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Caring for the Critically Ill Patient | ONLINE FIRST

Neurocognitive Development of Children 4 Years After Critical Illness and Treatment With Tight Glucose Control:  A Randomized Controlled Trial FREE

Dieter Mesotten, MD, PhD; Marijke Gielen, MD; Caroline Sterken, MPsych; Kirsten Claessens, MPsych; Greet Hermans, MD, PhD; Dirk Vlasselaers, MD, PhD; Jurgen Lemiere, MPsych, PhD; Lieven Lagae, MD, PhD; Marc Gewillig, MD, PhD; Benedicte Eyskens, MD, PhD; Ilse Vanhorebeek, MEng, PhD; Pieter J. Wouters, MSc; Greet Van den Berghe, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Intensive Care Medicine (Drs Mesotten, Gielen, Hermans, Vlasselaers, Vanhorebeek, and Van den Berghe and Mss Sterken and Claessens and Mr Wouters), Child and Adolescent Psychiatry (Dr Lemiere), Pediatric Neurology (Dr Lagae), and Pediatric and Congenital Cardiology (Drs Gewillig and Eyskens), Catholic University of Leuven, Leuven, Belgium.


Caring for the Critically Ill Patient Section Editor: Derek C. Angus, MD, MPH, Contributing Editor, JAMA (angusdc@upmc.edu).

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JAMA. 2012;308(16):1641-1650. doi:10.1001/jama.2012.12424.
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Context A large randomized controlled trial revealed that tight glucose control (TGC) to age-adjusted normoglycemia (50-80 mg/dL at age <1 year and 70-100 mg/dL at age 1-16 years) reduced intensive care morbidity and mortality compared with usual care (UC), but increased hypoglycemia (≤40 mg/dL) (25% vs 1%).

Objective As both hyperglycemia and hypoglycemia may adversely affect the developing brain, long-term follow-up was required to exclude harm and validate short-term benefits of TGC.

Design, Setting, and Patients A prospective, randomized controlled trial of 700 patients aged 16 years or younger who were admitted to the pediatric intensive care unit (ICU) of the University Hospitals in Leuven, Belgium, between October 2004 and December 2007. Follow-up was scheduled after 3 years with infants assessed at 4 years old between August 2008 and January 2012. Assessment was performed blinded for treatment allocation, in-hospital (83%) or at home/school (17%). For comparison, 216 healthy siblings and unrelated children were tested.

Main Outcome Measures Intelligence (full-scale intelligence quotient [IQ]), as assessed with age-adjusted tests (Wechsler IQ scales). Further neurodevelopmental testing encompassed tests for visual-motor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration); attention, motor coordination, and executive functions (Amsterdam Neuropsychological Tasks); memory (Children's Memory Scale); and behavior (Child Behavior Checklist).

Results Sixteen percent of patients declined participation or could not be reached (n = 113), resulting in 569 patients being alive and testable at follow-up. At a median (interquartile range [IQR]) of 3.9 (3.8-4.1) years after randomization, TGC in the ICU did not affect full-scale IQ score (median [IQR], 88.0 [74.0-100.0] vs 88.5 [74.3-99.0] for UC; P = .73) and had not increased incidence of poor outcomes (death or severe disability precluding neurocognitive testing: 19% [68/349] vs 18% [63/351] with UC; risk-adjusted odds ratio, 0.93; 95% CI, 0.60-1.46; P = .72). Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Tight glucose control improved motor coordination (9% [95% CI, 0%-18%] to 20% [95% CI, 5%-35%] better, all P ≤ .03) and cognitive flexibility (19% [95% CI, 5%-33%] better, P = .02). Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome.

Conclusion At follow-up, children who had been treated with TGC during an ICU admission did not have a worse measure of intelligence than those who had received UC.

Trial Registration clinicaltrials.gov Identifier NCT00214916.

Figures in this Article

In critically ill patients, adults as well as children, hyperglycemia is associated with adverse outcome.19 In 2009, a randomized controlled trial (RCT) of 700 patients, performed in a tertiary referral pediatric intensive care unit (ICU), revealed that tight glucose control (TGC) with insulin infusion targeting age-adjusted normoglycemia (50-80 mg/dL for infants and 70-100 mg/dL for children) prevented serious ICU morbidity compared with the usual care (UC), which tolerated hyperglycemia up to 215 mg/dL.10 Specifically, the number of patients with new infections was reduced with TGC, with less inflammation, less myocardial damage, shorter duration of hemodynamic support, and a shorter stay in the ICU (ICU mortality was also reduced by an absolute 3%).

However, because the targets for blood glucose, the normal fasting levels for age,11 were much lower in these young children than in adults, the incidence of hypoglycemia of 40 mg/dL or lower increased from 1% with UC to 25% with TGC. The hypoglycemia episodes were not detectably symptomatic and always short-lasting, because they were quickly diagnosed with accurate tools and treated carefully in the setting of the study protocol.10 Symptomatic hypoglycemia in young children has been associated with variable brain damage comprising diffuse white matter injury, hemorrhage and infarction, basal ganglia/thalamic abnormalities, and commonly cortical lesions.12 However, hyperglycemia may also deleteriously affect brain integrity and cognition.1315 A recent study16 on brain specimen of human patients and experimental animals showed that hyperglycemia during critical illness causes brain inflammation, impaired astrocyte function, and neuronal damage in hippocampus and frontal cortex. Therefore, the use of TGC in young patients in the ICU may have both beneficial and deleterious effects on various parts of the developing brain, with potentially long-term consequences for neurocognitive development.

To exclude harm and hereby validate the observed short-term ICU benefits of TGC in critically ill infants and children, a longer-term follow-up evaluation, particularly a broad and indepth assessment of neurocognitive development, was required. We herein report the results of this preplanned long-term follow-up study of the 700 patients originally included in the University Hospitals, Leuven, Belgium, pediatric TGC trial.10

Patients and Healthy Controls

Between October 2004 and December 2007, 700 patients aged 16 years or younger admitted to the pediatric ICU of the University Hospitals in Leuven, Belgium, had been enrolled in a prospective, randomized controlled study on TGC.10 For the full study protocol, we refer to the eProtocol and the report of the original acute outcome study.10 The study protocol and consent forms were approved by the institutional ethical review board (ML2586).

