The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines, is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website www.eso-stroke.org

A. Karolinska Stroke Update Consensus Statement

Management of hyperglycemia and diabetes mellitus in stroke

The following Consensus Statement was adopted by the 7th Karolinska Stroke Update meeting on November 18, 2008.

The consensus statement was proposed by the chairman of the session, Dr Keith Muir, Glasgow and the session secretary Dr Christina Sjöstrand, Stockholm, together with the speakers of the session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The text in the consensus statement is a revision of the current ESO guidelines.

The speakers in this session were Professor Per Wester, Umeå, and Professor Natan Bornstein, Tel Aviv.

Controversies to discuss at the 2008 consensus session:

• How frequently should blood glucose be monitored in acute stroke patients?
• Should hyperglycaemia be actively managed in non-diabetic patients in the acute phase?
• At what threshold should hyperglycaemia be actively treated with insulin-based therapies?
• If commenced, for how long should intensive glucose-lowering therapy be continued?
• What regime should be used for glucose control?
• How should acute phase hyperglycaemia be followed up?

Background

Hyperglycaemia occurs in up to 60% of stroke patients without known diabetes [1,2]. Hyperglycaemia after acute stroke is associated with larger infarct volumes and cortical involvement, and with poor functional outcome [3-5]. However, a causal link between hyperglycaemia and acute stroke worsening has not been clearly demonstrated. Glucose levels vary over the first 48 hours after stroke and are influenced by fluid regimes and feeding: it is not clear when blood glucose should be measured, or whether (or how frequently) it should be routinely repeated [4,6]. There is at present no evidence that active reduction of glucose in acute ischaemic stroke improves patient outcomes. The largest randomized trial of blood glucose lowering by glucose potassium insulin infusion [7], compared with standard intravenous saline infusion, found no difference in mortality or functional outcomes in patients with mild-to-moderate blood glucose elevations [median 137 mg/dl (7.6 m M )]. This regime was labour intensive and associated with episodes of hypoglycaemia.
Alternative insulin delivery regimes (eg IV or subcutaneous insulin infusion) have limited clinical evidence of safety and feasibility in acute stroke and more intensive insulin regimes may be associated with a higher risk of hypoglycaemia [8]. There are insufficient data on clinical outcomes from trials at present.

Discussion

Hyperglycemia

At present, the routine use of insulin infusion regimes in patients with moderate hyperglycaemia (up to 10mM / 180mg/dl) is not recommended. It is common practice in stroke units to reduce blood glucose levels exceeding 180 mg/dl (10 m M ) [9]. A recent study supports conventional rather than intensive glucose control in critically ill patients [10]. The use of intravenous saline and avoidance of glucose solutions in the first 24 h after stroke is common practice, and appears to reduce blood glucose levels.[7] The duration of treatment that is required is uncertain.

Acute phase hyperglycaemia may signify underlying impaired glucose tolerance or unrecognized diabetes, and repeat glucose measurement or glucose tolerance testing should be considered at review.[11]

Hypoglycaemia [ < 50 mg/dl (2.8 mM )] may mimic an acute stroke, and if present at initial presentation should be treated by intravenous dextrose bolus or infusion of 10–20% glucose. [12]

Secondary prevention after stroke in type II diabetics

The prospective, double-blind PROactive trial [13] randomized 5,238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone or placebo. In
patients with previous stroke (n=486 in the pioglitazone group, n=498 in the placebo
group), there was a trend towards benefit with pioglitazone for the combined end
point of death and major vascular events (HR 0.78; 95% CI 0.60-1.02; P=0.067). In a
secondary analysis, pioglitazone reduced fatal or nonfatal stroke (HR 0.53; 95% CI
0.34-0.85; P=0.0085) and cardiovascular death, nonfatal myocardial, or nonfatal stroke (HR 0.72; 95% CI 0.52-1.00; P=0.0467).

In patients with type II diabetes and CVD (appr one third of the study population) or other risk factors for CVD, two large clinical trials (The Action to Control Cardiovascular Risk in Diabetes Study Group, ACCORD and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial) randomized more than 21.000 patients to intensive glucose control aiming at glycated hemoglobin of ≤ 6,5 or ≤ 6.0% vs. ordinary treatment (7.0-7.9%). The ACCORD study [14 ] was stopped prematurely after an average follow time of 3,5 years due to excessive risk of death in the active treatment group. In the ADVANCE study,[15] there were fewer subjects who experienced new or worsening nephropathy, while the effect on retinopathy was neutral. Major macro-vascular complications including nonfatal stroke, nonfatal myocardial infarction and cardiovascular death were without difference between the study groups in the ADVANCE study. In the ACCORD and ADVANCE studies, more patients in the intensive glucose control group experienced hypoglycemic symptoms. Sub-group analyses of the effects in type II diabetics with stroke as inclusion criterion have not been published.

References:

    1   Kiers L, Davis SM, Larkins R, Hopper J, Tress B, Rossiter SC et al. Stroke topography and outcome in relation to hyperglycaemia and diabetes. J Neurol Neurosurg Psych 1992;55:263-70.

    2   Van Kooten F, Hoogerbrugge N, Naarding P, Koudstaal PJ. Hyperglycemia in the acute phase of stroke is not caused by stress. Stroke 1993;24:1129-32.

    3   Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol 2002;52:20-8.

    4   Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003;34:2208-14.

    5   Baird TA, Parsons MW, Barber PA, Butcher KS, Desmond PM, Tress BM et al. The influence of diabetes mellitus and hyperglycaemia on stroke incidence and outcome. J Clin Neurosci 2002;9:618-26.

    6   Wong AA, Schluter PJ, Henderson RD, O'Sullivan JD, Read SJ. Natural history of blood glucose within the first 48 hours after ischemic stroke. Neurology 2008;70:1036-41.

    7   Gray CS, Hildreth AJ, Sandercock PA, O'Connell JE, Johnston DE, Cartlidge NE et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007;6:397-406.

    8   Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ et al. Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke 2008;39:384-9.

    9   Langhorne P, Pollock A. What are the components of effective stroke unit care? Age Ageing 2002;31:365-71.

10   NICE-SUGAR Study Investigators. Intensive vs conventional glucose control in critically ill patients. N.Engl.J.Med 2009; 360: 1283-1297

  11   Gray CS, Scott JF, French JM, Alberti KG, O'Connell JE. Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke. Age Ageing 2004;33:71-7.

  12   Huff JS: Stroke mimics and chameleons. Emerg Med Clin North Am 2002;20:583-595

13 Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, Dormandy J: Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865-873
 
  14   Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, Buse JB et al. Effects of intensive glucose lowering in type 2 diabetes. N.Engl.J Med. 2008;358:2545-59.

  15   Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N.Engl.J.Med. 2008;358:2560-72.

B. Recommendation by Karolinska Stroke Update participants to ESO Guidelines Committee to revise ESO guidelines:

New text marked red

Secondary prevention

Optimal management of vascular risk factors

Recommendations

§ It is recommended that blood glucose should be checked regularly. It is
recommended that diabetes should be managed with lifestyle modification and
individualized pharmacological therapy (Class IV, GCP).