(Stroke. 1999;30:34-39.)
© 1999 American Heart Association, Inc.
Original Contributions |
From the University of Texas-Houston, Department of Neurology, Stroke Program (A.M.D., L.B.M., D.W.K., T.L.C., T.H.W., J.C.G.); University of Texas-Houston, School of Public Health Coordinating Center for Clinical Trials (R.J.H.); and University of Calgary, Department of Clinical Neurosciences (W.H., A.M.B.).
Correspondence to Lewis B. Morgenstern, MD, Department of Neurology, University of Texas-Houston, 6431 Fannin, MSB 7.044, Houston, TX 77030. E-mail lmorgen{at}neuro.med.uth.tmc.edu
| Abstract |
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MethodsBaseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis.
ResultsSymptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1.08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis.
ConclusionsSerum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.
Key Words: cerebral hemorrhage diabetes mellitus glucose stroke, acute thrombolytic therapy
| Introduction |
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Identifying patients who are at high risk of hemorrhagic complications may lead to improved patient selection and safety of this treatment. Few factors have been identified as predictors of symptomatic hemorrhage. In the NINDS rtPA trial,3 only stroke severity as defined by National Institutes of Health Stroke Scale (NIHSS) and CT changes of mass effect, edema, or hypodensity were independent predictors of symptomatic hemorrhage. A statistical trend (0.1>P>0.05) was seen for age and the dichotomous variable blood glucose >300 mg/dL as baseline predictors of symptomatic hemorrhage. A possible protective role of recent tobacco use was observed (0.1>P>0.05). In the ECASS rtPA trial,4 only age was identified as an independent predictor of parenchymal hematoma.
Elevated serum glucose has been identified as an independent predictor of poor outcome in acute stroke.5 Hyperglycemia accentuates ischemic injury with reperfusion, raising particular concern for hyperglycemia in a setting of thrombolytic use.6 7 8 Recent animal studies have confirmed an increase in hemorrhagic transformation, with elevated glucose levels.9 10 However no human clinical studies to date have closely examined the role of hyperglycemia in the setting of thrombolysis. We hypothesized that serum glucose as a continuous variable was an independent predictor of rtPA-related ICH and tested this hypothesis on a cohort of open-label patients treated at 2 academic centers.
| Subjects and Methods |
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Medical charts were reviewed retrospectively and information collected for the 4 predetermined variables (age, smoking status, pretreatment NIHSS, and pretreatment serum glucose) in 138 consecutive patients. These were chosen for the initial analysis because the NINDS rtPA trial identified these variables as the only pretreatment factors (P<0.1) predictive of symptomatic hemorrhage on univariate analysis. The pretreatment serum glucose level was performed at baseline in all patients. When the NIHSS was not documented in the chart, it was extrapolated from the recorded neurological examination.11
Other demographics collected included gender, history of risk factors, dosage of rtPA, and pretreatment platelet count. Patients were considered diabetic if their medical record stated a prior history of diabetes mellitus. Patients with elevated glucose levels or increased HbA1c levels without a history of diabetes were not considered diabetics for the purpose of this study.
Each initial pretreatment head CT scan was reevaluated by a stroke neurologist or neuroradiologist at each institution. CT reviewers were blinded to individual patient clinical information except for side of motor weakness. The initial CT scan was evaluated for any early acute changes. We classified major CT changes as evidence of hypodensity involving >33% of the middle cerebral artery (MCA) territory12 and included this variable in the intended univariate analysis.
The follow-up CT or MRI scan was also reevaluated by a stroke neurologist or neuroradiologist blinded to individual patient clinical information. The follow-up CT or MRI was performed within 24 to 36 hours in most cases. The standard practice of both institutions was to obtain these follow-up scans within the first 24 to 36 hours in order to decide whether antiplatelet or anticoagulant therapies should be initiated. Hemorrhage was classified as any area of increased density compared with normal brain present within the parenchyma or surrounding cerebrospinal fluid spaces that could not be attributed to thrombus within a vessel or to preexisting calcium deposits. The hemorrhage was graded as symptomatic hemorrhage if any neurological deterioration occurred within the first 48 hours that could be attributed to the presence of such hemorrhage.1 Each hemorrhage was graded by the ECASS criteria into parenchymal hematoma or hemorrhagic infarction. Parenchymal hematoma was defined as blood clot with space-occupying effect. Hemorrhagic infarction was defined as petechiae within the infarcted area, without space-occupying effect.4
Demographic characteristics of the patient population included in the
study were compared with the rtPA treatment group in the NINDS rtPA
trial with use of
2 and Student t
test statistical methods. Logistic regression analysis was
performed with all 5 variables to determine predictors of
symptomatic hemorrhage and all hemorrhage.