In brief, on admission, patients fulfilling inclusion criteria were randomly assigned to either TGC or UC, after written informed consent from the next-of-kin. Throughout the ICU stay, in the TGC group (n = 349), insulin infusions targeting blood glucose concentrations of 50 to 80 mg/dL in infants (aged <1 year) and concentrations of 70 to 100 mg/dL in children (aged 1-16 years) were initiated. In the UC group (n = 351), insulin infusion was only initiated when blood glucose exceeded 215 mg/dL twice and stopped when blood glucose concentration decreased below 180 mg/dL. Whole blood glucose was systematically measured in arterial blood at 1-hour to 4-hour intervals with an ABL700 analyzer (Radiometer Medical A/S). To convert blood glucose to mmol/L, multiply by 0.0555.

Follow-up of all patients included in the initial trial was scheduled 3 years after randomization. Patients who were infants at study inclusion were evaluated when they reached the age of 4 years so that intelligence could be uniformly quantified across the age range of the study population. Initial screening for survival status was performed via hospital notes or via contact with the general practitioner or referring pediatrician. When parents could be reached by telephone, they were invited to return to the University Hospitals, Leuven, Belgium, to have their child evaluated by a pediatrician and a psychologist. In case the parents refused to come to University Hospitals, Leuven, Belgium, it was proposed that the pediatrician and the psychologist would examine the child at his/her home or school.

To weigh any eventual difference between the TGC and UC groups against a healthy control population, patients' siblings were invited to participate in the neurocognitive evaluation. In addition, age-matched unrelated healthy children were asked to participate via school recruitment and mouth-by-mouth advertising all over Flanders, during the period required to recruit all patients. Parents of participating children, the few children who had reached 18 years at the time of follow-up, or both provided written informed consent.

The patients who participated in the RCT are further referred to as post-ICU patients to distinguish from healthy control children referred to as controls.

Death and severe disability precluding neurocognitive assessment at follow-up were a priori defined as poor outcomes.

Clinical Neurological Examination

The clinical neurological evaluation was performed by 1 pediatrician (M. Gielen) who had not been involved in the treatment of the patients in the ICU and was strictly blinded for randomization to either TGC or UC group. First, head circumference, body weight, and height were measured. Then, to exclude major neurological abnormalities, a classical neurological examination was performed. The result of the examination was scored normal or abnormal for 8 neurological domains17,18: (1) interaction/language skills, (2) gross motor function, (3) involuntary movements, (4) reflexes, (5) coordination and balance, (6) fine motor function, (7) cranial nerves, and (8) special senses (sensory, visual, and auditory function) (eMethods 1). An abnormal result for each of these domains was given 1 point and the sum of these domains gave the total score for neurological abnormalities.

Neurocognitive Testing

All participants were tested by 2 experienced pediatric psychologists (C.S. and K.C.), also strictly blinded for randomization to either TGC or UC group. After an extensive time of working together to guarantee similarity in judging the test results, the psychologists worked independently.

We aimed at a broad evaluation of neurocognitive functions, as previously performed for patients with type 1 diabetes.19 The neuropsychological test battery therefore comprised tests measuring general intellectual functioning, visual-motor integration, attention, motor coordination, inhibitory control and cognitive flexibility, verbal and visual-spatial learning and memory, and questionnaires on behavior. General intelligence was assessed with the Wechsler Intelligence Quotient (IQ) scales adapted for the Dutch language. Wechsler Preschool and Primary Scale of Intelligence-Revised20 was used for children aged 4 years to younger than 6 years, Wechsler Intelligence Scale for Children-3rd Edition21 was used for children aged 6 years to younger than 17 years, and Wechsler Adult Intelligence Scale-3rd Edition22 was used for children aged 17 years or older. Total IQ, verbal IQ, and performance IQ were scored. Visual-motor integration (total standard score) was assessed with the Beery-Buktenica Developmental Test of Visual-Motor Integration, 5th Edition (all ages).23

Attention, motor coordination, and executive functions were analyzed by computerized tasks of the Amsterdam Neuropsychological Tasks (ANT) system.24,25 The main advantage of the ANT, compared with paper-and-pencil tasks, is that the measurement of reaction times in combination with accuracy (error rate) contributes to the sensitivity to detect problems in these neurocognitive domains.26 We a priori selected the 3 ANT tasks that could be performed by all children within the wide age range of our study population.24,25,27,28 Baseline Speed assesses alertness by measuring simple reaction time to 32 visual stimuli (expressed in milliseconds). Mean reaction time and SD of the reaction time were obtained for the nondominant and dominant hands. The Tapping Task measures motor coordination. The number of taps in 10 seconds was counted for the nondominant hand, dominant hand, bimanual alternating, and bimanual synchronous. The Response Organization Objects test measures inhibitory control and cognitive flexibility by calculating the differences in reaction time and the differences in number of errors between tests of increasing demand.28,29

Out of the Children's Memory Scale (CMS) for children aged between 5 years and younger than 17 years, 4 tasks were selected to measure specific verbal-auditory memory and nonverbal, visual-spatial memory functions.30 The CMS numbers test measures verbal memory span (repeating numbers forward) and verbal working memory (repeating numbers backward). Standard scores for verbal memory span and working memory were analyzed. For CMS pictures, word pairs, and dots tests, with different age versions, proportional scores were analyzed (proportion of correct responses with proportional scores ranging from 0 to 1 [higher scores reflect better performance]). The CMS pictures test assesses visual-spatial memory span (proportion correctly recalled picture locations), and the CMS word pairs and dots tests measure verbal-auditory and nonverbal, visual-spatial learning (proportion correctly completed word pairs or correctly recalled dot locations during 3 learning trials), immediate memory (proportion correctly recalled word pairs or correctly recalled dot locations), delayed memory (proportion correctly recalled word pairs or correctly recalled dot locations after delay of 25-35 minutes), and recognition (proportion correctly recognized word pairs after delay of 25-35 minutes).

The Child Behavior Checklist (CBCL for 1.5-5 years or CBCL for 6-18 years) was filled out by the parents or the child's legal guardian to assess behavioral problems.31,32 For our study, the CBCL scores for internalizing, externalizing, and total problems were analyzed.

All these tests have been extensively used to quantify neurocognitive development in various pediatric populations.2729,3336

Statistical Analysis

The primary study goal was to analyze whether TGC caused harm to neurocognitive development, with intelligence (full-scale IQ) as the primary end point, the null hypothesis being no difference between the TGC and UC groups. A mean loss of 4 IQ points in the TGC group was considered to be the minimal effect size (exceeding the SE of the IQ tests), which is assumed to be functionally relevant.3740 The sample size of this study (n = 700) was determined for the primary ICU outcomes.10 The a priori calculated statistical power to detect a loss of 4 IQ points with TGC was 82% taking into account incomplete follow-up.

