Systematic review Intravenous insulin treatment in acute stroke: a systematic review and meta-analysis of randomized controlled trials G. Ntaios1*, V. Papavasileiou1, A. Bargiota2, K. Makaritsis1, and P. Michel3 Introduction Poststroke hyperglycemia has been associated with unfavorable outcome. Several trials investigated the use of intravenous insulin to control hyperglycemia in acute stroke. This meta-analysis summarizes all available evidence from randomized controlled trials in order to assess its efficacy and safety. Methods We searched PubMed until 15/02/2013 for randomized clinical trials using the following search items: ‘intravenous insulin’ or ‘hyperglycemia’, and ‘stroke’. Eligible studies had to be randomized controlled trials of intravenous insulin in hyperglycemic patients with acute stroke. Analysis was performed on intention-to-treat basis using the Peto fixed-effects method. The efficacy outcomes were mortality and favorable functional outcome. The safety outcomes were mortality, any hypoglycemia (symptomatic or asymptomatic), and symptomatic hypoglycemia. Results Among 462 potentially eligible articles, nine studies with 1491 patients were included in the meta-analysis. There was no statistically significant difference in mortality between patients who were treated with intravenous insulin and controls (odds ratio: 1·16, 95% confidence interval: 0·89–1·49). Similarly, the rate of favorable functional outcome was not statistically different (odds ratio: 1·01, 95% confidence interval: 0·81–1·26). The rates of any hypoglycemia (odds ratio: 8·19, 95% confidence interval: 5·60–11·98) and of symptomatic hypoglycemia (odds ratio: 6·15, 95% confidence interval: 1·88– 20·15) were higher in patients treated with intravenous insulin. There was no heterogeneity across the included trials in any of the outcomes studied. Conclusions This meta-analysis of randomized controlled trials does not support the use of intravenous insulin in hyperglycemic stroke patients to improve mortality or functional outcome. The risk of hypoglycemia is increased, however. Key words: acute stroke, functional outcome, hypoglycemia, intravenous insulin, mortality, poststroke hyperglycemia Correspondence: George Ntaios*, Department of Medicine & Research Lab, Medical School, University of Thessaly, Biopolis 41110, Larissa, Greece. E-mail: [email protected] 1 Department of Medicine and Research Lab, Medical School, University of Thessaly, Larissa, Greece 2 Department of Endocrinology, Medical School, University of Thessaly, Larissa, Greece 3 Neurology Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Received: 18 June 2013; Accepted: 14 October 2013; Published online 29 December 2013 Conflict of interest: GN was supported with scholarships from the European Stroke Organization and the Hellenic Society of Atherosclerosis. VP was supported with scholarships from the European Stroke Organization and the Hellenic Society of Atherosclerosis. AB and KM have no disclosures. PM has received speaker honoraria from Bayer and Boehringer Ingelheim and honoraria from scientific advisory boards for Bayer, Pfizer and Boehringer Ingelheim. He serves on the editorial board of the International Journal of Stroke. Funding: None. DOI: 10.1111/ijs.12225 © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization
Introduction Hyperglycemia is a frequent finding in patients with acute stroke (1). Human and animal model studies have shown that it exerts a deleterious effect on the ischemic brain mediated by several pathophysiologic pathways (2). Glycemia in the acute phase of stroke has been shown to be an independent predictor of stroke outcome (3). In this context, several trials have tried to investigate whether glucose control with intravenous insulin infusion in acute stroke patients is associated with improved outcome; however, results have been inconclusive (4–13). This meta-analysis summarizes all available evidence from randomized controlled trials of intravenous insulin in acute stroke patients in order to assess its efficacy and safety.