All variables were first tested in a univariate model.
Covariates significant at the P<0.25 critical level were
included in a multivariate model.
The identification of serum glucose as an independent predictor of ICH compelled us to also evaluate the history of diabetes mellitus. A logistic regression analysis was performed with diabetes included as a variable and serum glucose excluded. Both variables were not included together in a multivariate analysis owing to the limitations of a small sample size and the inherent close association between diabetes and baseline glucose levels.
| Results |
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Radiological evaluation of the baseline CT scan revealed >33% hypodensity within the MCA territory in 18% of patients (24 of 134). Evaluation of follow-up CT scan revealed any hemorrhage (including hemorrhagic transformation) in 30% of patients (42 of 138) and symptomatic hemorrhage in 9% of patients (13 of 138). The parenchymal hematoma rate was 14% (20 of 138), and the hemorrhagic transformation rate was 16% (22 of 138). The symptomatic hemorrhage in-hospital mortality rate was 54% (7 of 13), and the 6 symptomatic ICH survivors had severe neurological deficits (Rankin Index score of 4 to 5) at hospital discharge.
Two univariate logistic regression analyses were
performed for the 5 predetermined variables, with the dichotomous
dependent variable being all hemorrhage in one
analysis and symptomatic hemorrhage in the
other. The ORs and CIs are shown in Table 2
. In the all-hemorrhage
analysis, which included any hemorrhagic transformation or
parenchymal hematoma, all 5 variables were considered covariates
(P<0.25) and included in the final
multivariate logistic regression model. Only serum
glucose and NIHSS were independent predictors of all hemorrhage
on multivariate analysis (Table 3
).
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A similar logistic regression analysis was also performed for
symptomatic hemorrhage. Current smoking, NIHSS
score, >33% MCA territory hypodensity, and serum glucose were found
to be covariates (P
0.25) and were evaluated in a
multivariate model. Only serum glucose was an
independent predictor of symptomatic hemorrhage in
multivariate analysis (Table 3
).
Because of the close association between diabetes mellitus and
hyperglycemia, diabetes mellitus was tested in a separate
analysis excluding glucose level. Diabetes mellitus also was
determined to be a significant predictor of all hemorrhage and
symptomatic hemorrhage (Table 3
). A history
of diabetes mellitus was associated with a 25% (8 of 32)
symptomatic hemorrhage rate and 50%
all-hemorrhage rate (16 of 32) compared with a 5%
symptomatic hemorrhage rate (5 of 106) and 25%
all-hemorrhage rate (26 of 106) for nondiabetics.
The relationship between serum glucose and symptomatic
hemorrhage is illustrated in Figure 1
. The rate of symptomatic
hemorrhage increased gradually with increasing glucose levels.
The rate of all hemorrhage appeared to increase substantially
above the 8.4 mmol/L level. Fourteen of 16 subjects with serum
glucose levels >11.1 mmol/L were diabetics in this study.
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| Discussion |
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Animal models have demonstrated an important association between hyperglycemia and ischemic injury. Both increased17 18 and reduced19 20 21 injury have been demonstrated with hyperglycemia in permanent focal ischemia models. Initially, hyperglycemia may be neuroprotective22 by reducing ischemic depolarizations through delayed breakdown of transmembrane ion gradients with extended anaerobic glycolysis.23 24 With persistent ischemia, however, hyperglycemia produces a profound cellular acidosis due to the excessive substrate for the predominant anaerobic glycolysis occurring in hypoxemic/ischemic tissue.25 Once a critical threshold of acidosis is reached, hyperglycemia becomes detrimental.26 Proposed mechanisms for the deleterious effects of hyperglycemia and the resultant cellular acidosis include enzymatic dysfunction, enhanced free radical production (lipid peroxidation) through increased iron-catalyzed hydroxyl radical production,27 depressed mitochondrial function by inhibited ADP-stimulated respiratory activity,28 induction of endonucleases that may initiate programmed cell death,29 increased intracellular Ca2+ accumulation,30 and cellular swelling.31
In reversible focal ischemia, hyperglycemia consistently aggravates ischemic damage.6 7 8 32 Restoration of blood flow after 8 hours of occlusion is associated with a higher mortality than permanent occlusion.18 Hyperglycemia increases damage to the blood-brain interface,33 resulting in increased edema34 and hemorrhagic transformation with reperfusion. Very high tissue lactate concentrations in hyperglycemic cats increased the hemorrhagic conversion rate 5-old and hemorrhage size 25-fold.9 A glucose infusion resulted in a 75% hemorrhagic transformation rate compared with 9% in the normoglycemic group in another study.10 Hyperglycemia may increase hemorrhagic transformation by accelerating microvascular injury. Neuropathological studies have demonstrated reduced flow in the microcirculation,29 which may be due to increased capillary endothelial cell swelling that reduces luminal diameter.35 A severe perfusion deficit has been demonstrated with hyperglycemia, which may further aggravate injury.10 36 37
Therapeutic interventions aimed at lowering glucose levels or neutralizing the effects of the acidosis have recently been studied. Insulin therapy,18 32 38 tirilazad39 40 (a free radical scavenger), deferoxamine,41 and hypothermia33 have all shown promising neuroprotection in hyperglycemic animal models.