Poor outcomes (death or severe disability) are reported as numbers and percentages. Significance of differences was analyzed by χ2 testing for proportions followed by multivariable logistic regression analysis correcting for baseline risk factors (race, geographic and linguistic origin, sex, age group at randomization, history of diabetes mellitus, malignancy, a prerandomization syndrome or illness a priori defined as affecting neurocognitive development [further referred to as syndrome] as well as the diagnostic group, severity of illness, and blood glucose level on ICU admission).

For the children who were tested for neurocognitive function, results are presented as median (interquartile range [IQR]). Initial significance testing was performed with nonparametrical testing (Wilcoxon rank sum test) for continuous or ordinal variables (JMP version 9.0.0 [SAS Institute]). To exclude the possibility that incomplete follow-up induced bias, multiple data imputation using baseline factors was performed.41 Imputation was performed with IBM SPSS Statistics 19 (SPSS Inc). Data from 10 imputed data sets were subsequently pooled to obtain an intention-to-treat analysis estimate (eMethods 2). Ninety-five percent CIs for the difference of the medians were calculated with the method proposed by Bonett and Price.42 To further exclude any possible bias evoked by the poor outcomes (death or disability), a score inferior to the worst of the tested values was arbitrarily given to these patients followed by multivariable regression analysis.

To assess whether hypoglycemia during intensive care had affected neurocognitive development, patients who had experienced hypoglycemia in the TGC group were compared with patients from the UC group matched by propensity scores for baseline characteristics. Propensity score matching was performed with IBM SPSS Statistics 19 (SPSS Inc) and R statistical software version R2.10.1 (R Foundation for Statistical Computing).43,44 One-to-one nearest neighbor matching was performed by using a caliper of 0.2 (eMethods 3). In addition, in the total population and using multivariable linear regression analysis, the independent association of hypoglycemia with the studied neurocognitive outcomes was assessed, correcting for all baseline risk factors and for randomization to either TGC or UC group.

Two-sided P ≤.05 was considered statistically significant. No corrections were performed for multiple comparisons.

Follow-up was performed between August 2008 and January 2012 at a median (IQR) of 3.9 (3.8-4.1) years after inclusion in the RCT.

Neurocognitive Assessment

Of the total population, 569 patients were alive and testable at follow-up. Twenty-seven children could not be reached and 86 children declined participation (16% of the total population, no difference between TGC and UC groups; P = .42) (Figure). Demographics of tested patients were comparable except for slight imbalance in race, origin, language, and the presence of a prerandomization syndrome (syndrome or illness that is known to affect neurocognitive development) (Table 1). These imbalances were not evoked by biased recruitment to follow-up, because similar small differences were present in the total study population (N = 700) (Table 1). The neurocognitive testing was performed at a median (IQR) age of 5.2 (4.2-8.3) years. Eighty-three percent of the patients were tested in hospital (82.6% in TGC group vs 82.8% in UC group, P = .96).

Place holder to copy figure label and caption
Figure. Flow Diagram of Study Participants
Graphic Jump Location

DNR indicates do not resuscitate; ICU, intensive care unit. aThe 19 medical disorders that were considered unsuitable by the treating physician consisted of 2 patients dependent on home ventilation, 6 patients with metabolic disorders, 2 patients for whom it was the personal opinion of the treating physician that it would be inappropriate to participate in a study in view of poor prognosis (although the patients formally did not have a DNR code), and 9 patients who had already been treated with intensive insulin therapy elsewhere before assessment for participation.bCauses of death are shown in eTable 3. cMore information on the diagnoses of the severely disabled patients who could not be tested is shown in eTable 4.

Table Graphic Jump LocationTable 1. Demographics and Blood Glucose Control in the Total ICU Population, Tested Post-ICU Population, and Healthy Controlsa

The scores given by the 2 pediatric psychologists were comparable within each study group and scores did not change over the time. The subgroup of patients who were infants at the time of randomization behaved similarly to the older children for all applicable tests (P for all interaction ≥ .20).

Intelligence.Full-scale IQ, verbal IQ, and performance IQ scores were comparable in patients in the TGC and UC groups (Table 2). Full-scale IQ scores were 15 points (95% CI, 12-18; P < .001) lower in post-ICU patients than in healthy control children (eTable 1 and eTable 2); a difference that was reduced to 9 points (95% CI, 6-12; P < .001) after propensity score matching for baseline risks and biometrics at follow-up.

Table Graphic Jump LocationTable 2. Results of Neurocognitive Test Battery in Tested Post-ICU Population and Healthy Controlsa

Visual-Motor Integration.Beery-Buktenica Developmental Test of Visual-Motor Integration scores were comparable in patients in the TGC and UC groups (Table 2). In addition, post-ICU patients scored lower than healthy control children (P < .001) (eTable 2).

Attention, Motor Coordination, Inhibitory Control, and Cognitive Flexibility.None of the scores for the ANT tasks were worse in the TGC group than in the UC group. In the TGC group, motor coordination was actually improved (9% [95% CI, 0%-18%] to 20% [95% CI, 5%-35%] better, all P ≤ .03) and also cognitive flexibility (19% [95% CI, 5%-33%] better, P = .02; a posteriori calculated statistical power, 96%-99%) (Table 2). Despite improvement in the TGC group, the motor coordination performances remained inferior to those in the control group (all P ≤ .01), but the cognitive flexibility score was comparable with that of healthy children in the TGC group (P = .68 vs control group) but not in the UC group (P = .008 vs control group). Overall, the scores for the ANT tasks, except those for cognitive flexibility, were worse in post-ICU patients than in the control group (all P ≤ .02), although significance was lost after propensity score matching for baseline risks and biometrics at follow-up (eTable 2).

Memory.Memory could only be assessed in children aged between 5 and 17 years, because tests did not apply outside this age range. Again, no differences were present between the TGC and UC groups (Table 2). Overall, post-ICU patients performed worse than healthy children (P values between .05 and <.001 for most tests) (eTable 2).

Behavior.Behavior was assessed via the CBCL questionnaire filled out by the parents. The TGC and UC groups performed similarly (Table 2). Overall, post-ICU patients scored worse than healthy controls (all P ≤ .002), although significance was lost after propensity score matching for baseline risks and biometrics at follow-up (eTable 2).

Clinical Neurological Evaluation.In the TGC group, scores for neurological abnormalities were not worse than in the UC group (Table 2). Post-ICU patients scored worse than healthy children (P < .001), although the significance was lost after propensity score matching for baseline risks and biometrics at follow-up (eTable 2).

