Treatment Of Hyperglycemia

Although the association between hyperglycemia and poor outcome is well established in stroke patients, it remains unclear if patients benefit from tight glycemic control. In experimental stroke reduction in blood, glucose with insulin to the lower physiological range (3-4 mmol/L) reduced infarction size (118, 119). In human studies, treatment of hyperglycemia in patients with stroke remains the subject of debate.

Current guidelines from the American Heart Association (AHA) for the treatment of both ischemic (6) and hemorrhagic (5) stroke are cautious due to lack of evidence. Both guidelines state that "glucose concentrations

(possibly >7.8-10.3 mmol/L) should probably trigger the administration of insulin." This recommendation is based on two observations: first, the increased risk of poor outcome associated with hyperglycemia; second, the accumulating evidence from trials in other medical emergencies than stroke which demonstrates that tight glycemic control improves outcome such as in patients admitted to the ICU (3,120), patients with myocardial infarction (2, 121), or patients undergoing coronary artery bypass grafting (CABG) (122, 123). These results, however, cannot directly be extrapolated to patients with stroke and only a randomized clinical trial (RCT) can resolve this matter. Currently one RCT, the GIST-UK trial, has been published (17). The results of this very pragmatic trial did not favor tight glycemic control (OR for 90-day mortality: 1.1; 95%CI: 0.9-1.5). This trial, however, was affected by a premature discontinuation of patient recruitment (933 patients instead of the proposed sample size of 2,355 patients) and some other issues that will be outlined in the following paragraphs. In a retrospective study including 295 stroke patients, glycemic control was associated with a greater proportion of patients discharged home and a trend toward fewer in-hospital deaths (124).

The results of further trials that are currently still including patients or have recently been completed are eagerly awaited (125, 126). Although in these trials, clinical outcome is only a secondary outcome measure, the results can provide some indication of the effect of tight glycemic control on clinical outcome.

If one decides to treat hyperglycemia in patients with stroke, this poses several questions. It is not clear whether all type of stroke patients will benefit from glycemic control, which glucose levels should be targeted, and for how long this has to be maintained. Finally, although standard practice on the ICU, it is not clear how tight glycemic control can be practically implemented in stroke patients on a stroke care unit or regular ward.

We will address these questions in the following paragraphs, and we will attempt to give some directions for further research.

Who will Benefit from Glycemic Control?

The association between hyperglycemia and poor outcome varies for different stroke subtypes and is less clear in stroke patients with a history of DM compared to non-diabetic stroke patients (8, 16). These observations should warrant caution in selecting patients for treatment. In fact, the observation that hyperglycemia might even be beneficial in a subgroup of patients with lacunar infarction suggests that these patients should be abstained from intensive glycemic control maintaining glucose values in the lower physiological range. The GIST-UK trial included different types of stroke patients (including 21% lacunar infarction and 12% primary hemorrhagic stroke) irrespective of a previous history of DM (17% of included patients) (17). This could have contributed to the lack of efficacy of glycemic control on clinical outcome. A more directed approach, by selecting patients with cortical ischemic stroke, such as is currently performed in the GRASP trial (126), probably maximizes the probability to find a treatment effect associated with glycemic control. Such an approach does not suffer from a reduction in treatment effect due to the inclusion of patients where a minimal effect is anticipated and would therefore require fewer patients (127).

What Glucose Levels should be Targeted?

Some lessons can be learned from trials in other patient populations regarding the target to aim for (Table 1). The DIGAMI I study (2), a trial that investigated the clinical efficacy of glycemic control in patients with myocardial infarction, showed a significant 1-year mortality reduction of 29%. In a subsequent study, the DIGAMI II, these findings could not be reproduced (128). The lack of efficacy in the DIGAMI II is probably explained by the observation that during the decade that separated these trials the routine treatment of hyperglycemia in patients admitted for myocar-dial infarction had been intensified. Due to this, in DIGAMI II the control patients had relatively low mean glucose levels (10.0mmol/L) that are in fact comparable to the glucose levels of the treatment group in DIGAMI I (9.6 mmol/L). Tight glycemic control in DIGAMI II did not establish a contrast in the mean glucose levels between the treatment and control group which could explain the lack of treatment effect on clinical outcome.

Results from the GIST-UK trial in stroke patients (mean contrast in plasma glucose between the groups 0.57 mmol/L [17]) as well as the results from trials in other medical emergencies (121, 129, 130) also demonstrate that without a significant effect of tight glycemic control on the mean glucose level no benefit on clinical outcome was found. In contrast, most, but not all (131,132), trials that targeted glucose values in a lower physiological range (4.4-6.1. mmol/L), with intensive glucose control and/or that accomplished a contrast in the mean glucose levels between the treatment and control group, demonstrate a beneficial effect on clinical outcome when patients are treated for more than 2 days (3,120,122,123). We therefore suggest that for future clinical trials in stroke patients to be effective on clinical outcome, adequate glycemic control and targeting glucose levels in the lower physiological range are of paramount importance. Caution, however, is warranted as maintaining glucose values in the lower physiological range can result in an increase in (severe) hypoglycemic episodes with potential harmful effects (132).

Table 1

Overview of glucose lowering trials

Difference in

Intervention (duration) mean glucose and target glucose between Treatment effect

Author/Study Publication, Target levels in treatment treatment and on clinical

Difference in

Intervention (duration) mean glucose and target glucose between Treatment effect

Author/Study Publication, Target levels in treatment treatment and on clinical

name

Year

population (N)

group (mmol/L)

Endpoint

controls

outcome

Malmberg/ DIG AMI 1(2)

1995 and 1999

AMI (620)

IV insulin/24 h, followed by SC insulin > 3 months Target: 7-11

Mortality at

• 3.4 years

• 3.4 years: yes

Diaz / ECLA study (121)

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