistent.

The most common neuropathologic finding after neonatal cardiac surgery is injury to the periventricular white matter, or periventricular leukomalacia [9]. Periventricular leukomalacia results from hypoxic injury to immature oligodendrocytes. There is evidence that hypoxic injury to developing glial cells can be decreased by elevated glucose levels [37]. Thus, it is likely that different effects of hyperglycemia on brain injury between adults and children are related to maturational differences in glucose metabolism and susceptibility to hypoxic injury.

The current study evaluated both neonates and young infants undergoing cardiac surgery, in contrast to other studies that included a wider age range of patients. As discussed above, for the immature brain, hyperglycemia after hypoxia–ischemia may be protective, rather than deleterious. The findings of our study are consistent with this hypothesis. These findings suggest that tight control of glucose in the early postoperative period after infant cardiac surgery is not indicated. Further study is needed to determine whether glucose supplementation may be neuroprotective. In addition, because of the maturational differences in the response to hyperglycemia, it will be necessary to age stratify future studies.

This study is subject to the limitations of a retrospective analysis. In addition, the patient population is limited to patients with two-ventricle defects, and the findings may not be generalizable to patients with more-complex defects. The glucose values were not obtained at standardized times during the first 48 postoperative hours, and the glucose infusion rate for each patient was not standardized or related to the degree of hyperglycemia. Additionally, this was not a treatment trial, and management of hyperglycemia was not randomized. The effects of inotropic drugs, low cardiac output, or other physiologic stressors were not evaluated in this initial study. In addition, evaluation at 1 year of age may not be predictive of later outcomes. Because of the low mortality rate, death could not be evaluated as an end point.

In conclusion, the current study does not demonstrate an adverse effect of early postoperative hyperglycemia on neurodevelopmental outcome at 1 year of age in infants after surgery for congenital heart disease. Long-term follow-up of neurodevelopmental outcomes are necessary in this population to confirm this finding. In contrast to adult cardiac surgery patients, postoperative hyperglycemia may not affect the neonatal brain in a deleterious fashion. In addition, tight control leading to potential hypoglycemia may be more detrimental to the neonatal brain than transient hyperglycemia.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Supported by a grant from the Fannie E Rippel Foundation, an American Heart Association National Grant-in-Aid (9950480N), a grant from the National Institutes of Health (HL071834), and the Alice Langdon Warner and Daniel M. Tabas Endowed Chairs in Pediatric Cardiothoracic Surgery at The Children’s Hospital of Philadelphia.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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