data prospectively collected in the canadian alteplase for stroke effectiveness study ( cases ) were analyzed ( 16 ) . this was a national prospective cohort study that led to the full approval of iv - tpa for acute ischemic stroke in canada . sixty sites across the country participated over a period of 2.5 years and , where relevant , each center obtained institutional ethics approval for data collection . patients were treated at the discretion of the site neurologist according to canadian guidelines for intravenous thrombolytic treatment in acute stroke ( 17 ) . baseline demographic data were obtained as were pretreatment basic blood tests and data regarding timing of drug administration and stroke subtype as de - termined by the site investigator using the oxfordshire community stroke project classification . baseline glucose was determined before iv - tpa administration , either by laboratory blood testing or from capillary blood . the particular method used was determined by the site 's own usual practice and was not specifically recorded . the severity of the baseline neurological deficit was assessed with the national institutes of health stroke scale ( nihss ) before treatment . the nihss is a validated 11-domain systematic assessment tool that provides a quantitative measure of stroke - related neurologic deficit , such that a higher score corresponds to a more severe deficit ( mild 015 , severe > 15 , and maximum 42 ) . the outcome was measured using the 7-point modified rankin scale ( mrs ) at 90 days by clinicians who were not necessarily blinded to patients ' baseline glucose values . all patients underwent a follow - up head computed tomography ( ct ) scan at 2448 h. baseline and follow - up ct scans were centrally reviewed by a stroke neurologist and neuroradiologist blinded to clinical information , and the alberta stroke program early ct score ( aspects)was applied . aspects is a validated 10-point score assessing the extent of infarction in strokes of the middle cerebral artery using noncontrast ct . a lower score suggests a more extensive area of infarction ( minimum score 0 ) ( 18 ) . sich was defined as any hemorrhage documented on a follow - up ct scan that was associated with a decline in neurological status within the first 24 h after thrombolytic treatment as judged by the site investigator , who was not blinded to clinical information . asymptomatic ich involved hemorrhage on a follow - up ct scan without associated clinical deterioration . mmol / l in accordance with other studies ( 10,13,19 ) . as a primary analysis , patients were dichotomized into those with admission hyperglycemia and those without hyperglycemia and compared with regard to baseline characteristics , rate of sich , functional outcome at 90 days , and death . a secondary analysis examined the association of these outcomes with admission glucose as a continuous measure . fisher 's exact test and student 's t test were used to compare the two groups . both binomial regression and logistic regression were used to develop models for the three outcomes of interest depending upon use . the large sample size provided sufficient power to perform multivariable analysis . for graphical descriptions , multivariable logistic regression was used to plot adjusted curves . for tabular description of risk ratios ( rrs ) , multivariable binomial regression was used to identify predictors of outcome using a log - link function . the final models were all parsimonious models , meaning that variables that were not significant at p < 0.05 or variables that showed no evidence of confounding were eliminated from the final models . models were developed by backwards stepwise elimination beginning with the variables listed in table 1 . baseline patient characteristics data are means  sd , median , or n ( % ) . not all percentages are calculated from the total number of patients because certain clinical variables were not available for all patients . standard descriptive statistics were used to report the data . fisher 's exact test and student 's t test were used to compare the two groups . both binomial regression and logistic regression were used to develop models for the three outcomes of interest depending upon use . the large sample size provided sufficient power to perform multivariable analysis . for graphical descriptions , multivariable logistic regression was used to plot adjusted curves . for tabular description of risk ratios ( rrs ) , multivariable binomial regression was used to identify predictors of outcome using a log - link function . the final models were all parsimonious models , meaning