Hyperglycemia is a negative prognostic indicator in adult and pediatric TBI1–3, 5, 6, 10, 11
and this study provides the first estimate of the incidence and risk factors for perioperative hyperglycemia in children with TBI who underwent urgent/emergent craniotomy at our institution. The main findings of this study
are that in children with TBI: 1) perioperative hyperglycemia was common, 2) although most patients had at-least one glucose checked during general anesthesia, the sampling frequency for the majority of children was less than one serum glucose per anesthetic hour, 3) intraoperative hyperglycemia was common but few patients were treated with insulin, 5) Age < 4 years, severe TBI and presence of multiple lesions that include SDH on preoperative CT head were independent predictors of perioperative hyperglycemia, and 6) intraoperative hypoglycemia occurred independent of insulin treatment and was not rare.
In this study, we used a somewhat “arbitrary” definition of hyperglycemia (> 200 mg/dl). Previous studies have used different glucose values to define hyperglycemia in the context of pediatric TBI. These values vary and range from 150 mg/dl2
to as high as 270 mg/dl.4
However, the treatment threshold for hyperglycemia in both adults and children is controversial and some clinicians may not administer insulin for a glucose of 150 mg/dl for fear of hypoglycemia, and others may consider a glucose of 270 mg/dl to be too high a treatment threshold. In a randomized, controlled study involving more than 1500 critically ill adults, Van den Berghe et al. recommended intensive insulin therapy to maintain blood glucose ≤ 110 mg/dL to reduce morbidity and mortality.12
In a subsequent study analyzing of 63 of these patients with isolated TBI, they observed significant reduction in mean and maximum intracranial pressure, incidence of seizures and diabetes insipidus, and suggested that tight glucose control with insulin protects the central and peripheral nervous system and shortens the intensive care dependency, with improved long term rehabilitation.13
Despite the lack of consensus regarding the hyperglycemia definition threshold in TBI, we used a value of 200 mg/dl because in current clinical practice, this is a commonly used treatment threshold. Our data show that glucose > 200mg/dL is common during the perioperative period. In this study, we based our estimates of the incidence of hyperglycemia on available data, which was almost always obtained during each of the 3 study periods but only intermittently obtained within each study period. Therefore, the actual prevalence of intraoperative or perioperative hyperglycemia may be higher than currently estimated. In support of this idea is a recent study which reported that hyperglycemia was frequently not detected with intermittent laboratory glucose measurements in critically ill children.14
A continuous glucose monitoring system with real time read-outs might be one solution to decrease sampling bias and valuable for the real time detection and treatment of hyper and hypoglycemia during the perioperative period.14
Following initial trauma, TBI evolves and different periods of injury may be particularly stressful. This may be one explanation for the lack of correlation between glucose values that we observed during different study periods. Our data show that it may not be possible to predict intraoperative glucose on the basis of preoperative glucose or predict postoperative glucose on the basis of intraoperative glucose levels. Frequent sampling of glucose before, during and after surgery is therefore important.
In this study, risk factors for perioperative hyperglycemia were age < 4 years and severe TBI. We dichotomized age into a young vs. older age group because children less than 4 years are known to have the highest rate for TBI-related deaths, hospitalizations, and emergency department visits15
and have worse outcome than older chidren.16–18
The relationship between hyperglycemia and young age in this study suggests that hyperglycemia may be one mechanism that explains the observation that young children have poor outcomes after TBI. Our finding that children with severe TBI have more perioperative (including the intraoperative period) hyperglycemia is new and adds to the information on hyperglycemia in children with TBI, previously provided by Michaud et al
and Chiaretti et al
Unlike Michaud et al
however, we found an association between hyperglycemia and presence of multiple lesions including SDH on head CT. This difference could be due to the fact that we included surgical patients whereas Michaud et al
did not consider the intraoperative period. Similarly, the lack of association between head CT lesion type and hyperglycemia in Parish and Webb’s study4
may be due to operational differences in hyperglycemia definition (glucose > 270 mg/dL). Regardless of these differences, however, our finding suggests that severe TBI, whether it is clinically scored or radiographically assessed, predicts perioperative hyperglycemia in children undergoing urgent/emergent craniotomy.
