There are two principal findings of this study. First, though no insulin-induced hypoglycemia occurred, cerebral glucose decreased on days 1–4 after insulin onset, however without reaching critical levels. Second, median daily concentrations of glycerol as a marker of cellular membrane degradation showed an increase one day after insulin onset, returning to baseline on day 4.
In hours 9–12 of insulin infusion, a trend to a glycerol increase of unclear relevance had been observed previously (Schlenk et al 2008a). Regarding the long-term course, these glycerol changes might indicate a mild transient metabolic derangement following insulin infusion. However, the LPR remained stable and glutamate, a marker of neuronal injury and ischemia, decreased excluding ischemia as a relevant cause of cerebral glucose depletion and, even more important, indicating no substantial neuronal damage. Together, this pattern might be interpreted as absence of a relevant and continuous metabolic crisis following long-term insulin infusion, as long as cerebral glucose levels remain within the physiological range.
Hyperglycemia
Hyperglycemia at the time of brain injury, such as ischemic stroke or brain trauma, is known to be associated with increased morbidity and mortality (
Walia et al 2002;
Bhalla et al 2003). Persistence of hyperglycemia during the post-stroke episode was found to be independently associated with infarct expansion and adverse outcome (
Baird et al 2003). Preventive glycemic control with levels not substantially exceeding 6.1 mmol/L (110 mg/dL) reduced mortality during intensive care by more than 40% (
van den Berghe et al 2001). Nevertheless, thresholds for glucose levels to be treated with insulin vary considerably for SAH patients (
van den Berghe et al 2001;
Badjatia et al 2005;
Frontera et al 2006). Since hyperglycemia appears to be injurious in brain ischemia conditions, avoidance of hyperglycemia should be a general strategy in treatment of SAH (
Lanzino et al 1993;
Scott et al 1999;
Sarrafzadeh et al 2004;
Badjatia et al 2005;
Frontera et al 2006). However, the cause-effect relationship between hyperglycemia and unfavorable outcome remains controversial as hyperglycemia might either occur stress-related and reflect – as a symptom – the severity of the primary injury, or act as a secondary force deteriorating brain damage and thereby contributing to adverse outcome. Furthermore, postulating an intact blood-brain barrier, high blood glucose does not necessarily imply high cerebral glucose levels. Several glucose transport proteins (GLUT) are involved in the delivery of glucose from the circulation to the brain, such as GLUT1 in glia and the microvascular endothelial cells forming the blood-brain barrier, and GLUT3 in neurons (
Hamlin et al 2001).
Our results, though limited by various factors, indicate a significant insulin-related decrease in cerebral glucose levels though blood glucose remained stable. This lack of a significant decrease in blood glucose might be attributed to diverse factors such as catecholamines (either endogenous or iatrogenic administered) or the loose protocol for glycemic control rather accepting marginally elevated glucose levels than inducing hypoglycemia.
Since cerebral glucose remained within the physiological range even after the observed decrease, the complete recovery of the initial glycerol elevation and the lack of deterioration in the other markers of metabolic crisis (LPR and glutamate) are consistent. Future studies might detect relevant metabolic derangements when insulin is administered to patients with cerebral glucose levels already lowered in a critical way.
Insulin and cerebral metabolism
The debate about the role of insulin in cerebral glucose metabolism has not been resolved. In-vitro and experimental data demonstrated that insulin can penetrate the blood-brain barrier and enter the brain (
Steffens et al 1988). The proof of insulin receptors in neuronal tissue raises the question of their functional significance (
Kenner et al 1995). Recent data give evidence that physiologic levels of circulating insulin do not affect brain glucose uptake and that cerebral glucose uptake and metabolism is predominantly an insulin-independent process in humans (
Cranston et al 1998;
Seaquist et al 2001). Nevertheless, data from TBI patients support the concern that a reduction in serum glucose could create substrate limitation in the injured brain (
Vespa et al 2006). In the present study, insulin treatment appeared to be safe as median cerebral glucose concentrations did not fall below a critical threshold during insulin infusion. However, it is unclear whether insulin can be recommended in patients with low intracerebral glucose levels which might decrease further to critically low levels and compromise cerebral energy metabolism substantially. Therefore, in our view the monitoring of cerebral glucose especially at onset of and during insulin treatment is valuable in SAH patients. This might be relevant as a correlation between low cerebral glucose levels (<0.2 mmol/L) and unfavorable outcome could be shown in TBI patients (
Vespa et al 2003).
Current approaches for glycemic control in SAH
The strategy of insulin treatment in this study was to rather tolerate marginally elevated blood glucose levels than to induce hypoglycemia. With the applied blood glucose target range (4.4–7.8 mmol/L; 80–140 mg/dL), no hypoglycemia but frequent hyperglycemia was observed. In a much-noticed publication on glucose control in critically ill patients, Van den Berghe suggests blood glucose levels between 4.4 and 6.1 mmol/L (80–110 mg/dL), referring to data from cardiac surgery patients (
van den Berghe et al 2001). A more recent publication, studying 63 patients with brain lesions (including brain tumors) demonstrated that intensive insulin therapy with blood glucose levels <6.1 mmol/L (<110 mg/dL) shortened intensive care dependency and reduced intracranial pressure as well as the need for vasopressors for maintaining adequate cerebral perfusion pressure (
Van den Berghe et al 2005). It is questionable if these thresholds are applicable for patients with possibly compromised cerebral metabolism and regionally increased cerebral energy demand as described in aneurysmal SAH. Recently, the effect of intensive insulin therapy (4.4–6.7 mmol/L vs 4.4–12.2 mmol/L; 80–120 mg/dL vs 80–220 mg/dL) was studied in 78 aneurysmal SAH patients, revealing that infection rates could be lowered by strict glycemic control, while a benefit concerning the incidence of DIND, outcome, and mortality was not found (
Bilotta et al 2007).
Limitations of this study
The small and heterogenous study groups limit the conclusions that can be drawn concerning the effects of insulin, especially as patients with more severe hemorrhage are predominantly found in the insulin-treatment group. However, this was unavoidable as it seems not justifiable to exclude hyperglycemic patients from insulin treatment considering the strong evidence for an association between hyperglycemia and unfavorable outcome. Further, microdialysis is a regional method and the volume of brain tissue monitored by the microdialysis catheter covers only a few millimeters from the membrane. Some possibly serious effects of insulin on blood glucose might not have been detected because of the discontinuous blood glucose monitoring. To evaluate whether normalization of cerebral glucose levels can improve outcome in SAH patients, further studies are necessary.