that variables that were not significant at p < 0.05 or variables that showed no evidence of confounding were eliminated from the final models . models were developed by backwards stepwise elimination beginning with the variables listed in table 1 . baseline patient characteristics data are means  sd , median , or n ( % ) . not all percentages are calculated from the total number of patients because certain clinical variables were not available for all patients . of 1,135 patients enrolled in cases , 1,098 had adequate admission glucose data for inclusion in the current study . of these patients , median age was 73 years , 45% were women , 96% had an anterior circulation stroke , and 16% had a known prior history of diabetes . a glucose value of 8.0 mmol / l corresponded to the 75th percentile and , overall , 296 ( 27% ) patients had admission hyperglycemia . hyperglycemia was present in 70% of those with diabetes and 18% of those without diabetes . hyperglycemic patients were older ; were more likely to be non - caucasian ; were more likely to have atrial fibrillation , hypertension , congestive heart failure , coronary artery disease , and known diabetes ; and were less likely to be current smokers . the greater prevalence of comorbid illness in the hyperglycemic group is probably explained by older age and the higher proportion of diabetes . there were no differences in sex , stroke subtype , or baseline stroke severity between groups ( table 1 ) . a total of 49 ( 4.5% ) patients had sich . among hyperglycemic patients , this proportion was 6.8% compared with 3.6% for nonhyperglycemic patients ( p = 0.03 ) , resulting in an unadjusted rr of 1.87 ( 95% ci 1.073.25 ) for sich in patients with baseline glucose > 8.0 mmol / l ( table 2 ) . multivariable regression attenuated this relationship somewhat , yielding an adjusted rr of 1.69 ( 95% ci 0.953.00 ) . outcome at 90 days and sich in hyperglycemic ( baseline glucose > 8 mmol / l ) and nonhyperglycemic patients with unadjusted and adjusted rrs ( after multivariate logistic regression ) data are n ( % ) . not all percentages are calculated from the total number of patients because certain outcome variables were not available for all patients . clinical outcomes at 90 days , unadjusted for confounders , are shown in fig . 1 . only 80 ( 27.7% ) hyperglycemic patients experienced a favorable functional outcome ( mrs 01 ) compared with 316 ( 40% ) nonhyperglycemic patients ( p = 0.0002 ) . the proportion of patients who were dead at the 3 month follow - up was also significantly higher among patients with admission glucose > 8.0 mmol / l ( 30.8 vs. 18.7% , p < 0.0001 ) . unadjusted risk ratios for favorable outcome and death among hyperglycemic patients were 0.69 ( 95% ci 0.560.85 ) and 1.64 ( 1.312.06 ) , respectively . patient outcome at the 90-day follow - up by baseline glucose ( unadjusted for other predictors of outcome ) . mrs 01 , excellent outcome ; mrs 23 , moderate disability ; mrs 45 , severe disability ; and mrs 6 , dead . after multivariable regression , adjusted risk ratios were 0.7 ( 95% ci 0.50.9 ) for favorable outcome and 1.5 ( 1.21.9 ) for death . multivariable analysis showed that independent predictors of 90-day outcome and death were age , baseline nihss , baseline aspects , and admission glucose . each of these had a comparable magnitude of association with outcome . when dichotomized as age > 80 years , baseline nihss > 15 , and aspects > 7 , unadjusted rrs for favorable functional outcome were 0.64 ( 95% ci 0.520.80 ) , 0.40 ( 0.320.48 ) , and 1.53 ( 1.261.86 ) , respectively . the negative association between admission glucose and functional outcome and death persisted even after exclusion of patients with sich , a known independent predictor of death and disability after thrombolysis ( 4,20 ) . these relationships were not different for patients with and without diabetes ( no evidence of an interaction effect ) . no heterogeneity was found with regard to the association between baseline hyperglycemia and a favorable clinical outcome when analyzed by oxfordshire community stroke project stroke subtype (  test , p = 0.80 ) or when mild strokes ( nihss 5 ) and moderate - to - severe strokes were compared (  test , p = 0.29 ) , suggesting a deleterious effect of hyperglycemia on outcome regardless of stroke subtype or severity . with glucose as a continuous variable , the predicted probability of sich adjusted for age , atrial fibrillation , onset - to - treatment time , and sex was calculated and represented as a fractional polynomial estimate of best fit ( fig . similarly , the predicted probability of