Elsevier

The Lancet Neurology

Volume 6, Issue 5, May 2007, Pages 397-406
The Lancet Neurology

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Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK)

https://doi.org/10.1016/S1474-4422(07)70080-7Get rights and content

Summary

Background

Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days.

Methods

Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6·0–17·0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4–7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803)

Findings

The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1·14, 95% CI 0·86–1·51, p=0·37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0·57 mmol/L, p<0·001; mean difference in blood pressure 9·0 mmHg, p<0·0001).

Interpretation

GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.

Introduction

Accumulating evidence suggests that the provision of organised stroke care is associated with improved outcomes, namely reduced mortality, dependency, and the need for institutional care. Although it is not clear precisely what aspect of stroke-unit care confers these benefits, the differing processes of care (early mobilisation, early identification, and management of swallowing disorders and infection) would seem to be associated with improved patient outcomes. An integral part of acute stroke care has become the measurement and monitoring of physiological variables, including plasma glucose concentration, which if increased has been shown to be associated with an adverse prognosis after stroke.1, 2, 3

Post-stroke hyperglycaemia is a common finding with a reported prevalence of 43–68%.4 Whereas post-stroke hyperglycaemia possibly represents a stress response to a large cerebral event, it is prevalent across the spectrum of stroke severities and is not just confined to those most severely affected (total anterior circulation syndromes).5 Several large clinical studies have now shown a positive association between post-stroke hyperglycaemia and poor outcome from stroke in terms of greater mortality and reduced functional recovery.4, 5, 6, 7 There are many potential mechanisms by which hyperglycaemia can exert a harmful effect on cerebral tissue, and thus an important relation probably exists between glucose and stroke outcome. Hyperglycaemia is also a common finding after myocardial infarction and in patients with major acute medical and surgical illness, and there is increasing evidence that intensive management of hyperglycaemia with an insulin-based regimen may be associated with benefit.8, 9, 10, 11

The UK Glucose Insulin in Stroke Trial (GIST-UK) research programme has previously shown12 both the practicability and effectiveness of glucose-potassium-insulin (GKI) infusions to correct hyperglycaemia and maintain euglycaemia in the first 24 h after stroke. Although routine management of post-stroke hyperglycaemia has increasingly become part of acute stroke care, there is no clinical evidence for its safety and efficacy.12 By means of a pragmatic randomised controlled clinical trial we sought to determine whether outcome from acute stroke can be favourably influenced by GKI-induced and GKI-maintained euglycaemia, if delivered as part of routine clinical care.

Section snippets

Methods

GIST-UK was an academic multicentre randomised controlled trial with blinded outcome assessments that compared GKI-induced and GKI-maintained euglycaemia with euvolaemic saline hydration and no glucose management in the first 24 h after hospital admission with acute stroke. The trial was done in accordance with the UK 2004 Medicines for Human Use (Clinical Trials) Regulations,13 with City Hospitals Sunderland acting as sponsor for the trial. GIST-UK was approved by the UK multicentre research

Results

933 patients were randomly assigned treatment, seven of whom were withdrawn from the trial before treatment was started due to protocol violations identified after randomisation (six patients) and in one case, withdrawal of consent. Trial treatment was discontinued in a further 27 patients because of protocol violations (figure 1). Overall, 899 (96·4%) patients were randomised within the protocol and received some or all of the treatment. These patients were analysed as the safety dataset. The

Discussion

This randomised clinical trial (GIST-UK) sought to assess the effectiveness of glucose modulation with insulin in acute stroke. Despite repeated observations of an association between hyperglycaemia and stroke outcome,4 we found no beneficial effect for GKI treatment on the primary and secondary outcomes, as outlined in the trial protocol. Furthermore, there was no evidence for benefit in any of the subgroups represented by the prespecified stratification variables.

GIST-UK was also designed as

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