Experimental studies fully support previous clinical studies identifying the detrimental effects of hyperglycemia. Berger and Hakim42 demonstrated that hyperglycemia is frequently associated with cerebral edema in stroke patients, while other stroke studies have consistently shown hyperglycemia to be associated with increased morbidity and mortality.42 43 44 This association appears independent of stroke severity.5 Early pilot studies are now being planned for a trial of glucose-insulin treatment in acute stroke.45 46
In this study, clinical stroke severity measured by NIHSS was also an independent predictor of all hemorrhage but not symptomatic hemorrhage. The importance of NIHSS only in all hemorrhage may be explained by the definition of symptomatic hemorrhage, which requires a clinical deterioration attributable to hemorrhage. The severe clinical neurological deficit may mask any deterioration, even in the presence of large hemorrhages. One limitation of this study is the extrapolation of NIHSS score based on recorded neurological examination required in some cases. This may have led to inaccurate estimation of the NIHSS score, therefore minimizing the importance of this variable in the univariate and multivariate models.
A statistical trend for the unique protective role of current smoking initially suggested in the NINDS rtPA trial hemorrhage analysis3 was also observed in the univariate analysis of all hemorrhage. Similar results of reduced intracranial hemorrhage have been obtained for smoking in myocardial infarction thrombolytic studies.47 48 Animal studies provide a biological basis for this protection. Nicotine administration leads to an upregulation of endothelial expression of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of rtPA.49 This increase in PAI-1 may reduce the serine protease effect of rtPA that may produce increased endothelial damage and blood-brain barrier breakdown, leading to hemorrhagic complications.50 This curious role for smoking should be explored further.
A positive but insignificant effect was seen (Table 1
) between
major CT changes and symptomatic hemorrhage in our
cohort. This finding requires explanation, considering the importance
of these changes in predicting ICH in the NINDS rtPA trial. One
explanation is the difference in definitions of CT changes used in the
2 studies. Major CT changes were defined as >33% MCA territory
involvement in this study, whereas major CT changes were defined as
edema or mass effect in the NINDS rtPA trial. Another explanation is
the limitations of a small sample size. Both analyses did
demonstrate a positive effect that was not statistically significant
and may indicate a type 2 error. Alternatively, another consideration
may be poor recanalization frequencies in patients
with involvement of large regions of the MCA territory. Hypodensities
>33% of the MCA territory are frequently due to terminal ICA or MCA
stem occlusions, which are known to have a lower frequency of
recanalization in previous intravenous
rtPA angiographic studies.51 52 If
recanalization is essential to the development of
hemorrhagic complications, an association between major CT changes and
hemorrhage may be modest and not clearly demonstrated in a
smaller cohort.
This study suggests glucose level predicts hemorrhage with intravenous rtPA treatment in acute ischemic stroke, a finding at least partially explained by the high symptomatic hemorrhage rate among diabetics in this cohort. The results of this study should be interpreted with caution and should not at present affect clinical decision making, given the limited sample size and retrospective nature of this work. However, the association of glucose with ICH may have important implications for future stroke treatment and requires further prospective evaluation. Until such further studies have been performed we do not feel this study provides enough conclusive evidence to change currently FDA approved guidelines for thrombolytic therapy.
| Acknowledgments |
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Received September 16, 1998; revision received October 15, 1998; accepted October 22, 1998.
| References |
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