death at 90 days according to admission glucose , adjusted for age , baseline nihss , aspects , onset - to - treatment time , and sex was calculated and represented using a linear least - squares line of best fit ( fig . finally , the predicted probability of a favorable outcome at 90 days , adjusted for age , baseline nihss , aspects , congestive heart failure , atrial fibrillation , and diabetes was determined , yielding an inverse relationship between admission glucose levels and the probability of achieving an mrs of 01 ( fig . the predicted probability of a favorable outcome was also determined for only those patients with baseline glucose < 8 mmol / l . even among these nonhyperglycemic patients , a linear decline in the probability of a good outcome was seen with increasing glucose levels . quadratic polynomial line of best fit with range and 95% cis adjusted for age , baseline nihss score , sex , onset - to - treatment time , and atrial fibrillation . mmol / l of serum glucose , the relative risk of sich rises by 10% . the line and 95% cis are based upon a linear regression of predicted probability of death adjusted for age , baseline nihss score , sex , onset - to - treatment time , and baseline aspects score . for every 1 mmol / l rise in the baseline serum glucose , the probability of death at 90 days increases by an absolute risk of 2% . the line and 95% cis are derived from a fractional polynomial regression of baseline serum glucose and the predicted probability of good outcome adjusted for age , baseline nihss score , baseline aspects , sex , and onset - to - treatment time . for every increase of 1 mmol / l of baseline serum glucose , the relative risk of a good outcome falls by 12% . of 1,135 patients enrolled in cases , 1,098 had adequate admission glucose data for inclusion in the current study . of these patients , median age was 73 years , 45% were women , 96% had an anterior circulation stroke , and 16% had a known prior history of diabetes . a glucose value of 8.0 mmol / l corresponded to the 75th percentile and , overall , 296 ( 27% ) patients had admission hyperglycemia . hyperglycemia was present in 70% of those with diabetes and 18% of those without diabetes . hyperglycemic patients were older ; were more likely to be non - caucasian ; were more likely to have atrial fibrillation , hypertension , congestive heart failure , coronary artery disease , and known diabetes ; and were less likely to be current smokers . the greater prevalence of comorbid illness in the hyperglycemic group is probably explained by older age and the higher proportion of diabetes . there were no differences in sex , stroke subtype , or baseline stroke severity between groups ( table 1 ) . rates of ich , 90-day outcomes , and mortality are shown in table 2 . a total of 49 ( 4.5% ) patients had sich . among hyperglycemic patients , this proportion was 6.8% compared with 3.6% for nonhyperglycemic patients ( p = 0.03 ) , resulting in an unadjusted rr of 1.87 ( 95% ci 1.073.25 ) for sich in patients with baseline glucose > 8.0 mmol / l ( table 2 ) . multivariable regression attenuated this relationship somewhat , yielding an adjusted rr of 1.69 ( 95% ci 0.953.00 ) . outcome at 90 days and sich in hyperglycemic ( baseline glucose > 8 mmol / l ) and nonhyperglycemic patients with unadjusted and adjusted rrs ( after multivariate logistic regression ) data are n ( % ) . not all percentages are calculated from the total number of patients because certain outcome variables were not available for all patients . hyperglycemic patients experienced a favorable functional outcome ( mrs 01 ) compared with 316 ( 40% ) nonhyperglycemic patients ( p = 0.0002 ) . the proportion of patients who were dead at the 3 month follow - up was also significantly higher among patients with admission glucose > 8.0 mmol / l ( 30.8 vs. 18.7% , p < 0.0001 ) . unadjusted risk ratios for favorable outcome and death among hyperglycemic patients were 0.69 ( 95% ci 0.560.85 ) and 1.64 ( 1.312.06 ) , respectively . patient outcome at the 90-day follow - up by baseline glucose ( unadjusted for other predictors of outcome ) . mrs 01 , excellent outcome ; mrs 23 , moderate disability ; mrs 45 , severe disability ; and mrs 6 , dead . after multivariable regression , adjusted risk ratios were 0.7 ( 95% ci 0.50.9 ) for favorable outcome and 1.5 ( 1.21.9 ) for death . multivariable analysis showed that independent predictors of 90-day outcome and death were age , baseline nihss , baseline aspects , and admission glucose . when dichotomized as age > 80 years , baseline nihss > 15 , and aspects > 7 , unadjusted rrs for favorable