Poor Outcomes

The number of patients with a poor outcome (death or disability) at follow-up was similar in the TGC (68/349 [19%]) and UC (63/351 [18%]) groups (risk-adjusted odds ratio [OR], 0.93; 95% CI, 0.60-1.46; P = .72) (Figure). Nine percent (31/349) of the children allocated to the TGC group and 11% (37/351) of the children in the UC group had died (risk-adjusted OR, 0.45; 95% CI, 0.21-0.94; P = .03) (causes of death are shown in eTable 3). Thirty-seven children in the TGC group (11%) and 26 children in the UC group (7%) were severely disabled (risk-adjusted OR, 1.20; 95% CI, 0.66-2.18; P = .56). In 60 of these 63 disabled children, the disability was explained by the prerandomization presence of a syndrome (eTable 4). The dominant independent determinant for severe disability at follow-up was a prerandomization syndrome (risk-adjusted OR, 44.71; 95% CI, 15.51-190.44; P < .001).

Association With Hypoglycemia During Intensive Care

Propensity score matching of all patients in the TGC group who experienced hypoglycemia with patients in the UC group resulted in a matched population of 160 patients (eTable 5). In this selection, 15% of patients in the TGC group had died 4 years after inclusion vs 16% of patients in the UC group (P = .82) and the proportion of disabled patients was also comparable (15% in the TGC group and 11% in the UC group, P = .64). Ninety-one patients were tested for neurocognitive development. Most neurocognitive outcomes revealed no significant differences, whereas patients who experienced TGC-induced hypoglycemia performed better for cognitive flexibility than matched patients in the UC group (P = .04) (Table 3).

In multivariable regression analysis performed on the total population of 700 patients, hypoglycemia was never a significant independent risk factor for worse neurocognitive outcomes (eTable 6). The severity of hypoglycemia also was not associated with neurocognitive outcome.

Four years after participating in an RCT in the pediatric ICU, treatment with TGC during ICU treatment did not increase the incidence of poor outcomes (death or severe disability) and did not adversely affect any of the tested domains of neurocognitive development. Scores for intelligence, visual-motor integration, and memory were not statistically significantly different, whereas TGC improved motor coordination and cognitive flexibility, the latter up to the level of healthy children. Hypoglycemia during ICU treatment, which often occurred with TGC, was not independently associated with worse neurocognitive outcome.

This follow-up study was performed to exclude harm evoked by TGC during ICU treatment in the pediatric population. Our finding that even minor effects of TGC on intelligence were absent, and that TGC evoked benefit for some of the more subtle domains of cognition, is striking. Indeed, in contrast with a blood glucose target of 80 to 110 mg/dL (normal for adults but not for young children), which showed circulating blood glucose levels virtually unaltered in children after cardiac surgery,49 targeting the much lower age–normal blood glucose range in our study effectively prevented hyperglycemia but also increased the risk of brief episodes of severe hypoglycemia (from 1% to 25%).10 Hypoglycemia is traditionally considered to be a potential cause of long-term cognitive impairment in patients with early onset diabetes mellitus.50 However, in adolescents with type 1 diabetes who participated in the follow-up of the Diabetes Control and Complications Trial, a study that investigated the effect of tight blood glucose control with insulin, cognitive functions did not decline over time despite relatively high rates of severe hypoglycemia.51 In adult patients who were critically ill, hypoglycemia was associated with subtle disturbances of neurocognitive functions,52 but causality was never proven. In a large study of patients with cardiac disease,53 only spontaneous but not insulin-induced hypoglycemia was associated with adverse outcome.

We previously measured circulating markers of neuronal and astrocyte damage in relationship to hypoglycemia during ICU treatment.54 Although higher levels of these biomarkers were observed in children who developed hypoglycemia, they were already increased before the hypoglycemic insult and related to the severity of illness. Hypoglycemia, which was always rapidly detected and treated, did not affect these markers. In addition, the current functional neurocognitive follow-up could not attribute a causal damaging role to brief hypoglycemia. This suggests that transient hyperglycemia during critical illness may be more damaging to the brain than brief hypoglycemia, at least in those ICU settings that use accurate tools to monitor blood glucose for titration of insulin.5557 Indeed, the use of inaccurate glucose monitoring tools recently was shown to evoke risk of harm associated with hypoglycemia.58,59 Furthermore, experimental evidence supports the damaging effect of hyperglycemia and of increased glucose levels after hypoglycemia, more so than hypoglycemia per se.60 Therefore, the mode of correcting hypoglycemia, avoiding large fluctuations of hyperglycemia following hypoglycemia, similar to what was performed in our study,10 may be important to avoid brain damage. The data by no means argue against all efforts to avoid hypoglycemia. However, when trained nurses and accurate monitoring tools are available, efforts to avoid hyperglycemia in children who are critically ill should not be abandoned solely because of the risk of brief hypoglycemia.

The finding that specifically motor coordination and cognitive flexibility were improved by TGC during ICU treatment suggests that the controlling brain areas may be specifically sensitive to hyperglycemia. These regions comprise the prefrontal cortex, as evidenced in patients with frontal lobe lesions and by neuroimaging studies of executive tasks.6163 Deleterious effects of hyperglycemia to the frontal cortical areas are in line with previous observations of children with diabetes mellitus13 and with results from recent neuropathological studies in critical illness.16 Imaging studies are required to investigate this further.

Our data also provide evidence that some of the neurocognitive impairment previously reported in children who have been critically ill could be beneficially affected by altering medical care.6466 This is in line with previous studies showing that the choice of surgical technique for correction of congenital cardiac anomalies affects the cognitive potential of young children.6769

The strength of our study is the documentation of long-term vital status of all 700 patients and the neurocognitive follow-up data (dead, disabled, or quantified by testing) of 84% of this population. The recruitment rate was high and therefore risk of biased conclusions was low. The imputation strategies, performed to correct for missing data, confirmed the results. The sample size was large enough to exclude minimal harm of TGC with a high statistical power. In addition, the exhaustive and meticulous ascertainment of neurocognitive status certainly was a strength.

