Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment. Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Glucose Regulation in Acute Stroke Patients (GRASP) trial: a randomized pilot trial.
In patients with acute ischaemic stroke, hyperglycaemia has been retrospectively associated with negative outcome. There is an ongoing discussion as to which treatment algorithm, if any, provides the most effective prospective intervention. Here we test the safety and feasibility of an intravenous insulin-only infusion protocol designed for pragmatic routine clinical use.
                40 ischaemic stroke patients with onset <24 h ago, admitted to our stroke unit, were randomized either to the study regimen (50 IU insulin in 50 ml 0.9% saline solution applied intravenously via a perfusor pump), with the aim of reaching and maintaining blood glucose levels between 4.44 mmol/l (80 mg/dl) and 6.11 mmol/l (110 mg/dl), or were treated with insulin subcutaneously if concentrations were above 11.10 mmol/l (200 mg/dl). Treatment was continued for 5 days. Primary outcome was the number of hypoglycaemic (<3.33 mmol/l; <60 mg/dl) and severe hyperglycaemic (>16.65 mmol/l; >300 mg/dl) events.
                Hypoglycaemic events were significantly more common in patients treated intensively (total n = 25; incidence rate ratio, IRR = 5.3; 95% CI = 1.2-22.4; p < 0.05). Symptomatic events were rare (total n = 5). Severe hyperglycaemia was associated with conventional treatment (IRR = 4.9; 95% CI = 1.5-15.9; p < 0.05). Though those treated intensively attained near-normoglycaemic levels quicker and had significantly lower blood glucose levels over the study period (6.49 +/- 2.19 mmol/l vs. 8.01 +/- 3.06 mmol/l; 95% CI = -1.78 to -1.28, p < 0.0005), treatment imposes considerable strain on both patients and caregivers.
                The intensive intravenous insulin infusion protocol effectively lowers blood glucose levels with an increased risk of manageable hypoglycaemic events. However, a highly motivated and trained staff seems essential, limiting feasibility outside of specialty care settings.
                Copyright (c) 2008 S. Karger AG, Basel. Hyperglycemia may worsen brain injury during acute cerebral infarction. We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infarction.
                We conducted a randomized, multicenter, blinded pilot trial for patients with cerebral infarction within 12 hours after onset, a baseline glucose value >or=8.3 mmol/L (>or=150 mg/dL), and a National Institutes of Health Stroke Scale score of 3 to 22. Patients were randomized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed (usual care). Target glucose levels were <7.2 mmol/L (<130 mg/dL) in the aggressive-treatment group and <11.1 mmol/L (<200 mg/dL) in the usual-care group. Glucose was monitored every 1 to 2 hours, and the protocol treatments continued for up to 72 hours. Final clinical outcomes were assessed at 3 months.
                We randomized 46 patients (31 to aggressive treatment and 15 to usual care). All patients in the aggressive-treatment group and 11 (73%) in the usual-care group had diabetes (P=0.008). Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment (7.4 vs 10.5 mmol/L [133 vs 190 mg/dL], P<0.001). Hypoglycemia <3.3 mmol/L (<60 mg/dL) occurred only in the aggressive-treatment group (11 patients, 35%), 4 (13%) of whom had brief symptoms, including only 1 (3%) neurologic. Final clinical outcomes were nonsignificantly better in the aggressive-treatment group.
                The intravenous insulin protocol corrected hyperglycemia during acute cerebral infarction significantly better than usual care without major adverse events and should be investigated in a clinical efficacy trial. Hyperglycaemia on presentation with acute ischaemic stroke (AIS) is associated with poor outcome, but intervention is unproven. We investigated the safety and tolerability of one method of glycaemic control.
                Patients within 24 h of AIS and plasma glucose 8-20 mmol/l were randomised to receive either rigorous glycaemic control (RC) or standard management (SM) for 48 h. RC comprised i.v. insulin at a variable rate adjusted for target glucose concentration of 5-8 mmol/l, and intravenous crystalloid. The SM group received intravenous crystalloid alone in an open-label design.
                Thirteen patients were randomised to RC and 12 to SM (age 75 +/- 6.2 years; 40% male; 20% lacunar stroke; time to treatment 8 +/- 6.1 h; plasma glucose 10.6 +/- 0.9 mmol/l; known diabetes 52%; NIHSS 8, range 2-28). The glucose concentration-time curve was reduced in the RC group (AUC 324 +/- 15 versus 385 +/- 28 h.mmol/l, p = 0.04). By 48 h, plasma glucose in both groups was 6.8 +/- 1.1 and 7.5 +/- 1.3 mmol/l respectively, but mean hourly insulin requirements in the RC group had dropped from 3.25 +/- 0.32 units to 1.25 +/- 0.5 units (p < 0.01). One transient episode of hypoglycaemic symptoms occurred in the RC group.
                Glycaemic control with sliding scale insulin for 48 h is feasible and well-tolerated after AIS. Treatment after 48 h may be unnecessary.
                Copyright 2006 S. Karger AG, Basel. 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.
                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)
                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).
                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. Hyperglycemia is associated with worse outcome in patients with acute stroke.
                We conducted a prospective, randomized, multicenter, 3-arm trial (tight control [target 70 to 110 mg/dL], loose control [target 70 to 200 mg/dL], and control usual care [70 to 300 mg/dL]) to assess the feasibility and safety of 2 insulin infusion protocol targets in patients with acute ischemic stroke. The planned sample was 72 subjects.
                A total of 74 subjects were enrolled. Seventy-two (97%) had data available for the primary analyses and 73 (99%) had 3-month clinical outcome data. Median age was 67 years, median National Institutes of Health Stroke Scale score was 8, median glucose was 163 mg/dL, and median time to randomization was 10.7 hours. Fifty-nine percent of patients were diabetic, 35% received thrombolysis, and 14% of subjects died within 3 months. The loose control and usual care groups had median glucose concentrations of 151 mg/dL. The tight control group had a median glucose concentration of 111 mg/dL. The loose control group spent 90% of the first 24 hours in target and the tight group 44% of time in target. There was only one symptomatic patient with hypoglycemia in the loose control group (4%) and zero in the tight control group. The overall rates of hypoglycemia (<55 mg/dL) were 4% in control, 4% in loose, and 30% in tight. Exploratory efficacy analysis was conducted.
                Insulin infusion for patients with acute ischemic stroke is feasible and safe using the insulin infusion protocol in the Glucose Regulation in Acute Stroke Patients (GRASP) trial. Exploratory efficacy analysis supports further comparative study.
With the current evidence, we found that the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischaemic stroke does not provide benefit in terms of functional outcome, death, or improvement in final neurological deficit and significantly increased the number of hypoglycaemic episodes. Specifically, those who were maintained within a more tight range of glycaemia with intravenous insulin experienced a greater risk of symptomatic and asymptomatic hypoglycaemia than those individuals in the control group.