functional outcome were 0.64 ( 95% ci 0.520.80 ) , 0.40 ( 0.320.48 ) , and 1.53 ( 1.261.86 ) , respectively . the negative association between admission glucose and functional outcome and death persisted even after exclusion of patients with sich , a known independent predictor of death and disability after thrombolysis ( 4,20 ) . these relationships were not different for patients with and without diabetes ( no evidence of an interaction effect ) . no heterogeneity was found with regard to the association between baseline hyperglycemia and a favorable clinical outcome when analyzed by oxfordshire community stroke project stroke subtype (  test , p = 0.80 ) or when mild strokes ( nihss 5 ) and moderate - to - severe strokes were compared (  test , p = 0.29 ) , suggesting a deleterious effect of hyperglycemia on outcome regardless of stroke subtype or severity . with glucose as a continuous variable , the predicted probability of sich adjusted for age , atrial fibrillation , onset - to - treatment time , and sex was calculated and represented as a fractional polynomial estimate of best fit ( fig . similarly , the predicted probability of death at 90 days according to admission glucose , adjusted for age , baseline nihss , aspects , onset - to - treatment time , and sex was calculated and represented using a linear least - squares line of best fit ( fig . finally , the predicted probability of a favorable outcome at 90 days , adjusted for age , baseline nihss , aspects , congestive heart failure , atrial fibrillation , and diabetes was determined , yielding an inverse relationship between admission glucose levels and the probability of achieving an mrs of 01 ( fig . 2c ) . the predicted probability of a favorable outcome was also determined for only those patients with baseline glucose < 8 mmol / l . even among these nonhyperglycemic patients , a linear decline in the probability of a good outcome was seen with increasing glucose levels . a : probability of sich by baseline glucose level . quadratic polynomial line of best fit with range and 95% cis adjusted for age , baseline nihss score , sex , onset - to - treatment time , and atrial fibrillation . for each increase of 1 mmol / l of serum glucose , the line and 95% cis are based upon a linear regression of predicted probability of death adjusted for age , baseline nihss score , sex , onset - to - treatment time , and baseline aspects score . for every 1 mmol / l rise in the baseline serum glucose , the probability of death at 90 days increases by an absolute risk of 2% . the line and 95% cis are derived from a fractional polynomial regression of baseline serum glucose and the predicted probability of good outcome adjusted for age , baseline nihss score , baseline aspects , sex , and onset - to - treatment time . for every increase of 1 mmol / l of baseline serum glucose this study further confirms the relationship between admission hyperglycemia and sich , death , and poor functional outcome in ischemic stroke patients treated with iv - tpa . our findings bolster and expand on those of previous studies , the majority of which examined smaller numbers of nonthrombolyzed stroke patients and some of which analyzed hemorrhagic and ischemic strokes together ( 13,10 ) . published studies of baseline hyperglycemia in stroke patients treated with thrombolysis have been few , were generally small , and often did not report 3-month outcomes ( 4,6,1215 ) . however , all have suggested an increased risk of poor outcome with elevated glucose , despite using different cutoff levels to define hyperglycemia ( from 7.7 to 10 mmol / l ) ( 4,6,1215 ) . one study included 312 tpa - treated patients from the original national institute of neurological disorders and stroke iv - tpa trial and analyzed these together with 312 placebo - treated patients ( 4 ) . this study showed that regardless of treatment assignment , as admission glucose level increased , the odds for a favorable outcome progressively decreased and the odds of sich increased ( 4 ) . a recent post hoc analysis of 748 patients from the european cooperative acute stroke study ( ecass - ii ) , a trial of iv - tpa given within 6 h of stroke onset , examined the prognostic value of hyperglycemia at baseline and 24 h ( 6 ) . patients were classified into four groups : isolated baseline hyperglycemia , isolated 24-h hyperglycemia , hyperglycemia persisting at both time points , and persistent normoglycemia . thrombolyzed ( n = 384 ) and nonthrombolyzed ( n = 364 ) patients were analyzed together . interestingly , isolated baseline hyperglycemia was not found to independently predict poor