Some weaknesses of our study should be highlighted. First, the age of the youngest children in the study, who were infants at the time of inclusion, did not allow to assess memory in that subgroup, because tests are only available on children aged 5 years or older. However, all other cognitive functions could be assessed and did not suggest specific vulnerability of this subgroup. Nevertheless, a further follow-up of these children is needed. Second, neuroimaging studies were not performed to further define the most vulnerable areas in the brain. Third, given the high proportion of patients with cardiac surgery, extrapolation to other ICU populations should be performed with caution. Fourth, this was a single-center trial; therefore, the experience of the clinical staff may have weighed heavily on the results. Nevertheless, this is a proof-of-concept study, performed in a well-controlled setting of an RCT, which was able to address the key issue of potential harm to neurocognitive outcome evoked by hyperglycemia vs hypoglycemia during childhood critical illness. Because randomized trials that deliberately induce hypoglycemia in patients are impossible for evident ethical considerations, our study provides high-quality data to fill this gap in clinical knowledge.

In conclusion, 4 years after childhood critical illness, TGC to age-adjusted normoglycemia in an experienced ICU, despite having frequently evoked brief episodes of hypoglycemia, did not cause any detectable harm to intelligence and improved other areas of cognition.

Corresponding Author: Greet Van den Berghe, MD, PhD, Department of Intensive Care Medicine, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium (greet.vandenberghe@med.kuleuven.be).

Published Online: October 17, 2012. doi:10.1001/jama.2012.12424

Author Contributions: Dr Van den Berghe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mesotten and Gielen and Ms Sterken contributed equally to the manuscript.

Study concept and design: Mesotten, Gielen, Sterken, Vlasselaers, Lemiere, Lagae, Vanhorebeek, Wouters, Van den Berghe.

Acquisition of data: Gielen, Sterken, Claessens, Vlasselaers, Gewillig, Eyskens.

Analysis and interpretation of data: Mesotten, Gielen, Sterken, Hermans, Van den Berghe.

Drafting of the manuscript: Mesotten, Gielen, Sterken, Van den Berghe.

Critical revision of the manuscript for important intellectual content: Mesotten, Gielen, Sterken, Claessens, Hermans, Vlasselaers, Lemiere, Lagae, Gewillig, Eyskens, Vanhorebeek, Wouters, Van den Berghe.

Statistical analysis: Mesotten, Gielen, Sterken, Hermans, Van den Berghe.

Obtained funding: Mesotten, Gielen, Vanhorebeek, Van den Berghe.

Administrative, technical, or material support: Claessens, Vlasselaers, Gewillig, Vanhorebeek, Wouters.

Study supervision: Mesotten, Lemiere, Lagae, Gewillig, Eyskens, Vanhorebeek, Van den Berghe.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lagae reported having board membership and receiving consultancy fees and payment for lectures from Viropharma and Cyberonics, and receiving payment for lectures from Eisai and UCB. No other authors reported any disclosures.

Funding/Support: This research was fully supported by official research grants IWT/070695/TBM from the Institute for Science and Technology, Flanders, Belgium (via Catholic University of Leuven to Drs Van den Berghe, Mesotten, and Vanhorebeek); METH08/07 from the Methusalem Program of the Flemish Government (via Catholic University of Leuven to Dr Van den Berghe); from the FWO Research Foundation–Flanders, Belgium (PhD fellowship to Dr Gielen and postdoctoral fellowship to Dr Mesotten); and from the Clinical Research Fund of the Leuven University Hospital (postdoctoral fellowship to Dr Hermans).

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: We thank all patients, healthy volunteers, and their families for enthusiastic participation in this study. Peter Stiers, MPsych, PhD and Heidi Wouters, MPsych (Department of Pediatric Neurology, Catholic University of Leuven, Leuven, Belgium), provided valuable discussions about the choice of the neurocognitive test battery; Andrea Freys and Astrid Vloemans (Department of Pediatric and Congenital Cardiology, Catholic University of Leuven, Leuven, Belgium) ensured a smooth transition from pediatric cardiology consultation to follow-up assessments; and Jenny Gielens (Department of Intensive Care Medicine, Catholic University of Leuven, Leuven, Belgium) provided secretarial help. Steffen Fieuws, MSc, PhD (Department of Biostatistics, Catholic University of Leuven, Leuven, Belgium), provided help with the multiple imputation approach. These collaborators did not receive any compensation for their contributions.