Hyperglycemia may reflect TBI severity 2, 9, 11, 19
as it often occurs in children as a normal response to stress, secondary to an increase in the concentrations of stress hormones resulting in stimulation of gluconeogenesis and glycogenolysis.20, 21
However, we did not have hormone levels to directly assess stress. We did examine surrogates of stress and potential confounding factors for hyperglycemia such as extracranial injuries, perioperative fluid administration, use of mannitol, duration of anesthesia, hypotension, and fever were not found to affect hyperglycemia in our study (,). We did not enter perioperative fluid administered and presence of any SDH into the final multivariate analysis model because there were large numbers of missing data (29 missing data) for perioperative fluid, and every patient who had multiple lesions had SDH. On the other hand, hyperglycemia may exacerbate the impact of ischemia and hypoxia and lead to poor outcome22, 23
by potentiating brain cellular and tissue lactic acidosis.6, 7, 24–26
Therefore, there is no consensus as to whether transient hyperglycemia after TBI should be treated and Parish and Webb have suggested that insulin should not be used to treat hyperglycemia during first 40 hours after pediatric TBI4
. However, when hyperglycemia is persistent poor outcomes may ensue. 2, 4, 5
Twelve of the 15 children with in-hospital mortality in our series had perioperative hyperglycemia and 7 (39%) of the 18 children with persistent hyperglycemia died. Although the aim of this study was to examine the risk factors for hyperglycemia and we did not study mortality as an outcome measure (and thus did not enter mortality into multivariate analysis model), we observed higher in-hospital mortality in children with perioperative hyperglycemia than those without hyperglycemia (), a finding which has previously been reported.2,3,5
Approximately 2% children had perioperative hypoglycemia and this can be equally detrimental to outcome of and the real incidence of hypoglycemia may also be higher with more frequent sampling. Vespa et al. have demonstrated that intensive insulin therapy results in a net reduction in cerebral microdialysis glucose, but elevates lactate/pyruvate ratio and global oxygen extraction fraction, with no functional advantage.27
While the observations of elevated lactate/pyruvate ratio in the context of reduction of blood glucose from insulin remain unexplained, the occurrence of increased number of hypoglycemic events during the intensive insulin treatment raises concern regarding its routine use in TBI.28–31
The occurrence of 2 episodes of hypoglycemia in 2 patients in our study, independent of insulin, suggests that the risk of hypoglycemia is not theoretical. We speculate that the concern for hypoglycemia was primarily responsible for the infrequent use of intraoperative insulin during general anesthesia, even when glucose values exceeded 200g/dL. However, currently there are insufficient data to support insulin treatment and our study does not address the issue whether or not glucose above 200 mg/dL should be treated. Insulin administration in such circumstances may be dangerous and should be initiated with caution.
The major limitations of this study are the retrospective design of the study and the lack of long term outcome data. This study represents data from one institution and other biological markers of stress injury following TBI were not available. We could not determine the effect of multiple lesions without SDH on perioperative hyperglycemia because all these patients had SDH in addition to other lesions on preoperative head CT. In this study, perioperative hyperglycemia was associated with in-hospital mortality, but the number of deaths was small and we were not able to determine if perioperative hyperglycemia was an independent predictor of death. Despite these limitations, these data provide new information regarding the incidence and risk factors for perioperative hyperglycemia, and of the incidence of hypoglycemia in children during general anesthesia and the perioperative period.
This study demonstrates that perioperative hyperglycemia was common and that intraoperative hypoglycemia was not rare in children with TBI requiring urgent/emergent craniotomy. We have also shown that perioperative hyperglycemia can be predicted by young age, severe TBI and multiple TBI lesions that include SDH. Since intermittent intraoperative sampling may have underestimated the actual frequency of both hyper-and hypoglycemia, more frequent if not continuous perioperative glucose monitoring in children with TBI may be needed.