Methods Search strategy and inclusion criteria We searched PubMed for potentially eligible trials from 01/01/ 1966 to 15/02/2013. The search items were ‘intravenous insulin’ or ‘hyperglycemia’, and ‘stroke’. We also screened the references of related letters, editorials, reviews, and meta-analyses to identify potentially eligible studies. Eligible studies had to be randomized controlled trials of intravenous insulin in hyperglycemic patients with acute stroke, both blinded or not. This work was performed according to the PRISMA statement (14). Outcomes and data extraction The efficacy outcomes analyzed were mortality and functional outcome. The safety outcomes analyzed were mortality, any hypoglycemia (asymptomatic or symptomatic), and symptomatic hypoglycemia. For each outcome, sub-group analysis was also performed according to the control intervention (subcutaneous insulin or normal saline). Data extraction was performed independently by two reviewers (G. N. and V. P.). For each outcome, the number of patients who were originally randomized to each treatment arm was extracted. In case that data were unavailable in the current publications, the trial investigators were contacted personally. Any uncertainty about the extracted data was resolved by consensus among the authors. Statistical analysis Data were analyzed in an intention-to-treat basis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each outcome using the Peto fixed-effects method. Heterogeneity between trials was assessed by the I2 index, which measures the percentage of the variability in effect estimates that is attributable to heterogeneity. All analyses were performed with the Review Manager (RevMan) version 5·1 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, Copenhagen, Denmark). Vol 9, June 2014, 489–493
489
Systematic review Potentially eligible publications (n=462)
Not relevant studies (n=319)
Letters-to-the-Editor or editorials (n=43)
Review articles or meta-analyses (n=90)
Overlap with the main publication of the trial (n=1)
Studies included in the meta-analyses (n=9) Fig. 1 Flowchart of search and study selection strategy.
Results Among 462 potentially eligible publications that were identified in the literature, nine studies fulfilled our criteria and were included in the analysis (Fig. 1). Among 1491 patients included in these trials, 766 patients were allocated to intravenous insulin infusion and 725 formed the control group. The vast majority were patients with ischemic strokes with only 114 patients (7·6%) with primary intracerebral hemorrhage recruited in one trial (11). Various intravenous insulin regimens were used in the included studies: (a) 400 ml of 0·9% NaCl, 40 ml of 3% KCl, 10 ml of 25% magnesium sulfate and Farmasulin (Farmak, Ukraine) (13); (b) infusion of insulin (Human Actrapid, Novo Nordisk, Bagsværd, Denmark) with dosage adjustment according to a sliding scale (4); (c) 500 ml glucose-potasium-insulin regimen of 10% dextrose and 20 mmol potassium chloride with an initial insulin dose of 16 units of soluble recombinant human insulin (11); (d) 50 IU of actrapid insulin in 50 ml of 0·9% sodium chloride with an initial infusion dose of 2 IU/h (6); (e) 25 IU in 500 ml normal saline (5); (f) 50 IU normal insulin in 50 ml of 0·9% saline solution (9); (g) Novolin brand insulin in normal saline (1 U/1 ml) as a continuous infusion (10); (h) 500 ml of 10% dextrose, 20 mmol potassium chloride, and 16 units of soluble recombinant human insulin (8); and (i) soluble human Actrapid insulin was administered in an intravenous continuous infusion with hourly dose adaptation (7). The control group was treated with normal saline in three studies (4,8,11) or subcutaneous insulin in five studies (5–7,9,10). Various target glycemia levels were used: 3·9–6·1 mmol/l (10), 4–7 mmol/l (8,11), 4·4–6·1 mmol/l (9), 4·4–7 mmol/l (6), 5–7·2 mmol/l (5), 5–7·9 mmol/l (4), and < 7 mmol/l (7,13). Favorable outcome was defined with the modified Rankin score in six studies (5–9,11) and the Barthel index in two studies (10,13). Favorable outcome and mortality were assessed at 1
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Vol 9, June 2014, 489–493
G. Ntaios et al. (8,13), 3 (5–7,10,11), or 4 (9) months after stroke. Hypoglycemia was defined as a glucose value
Introduction Hyperglycemia is a frequent finding in patients with acute stroke (1). Human and animal model studies have shown that it exerts a deleterious effect on the ischemic brain mediated by several pathophysiologic pathways (2). Glycemia in the acute phase of stroke has been shown to be an independent predictor of stroke outcome (3). In this context, several trials have tried to investigate whether glucose control with intravenous insulin infusion in acute stroke patients is associated with improved outcome; however, results have been inconclusive (4–13). This meta-analysis summarizes all available evidence from randomized controlled trials of intravenous insulin in acute stroke patients in order to assess its efficacy and safety.