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Faustino EV, Apkon M. Persistent hyperglycemia in critically ill children.  J Pediatr. 2005;146(1):30-34
PubMed   |  Link to Article
Branco RG, Garcia PC, Piva JP, Casartelli CH, Seibel V, Tasker RC. Glucose level and risk of mortality in pediatric septic shock.  Pediatr Crit Care Med. 2005;6(4):470-472
PubMed   |  Link to Article
Yates AR, Dyke PC II, Taeed R,  et al.  Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient.  Pediatr Crit Care Med. 2006;7(4):351-355
PubMed   |  Link to Article
Vlasselaers D, Milants I, Desmet L,  et al.  Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study.  Lancet. 2009;373(9663):547-556
PubMed   |  Link to Article
Brown TC, Connelly JF, Dunlop ME, McDougall PN, Tibballs J. Fasting plasma glucose in children.  Aust Paediatr J. 1980;16(1):28-29
PubMed
Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia.  Pediatrics. 2008;122(1):65-74
PubMed   |  Link to Article
Perantie DC, Wu J, Koller JM,  et al.  Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes.  Diabetes Care. 2007;30(9):2331-2337
PubMed   |  Link to Article
Schoenle EJ, Schoenle D, Molinari L, Largo RH. Impaired intellectual development in children with Type I diabetes: association with HbA(1c), age at diagnosis and sex.  Diabetologia. 2002;45(1):108-114
PubMed   |  Link to Article
Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients.  Neurology. 2005;64(8):1348-1353
PubMed   |  Link to Article
Sonneville R, den Hertog HM, Güiza F,  et al.  Impact of hyperglycemia on neuropathological alterations during critical illness.  J Clin Endocrinol Metab. 2012;97(6):2113-2123
PubMed   |  Link to Article
Hadders-Algra M. The neuromotor examination of the preschool child and its prognostic significance.  Ment Retard Dev Disabil Res Rev. 2005;11(3):180-188
PubMed   |  Link to Article
Peters LH, Maathuis KG, Kouw E, Hamming M, Hadders-Algra M. Test-retest, inter-assessor and intra-assessor reliability of the modified Touwen examination.  Eur J Paediatr Neurol. 2008;12(4):328-333
PubMed   |  Link to Article
Jacobson AM, Musen G, Ryan CM,  et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group.  Long-term effect of diabetes and its treatment on cognitive function.  N Engl J Med. 2007;356(18):1842-1852
PubMed   |  Link to Article
Vander Steene G, Bos A. WPPSI-R: Vlaams-Nederlandse Aanpassing. Lisse, the Netherlands: Swets & Zeitlinger BV; 1997
Kort W, Schittekatte M, Dekker PH,  et al.  Nederlandse Bewerking van de WISC-III: Handleiding en Verantwoording. Amsterdam, the Netherlands: Harcourt Test Publisher; 2005
Wechsler D. WAIS III Nederlandstalige Bewerking: Afname en Scoringshandleiding. Amsterdam, the Netherlands: Hartcourt Test Publisher; 2004
Beery KE, Beery NA. The Beery-Buktenica Developmental Test of Visual-Motor Integration: Administration, Scoring & Teaching Manual. 5th ed. Bloomington, MN: NCS Pearson Inc; 2006
de Sonneville LMJ. Amsterdam Neuropsychological Tasks: Manual (Handleiding). Amsterdam, the Netherlands: Boom Test Uitgevers; 2011
de Sonneville LMJ. Amsterdam Neuropsychological Tasks: a computer-aided assessment program.  In: den Brinker BPML, Beek PJ, Brand AN, Maarse SJ, Mulder LJM, eds. Cognitive Ergonomics, Clinical Assessment and Computer-Aided Learning: Computers in Psychology. Lisse, the Netherlands: Swets & Zeitlinger BV; 1999:187-203
Kalff AC, De Sonneville LM, Hurks PP,  et al.  Speed, speed variability, and accuracy of information processing in 5 to 6-year-old children at risk of ADHD.  J Int Neuropsychol Soc. 2005;11(2):173-183
PubMed   |  Link to Article
Koekkoek S, Eggermont L, De Sonneville L,  et al.  Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease.  J Neurol. 2006;253(12):1615-1624
PubMed   |  Link to Article
Rommelse NN, Altink ME, de Sonneville LM,  et al.  Are motor inhibition and cognitive flexibility dead ends in ADHD?  J Abnorm Child Psychol. 2007;35(6):957-967
PubMed   |  Link to Article
Rowbotham I, Pit-ten Cate IM, Sonuga-Barke EJ, Huijbregts SC. Cognitive control in adolescents with neurofibromatosis type 1.  Neuropsychology. 2009;23(1):50-60
PubMed   |  Link to Article
Cohen MJ. Children's Memory Scale: Manual.  San Antonio, TX: The Psychological Corporation, Harcourt Brace & Co; 1997
Achenbach TM, Rescorla LA. Manual for the ASEBA Preschool Forms and Profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families; 2000
Achenbach TM, Rescorla LA. Manual for the ASEBA School-age Forms and Profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families; 2001
Anderson V, Catroppa C, Morse S, Haritou F, Rosenfeld JV. Intellectual outcome from preschool traumatic brain injury: a 5-year prospective, longitudinal study.  Pediatrics. 2009;124(6):e1064-e1071
PubMed   |  Link to Article
Ellerbeck KA, Smith ML, Holden EW,  et al.  Neurodevelopmental outcomes in children surviving d-transposition of the great arteries.  J Dev Behav Pediatr. 1998;19(5):335-341
PubMed   |  Link to Article
Amant F, Van Calsteren K, Halaska MJ,  et al.  Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.  Lancet Oncol. 2012;13(3):256-264
PubMed   |  Link to Article
Mennes M, Stiers P, Vandenbussche E,  et al.  Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.  Pediatr Blood Cancer. 2005;44(5):478-486
PubMed   |  Link to Article
Beyerlein A, Ness AR, Streuling I, Hadders-Algra M, von Kries R. Early rapid growth: no association with later cognitive functions in children born not small for gestational age.  Am J Clin Nutr. 2010;92(3):585-593
PubMed   |  Link to Article
Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants.  N Engl J Med. 2002;346(3):149-157
PubMed   |  Link to Article
Weiss B. Pesticides as a source of developmental disabilities.  Ment Retard Dev Disabil Res Rev. 1997;3(3):246-256Link to Article
Link to Article
Halsey C, Buck G, Richards S, Vargha-Khadem F, Hill F, Gibson B. The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI.  J Hematol Oncol. 2011;4:42-53
PubMed   |  Link to Article
He Y. Missing data analysis using multiple imputation: getting to the heart of the matter.  Circ Cardiovasc Qual Outcomes. 2010;3(1):98-105
PubMed   |  Link to Article
Bonett DG, Price RM. Statistical inference for a linear function of medians: confidence intervals, hypothesis testing, and sample size requirements.  Psychol Methods. 2002;7(3):370-383
PubMed   |  Link to Article
Heinze G, Jüni P. An overview of the objectives of and the approaches to propensity score analyses.  Eur Heart J. 2011;32(14):1704-1708
PubMed   |  Link to Article
Thoemmes F. Propensity score matching in SPSS. http://arxiv.org/abs/1201.6385. Accessed September 18, 2012
Jaber L, Halpern GJ, Shohat M. The impact of consanguinity worldwide.  Community Genet. 1998;1(1):12-17
PubMed   |  Link to Article
Leteurtre S, Martinot A, Duhamel A,  et al.  Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study.  Lancet. 2003;362(9379):192-197
PubMed   |  Link to Article
Adams J, Weakliem DL, August B. Hollingshead's “Four Factor Index of Social Status”: from unpublished paper to citation classic.  Yale J Sociol. 2011;8:11-19
Hollingshead AB. Four Factor Index of Social Status.  Yale J Sociol. 2011;8:21-52
Agus MS, Steil GM, Wypij D,  et al.  Tight glycemic control versus standard care after pediatric cardiac surgery.  N Engl J Med. 2012;(epub ahead of print)
Bjørgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia.  Acta Paediatr. 1997;86(2):148-153
PubMed   |  Link to Article
Musen G, Jacobson AM, Ryan CM,  et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.  Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial.  Diabetes Care. 2008;31(10):1933-1938
PubMed   |  Link to Article
Duning T, van den Heuvel I, Dickmann A,  et al.  Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.  Diabetes Care. 2010;33(3):639-644
PubMed   |  Link to Article
Kosiborod M, Inzucchi SE, Goyal A,  et al.  Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction.  JAMA. 2009;301(15):1556-1564
PubMed   |  Link to Article
Vanhorebeek I, Gielen M, Boussemaere M,  et al.  Glucose dysregulation and neurological injury biomarkers in critically ill children.  J Clin Endocrinol Metab. 2010;95(10):4669-4679
PubMed   |  Link to Article
Scott MG, Bruns DE, Boyd JC, Sacks DB. Tight glucose control in the intensive care unit: are glucose meters up to the task?  Clin Chem. 2009;55(1):18-20
PubMed   |  Link to Article
Van den Berghe G, Schetz M, Vlasselaers D,  et al.  Clinical review: Intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target?  J Clin Endocrinol Metab. 2009;94(9):3163-3170
PubMed   |  Link to Article
Watkinson PJ, Barber VS, Amira E, James T, Taylor R, Young JD. The effects of precision, haematocrit, pH and oxygen tension on point-of-care glucose measurement in critically ill patients: a prospective study.  Ann Clin Biochem. 2012;49(pt 2):144-151
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The NICE-SUGAR Study Investigators.  Hypoglyemia and risk of death in critically ill patients.  N Engl J Med. 2012;367:1108-1118
Link to Article
Hirsch IB. Understanding low sugar from NICE-SUGAR.  N Engl J Med. 2012;367:1150-1153
Link to Article
Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase.  J Clin Invest. 2007;117(4):910-918
PubMed   |  Link to Article
Dove A, Pollmann S, Schubert T, Wiggins CJ, von Cramon DY. Prefrontal cortex activation in task switching: an event-related fMRI study.  Brain Res Cogn Brain Res. 2000;9(1):103-109
PubMed   |  Link to Article
Smith AB, Taylor E, Brammer M, Rubia K. Neural correlates of switching set as measured in fast, event-related functional magnetic resonance imaging.  Hum Brain Mapp. 2004;21(4):247-256
PubMed   |  Link to Article
Hernandez MT, Sauerwein HC, Jambaqué I,  et al.  Deficits in executive functions and motor coordination in children with frontal lobe epilepsy.  Neuropsychologia. 2002;40(4):384-400
PubMed   |  Link to Article
Elison S, Shears D, Nadel S, Sahakian B, Garralda ME. Neuropsychological function in children following admission to paediatric intensive care: a pilot investigation.  Intensive Care Med. 2008;34(7):1289-1293
PubMed   |  Link to Article
Miatton M, De Wolf D, François K, Thiery E, Vingerhoets G. Neurocognitive consequences of surgically corrected congenital heart defects: a review.  Neuropsychol Rev. 2006;16(2):65-85
PubMed   |  Link to Article
Knoester H, Grootenhuis MA, Bos AP. Outcome of paediatric intensive care survivors.  Eur J Pediatr. 2007;166(11):1119-1128
PubMed   |  Link to Article
Bellinger DC, Jonas RA, Rappaport LA,  et al.  Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.  N Engl J Med. 1995;332(9):549-555
PubMed   |  Link to Article
Bellinger DC, Wypij D, Kuban KC,  et al.  Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.  Circulation. 1999;100(5):526-532
PubMed   |  Link to Article
Bellinger DC, Wypij D, Rivkin MJ,  et al.  Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging.  Circulation. 2011;124(12):1361-1369
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Flow Diagram of Study Participants
Graphic Jump Location