outcome or ich . in this study , the strongest predictor of poor outcome , death , and ich was persistent hyperglycemia at baseline and 24 h , although this observation was only true in patients without known diabetes . the prognostic utility of hyperglycemia exclusively in those patients treated with iv - tpa can not be determined because this subgroup was not analyzed separately . two other studies of tpa - treated patients , one with intravenous treatment and the other with intra - arterial treatment , also showed that elevated glucose was an independent predictor of ich ( 5,11 ) . what remains unclear is whether hyperglycemia is merely an epiphenomenon of underlying stroke severity or if it is itself directly harmful to ischemic brain tissue . after adjustment for clinical stroke severity , a dose - response relationship between baseline glucose and unfavorable outcome is still suggested by our results and those of others ( 1,4,6,10 ) . there is ample animal literature suggesting plausible mechanisms by which glucose may exert a deleterious effect on ischemic brain , including cellular acidosis caused by anaerobic glycolysis , enhanced free radical production , increased blood - brain barrier permeability , impaired mitochondrial function , influx of intracellular ca , and cellular edema ( 21 ) . baseline hyperglycemia may represent an acute stress response from activation of the hypothalamic - pituitary - adrenal axis causing a rise in cortisol and catecholamines and , therefore , may simply be indicative of underlying stroke severity . furthermore , it may also be a result of injury or irritation of brain areas involved in glucose regulation , a theory supported by the association of hyperglycemia with strokes involving the insula ( 22 ) . the argument for causality is also further mitigated by the equivocal results of trials targeting aggressive glucose - lowering therapy in the acute phase after stroke ( 8,9 ) . the uk glucose insulin in stroke trial ( gist - uk ) was both stopped early and underpowered but suggested no difference in clinical outcome between patients randomly assigned to glucose - potassium - insulin infusion to maintain glucose levels at 47 mmol / l over the first 24 h and patients given saline without glucose - lowering interventions ( 9 ) . the lack of benefit may be related to the relatively late initiation of therapy after stroke ( median 14 h ) and the modest mean reduction in glucose achieved in the treatment arm ( 0.57 mmol / l ) . our prospective cohort study is the largest yet to report on the effect of admission glucose exclusively in stroke patients treated uniformly with iv - tpa . our results confirm the notion that poststroke hyperglycemia is a predictor of death , worse functional outcome , and sich in thrombolyzed patients . this association remains true regardless of stroke subtype or severity and in patients with and without diabetes . nonetheless , the data were prospectively collected from a large number of representative patients drawn from 60 hospitals across canada . contrary to data for acute coronary syndromes arguing that dynamic changes in glucose are not prognostically significant ( 23 ) , it has recently been suggested that changes in glucose over the first 24 h among stroke patients may provide additional prognostic value ( 6 ) . however , use of a single baseline glucose value presumably underestimates potential harm , because patients with the highest admission glucose levels would most likely have been treated earlier and more aggressively with glucose - lowering therapies . also , because thrombolytic treatment is necessarily rapid , a single admission glucose level has greater clinical utility for guiding acute treatment decisions . third , we did not collect a1c values and so we do not have any measures of chronic dysglycemia . however , in acute coronary syndromes , a1c levels convey little short - term prognostic value with respect to mortality ( 24 ) . fourth , the method of blood glucose determination was not uniform , with either capillary blood or laboratory glucose measurements used at different sites . both methods have been shown to provide comparable results in critically ill patients ( 25 ) . last , baseline differences between both groups may be potential confounders that can not be entirely accounted for using statistical adjustments . although it remains unclear whether correcting elevated glucose in the acute phase after ischemic stroke is beneficial , it is apparent that admission hyperglycemia rapidly identifies patients at higher risk for poor outcomes in whom glucose levels should be closely monitored .