Methods Search strategy and inclusion criteria We searched PubMed for potentially eligible trials from 01/01/ 1966 to 15/02/2013. The search items were ‘intravenous insulin’ or ‘hyperglycemia’, and ‘stroke’. We also screened the references of related letters, editorials, reviews, and meta-analyses to identify potentially eligible studies. Eligible studies had to be randomized controlled trials of intravenous insulin in hyperglycemic patients with acute stroke, both blinded or not. This work was performed according to the PRISMA statement (14). Outcomes and data extraction The efficacy outcomes analyzed were mortality and functional outcome. The safety outcomes analyzed were mortality, any hypoglycemia (asymptomatic or symptomatic), and symptomatic hypoglycemia. For each outcome, sub-group analysis was also performed according to the control intervention (subcutaneous insulin or normal saline). Data extraction was performed independently by two reviewers (G. N. and V. P.). For each outcome, the number of patients who were originally randomized to each treatment arm was extracted. In case that data were unavailable in the current publications, the trial investigators were contacted personally. Any uncertainty about the extracted data was resolved by consensus among the authors. Statistical analysis Data were analyzed in an intention-to-treat basis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each outcome using the Peto fixed-effects method. Heterogeneity between trials was assessed by the I2 index, which measures the percentage of the variability in effect estimates that is attributable to heterogeneity. All analyses were performed with the Review Manager (RevMan) version 5·1 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, Copenhagen, Denmark). Vol 9, June 2014, 489–493
489
Systematic review Potentially eligible publications (n=462)
Not relevant studies (n=319)
Letters-to-the-Editor or editorials (n=43)
Review articles or meta-analyses (n=90)
Overlap with the main publication of the trial (n=1)
Studies included in the meta-analyses (n=9) Fig. 1 Flowchart of search and study selection strategy.
Results Among 462 potentially eligible publications that were identified in the literature, nine studies fulfilled our criteria and were included in the analysis (Fig. 1). Among 1491 patients included in these trials, 766 patients were allocated to intravenous insulin infusion and 725 formed the control group. The vast majority were patients with ischemic strokes with only 114 patients (7·6%) with primary intracerebral hemorrhage recruited in one trial (11). Various intravenous insulin regimens were used in the included studies: (a) 400 ml of 0·9% NaCl, 40 ml of 3% KCl, 10 ml of 25% magnesium sulfate and Farmasulin (Farmak, Ukraine) (13); (b) infusion of insulin (Human Actrapid, Novo Nordisk, Bagsværd, Denmark) with dosage adjustment according to a sliding scale (4); (c) 500 ml glucose-potasium-insulin regimen of 10% dextrose and 20 mmol potassium chloride with an initial insulin dose of 16 units of soluble recombinant human insulin (11); (d) 50 IU of actrapid insulin in 50 ml of 0·9% sodium chloride with an initial infusion dose of 2 IU/h (6); (e) 25 IU in 500 ml normal saline (5); (f) 50 IU normal insulin in 50 ml of 0·9% saline solution (9); (g) Novolin brand insulin in normal saline (1 U/1 ml) as a continuous infusion (10); (h) 500 ml of 10% dextrose, 20 mmol potassium chloride, and 16 units of soluble recombinant human insulin (8); and (i) soluble human Actrapid insulin was administered in an intravenous continuous infusion with hourly dose adaptation (7). The control group was treated with normal saline in three studies (4,8,11) or subcutaneous insulin in five studies (5–7,9,10). Various target glycemia levels were used: 3·9–6·1 mmol/l (10), 4–7 mmol/l (8,11), 4·4–6·1 mmol/l (9), 4·4–7 mmol/l (6), 5–7·2 mmol/l (5), 5–7·9 mmol/l (4), and < 7 mmol/l (7,13). Favorable outcome was defined with the modified Rankin score in six studies (5–9,11) and the Barthel index in two studies (10,13). Favorable outcome and mortality were assessed at 1
490
Vol 9, June 2014, 489–493
G. Ntaios et al. (8,13), 3 (5–7,10,11), or 4 (9) months after stroke. Hypoglycemia was defined as a glucose value