DNR indicates do not resuscitate; ICU, intensive care unit. aThe 19 medical disorders that were considered unsuitable by the treating physician consisted of 2 patients dependent on home ventilation, 6 patients with metabolic disorders, 2 patients for whom it was the personal opinion of the treating physician that it would be inappropriate to participate in a study in view of poor prognosis (although the patients formally did not have a DNR code), and 9 patients who had already been treated with intensive insulin therapy elsewhere before assessment for participation.bCauses of death are shown in eTable 3. cMore information on the diagnoses of the severely disabled patients who could not be tested is shown in eTable 4.

Tables

Table Graphic Jump LocationTable 1. Demographics and Blood Glucose Control in the Total ICU Population, Tested Post-ICU Population, and Healthy Controlsa
Table Graphic Jump LocationTable 2. Results of Neurocognitive Test Battery in Tested Post-ICU Population and Healthy Controlsa

References

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PubMed   |  Link to Article
Faustino EV, Apkon M. Persistent hyperglycemia in critically ill children.  J Pediatr. 2005;146(1):30-34
PubMed   |  Link to Article
Branco RG, Garcia PC, Piva JP, Casartelli CH, Seibel V, Tasker RC. Glucose level and risk of mortality in pediatric septic shock.  Pediatr Crit Care Med. 2005;6(4):470-472
PubMed   |  Link to Article
Yates AR, Dyke PC II, Taeed R,  et al.  Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient.  Pediatr Crit Care Med. 2006;7(4):351-355
PubMed   |  Link to Article
Vlasselaers D, Milants I, Desmet L,  et al.  Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study.  Lancet. 2009;373(9663):547-556
PubMed   |  Link to Article
Brown TC, Connelly JF, Dunlop ME, McDougall PN, Tibballs J. Fasting plasma glucose in children.  Aust Paediatr J. 1980;16(1):28-29
PubMed
Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia.  Pediatrics. 2008;122(1):65-74
PubMed   |  Link to Article
Perantie DC, Wu J, Koller JM,  et al.  Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes.  Diabetes Care. 2007;30(9):2331-2337
PubMed   |  Link to Article
Schoenle EJ, Schoenle D, Molinari L, Largo RH. Impaired intellectual development in children with Type I diabetes: association with HbA(1c), age at diagnosis and sex.  Diabetologia. 2002;45(1):108-114
PubMed   |  Link to Article
Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients.  Neurology. 2005;64(8):1348-1353
PubMed   |  Link to Article
Sonneville R, den Hertog HM, Güiza F,  et al.  Impact of hyperglycemia on neuropathological alterations during critical illness.  J Clin Endocrinol Metab. 2012;97(6):2113-2123
PubMed   |  Link to Article
Hadders-Algra M. The neuromotor examination of the preschool child and its prognostic significance.  Ment Retard Dev Disabil Res Rev. 2005;11(3):180-188
PubMed   |  Link to Article
Peters LH, Maathuis KG, Kouw E, Hamming M, Hadders-Algra M. Test-retest, inter-assessor and intra-assessor reliability of the modified Touwen examination.  Eur J Paediatr Neurol. 2008;12(4):328-333
PubMed   |  Link to Article
Jacobson AM, Musen G, Ryan CM,  et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group.  Long-term effect of diabetes and its treatment on cognitive function.  N Engl J Med. 2007;356(18):1842-1852
PubMed   |  Link to Article
Vander Steene G, Bos A. WPPSI-R: Vlaams-Nederlandse Aanpassing. Lisse, the Netherlands: Swets & Zeitlinger BV; 1997
Kort W, Schittekatte M, Dekker PH,  et al.  Nederlandse Bewerking van de WISC-III: Handleiding en Verantwoording. Amsterdam, the Netherlands: Harcourt Test Publisher; 2005
Wechsler D. WAIS III Nederlandstalige Bewerking: Afname en Scoringshandleiding. Amsterdam, the Netherlands: Hartcourt Test Publisher; 2004
Beery KE, Beery NA. The Beery-Buktenica Developmental Test of Visual-Motor Integration: Administration, Scoring & Teaching Manual. 5th ed. Bloomington, MN: NCS Pearson Inc; 2006
de Sonneville LMJ. Amsterdam Neuropsychological Tasks: Manual (Handleiding). Amsterdam, the Netherlands: Boom Test Uitgevers; 2011
de Sonneville LMJ. Amsterdam Neuropsychological Tasks: a computer-aided assessment program.  In: den Brinker BPML, Beek PJ, Brand AN, Maarse SJ, Mulder LJM, eds. Cognitive Ergonomics, Clinical Assessment and Computer-Aided Learning: Computers in Psychology. Lisse, the Netherlands: Swets & Zeitlinger BV; 1999:187-203
Kalff AC, De Sonneville LM, Hurks PP,  et al.  Speed, speed variability, and accuracy of information processing in 5 to 6-year-old children at risk of ADHD.  J Int Neuropsychol Soc. 2005;11(2):173-183
PubMed   |  Link to Article
Koekkoek S, Eggermont L, De Sonneville L,  et al.  Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease.  J Neurol. 2006;253(12):1615-1624
PubMed   |  Link to Article
Rommelse NN, Altink ME, de Sonneville LM,  et al.  Are motor inhibition and cognitive flexibility dead ends in ADHD?  J Abnorm Child Psychol. 2007;35(6):957-967
PubMed   |  Link to Article
Rowbotham I, Pit-ten Cate IM, Sonuga-Barke EJ, Huijbregts SC. Cognitive control in adolescents with neurofibromatosis type 1.  Neuropsychology. 2009;23(1):50-60
PubMed   |  Link to Article
Cohen MJ. Children's Memory Scale: Manual.  San Antonio, TX: The Psychological Corporation, Harcourt Brace & Co; 1997
Achenbach TM, Rescorla LA. Manual for the ASEBA Preschool Forms and Profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families; 2000
Achenbach TM, Rescorla LA. Manual for the ASEBA School-age Forms and Profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families; 2001
Anderson V, Catroppa C, Morse S, Haritou F, Rosenfeld JV. Intellectual outcome from preschool traumatic brain injury: a 5-year prospective, longitudinal study.  Pediatrics. 2009;124(6):e1064-e1071
PubMed   |  Link to Article
Ellerbeck KA, Smith ML, Holden EW,  et al.  Neurodevelopmental outcomes in children surviving d-transposition of the great arteries.  J Dev Behav Pediatr. 1998;19(5):335-341
PubMed   |  Link to Article
Amant F, Van Calsteren K, Halaska MJ,  et al.  Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.  Lancet Oncol. 2012;13(3):256-264
PubMed   |  Link to Article
Mennes M, Stiers P, Vandenbussche E,  et al.  Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.  Pediatr Blood Cancer. 2005;44(5):478-486
PubMed   |  Link to Article
Beyerlein A, Ness AR, Streuling I, Hadders-Algra M, von Kries R. Early rapid growth: no association with later cognitive functions in children born not small for gestational age.  Am J Clin Nutr. 2010;92(3):585-593
PubMed   |  Link to Article
Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants.  N Engl J Med. 2002;346(3):149-157
PubMed   |  Link to Article
Weiss B. Pesticides as a source of developmental disabilities.  Ment Retard Dev Disabil Res Rev. 1997;3(3):246-256Link to Article
Link to Article
Halsey C, Buck G, Richards S, Vargha-Khadem F, Hill F, Gibson B. The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI.  J Hematol Oncol. 2011;4:42-53
PubMed   |  Link to Article
He Y. Missing data analysis using multiple imputation: getting to the heart of the matter.  Circ Cardiovasc Qual Outcomes. 2010;3(1):98-105
PubMed   |  Link to Article
Bonett DG, Price RM. Statistical inference for a linear function of medians: confidence intervals, hypothesis testing, and sample size requirements.  Psychol Methods. 2002;7(3):370-383
PubMed   |  Link to Article
Heinze G, Jüni P. An overview of the objectives of and the approaches to propensity score analyses.  Eur Heart J. 2011;32(14):1704-1708
PubMed   |  Link to Article
Thoemmes F. Propensity score matching in SPSS. http://arxiv.org/abs/1201.6385. Accessed September 18, 2012
Jaber L, Halpern GJ, Shohat M. The impact of consanguinity worldwide.  Community Genet. 1998;1(1):12-17
PubMed   |  Link to Article
Leteurtre S, Martinot A, Duhamel A,  et al.  Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study.  Lancet. 2003;362(9379):192-197
PubMed   |  Link to Article
Adams J, Weakliem DL, August B. Hollingshead's “Four Factor Index of Social Status”: from unpublished paper to citation classic.  Yale J Sociol. 2011;8:11-19
Hollingshead AB. Four Factor Index of Social Status.  Yale J Sociol. 2011;8:21-52
Agus MS, Steil GM, Wypij D,  et al.  Tight glycemic control versus standard care after pediatric cardiac surgery.  N Engl J Med. 2012;(epub ahead of print)
Bjørgaas M, Gimse R, Vik T, Sand T. Cognitive function in type 1 diabetic children with and without episodes of severe hypoglycaemia.  Acta Paediatr. 1997;86(2):148-153
PubMed   |  Link to Article
Musen G, Jacobson AM, Ryan CM,  et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.  Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial.  Diabetes Care. 2008;31(10):1933-1938
PubMed   |  Link to Article
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PubMed   |  Link to Article
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Supplemental Content

Mesotten D, Gielen M, Sterken C, et al. Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial. JAMA. doi:10.1001/jama.2012.12424

eMethods 1. Details on the clinical neurological examination

eMethods 2. Details on imputation

eMethods 3. Details on propensity score matching for the analysis of hypoglycemia

eTable 1. Comparison healthy vs. critically ill

eTable 2. Results post–ICU patients vs. healthy controls

eTable 3. Causes of death in the 2 glucose management groups

eTable 4. Not-testable children and pre-randomization “syndromes”

eTable 5. Hypoglycemia vs. no hypoglycemia

eTable 6. Impact of hypoglycemia in multivariable linear regression analysis

eReferences

eProtocol. Long-term follow-up study and acute outcome study

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