Title page
Admission hyperglycemia and poor prognosis within 90 days after acute ischemic stroke in the Chinese
population
Running Title
hyperglycemia and prognosis after acute ischemic stroke
Author names
Meijuan Xiao1, Hai Zou1*, Liping Tao2, Yongyong Lu3
1
Department of Neurology of the first Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000,
Zhejiang Province, China
2
Department of Gastroenterology of the first Affiliated Hospital of Wenzhou Medical University, Wenzhou
325000, Zhejiang Province, China.
3
Department of Urology of the first Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000,
Zhejiang Province, China.
*Co-corresponding author
Hai Zou, Department of Neurology of the first Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue
lane,Wenzhou 325000, Zhejiang Province, China, E-mail: [email protected]; fax: (86) 577-55579191; tel:
(86) 577-55579191.
Conflicts of Interest
The authors disclose no conflicts.
Background
Admission hyperglycemia has been associated with worse outcomes in ischemic stroke. However,the impact of
admission hyperglycemia on prognosis after ischemic stroke in the Chinese population is unclear.
Purpose
We investigated the associations between admission hyperglycemia and death, dependency, and stroke
recurrence in patients after acute ischemic stroke onset in the Chinese population.
Methods
913 patients with acute ischemic stroke who were consecutively admitted to our hospital during the period of
March 2007 through October 2009 were selected for this study. 312 patients had strokes with hyperglycemia(＞
8.0mmol/L) at admission.601 patients had strokes without hyperglycemia(≤8.0mmol/L) at admission. The
patients who were prospectively followed up for clinical and functional outcomes (death, dependency, and
stroke recurrence) at 90 days after disease onset. Multivariable logistic regression was performed to analyze the
association between admission hyperglycemia and stroke outcomes after adjusting for potential confounding
including age, sex, DM,History of dyslipisemia,history of stroke,smoking, LDL cholesterol.
Results
Compared with stroke patients without admission hyperglycemia, patients with admission hyperglycemia had a
significantly higher incidence of death or dependency at 3 months after stroke onset.In multivariate logistic
regression analysis, admission Hyperglycemia was found to be remarkably associated with death or
dependency(adjusted odds ratio 1.442,95% confidence interval, 1.051 to 1.998) in patients with ischemic stroke
at 3 months after onset, after adjusting for the confounding factors.
Conclusions
Admission hyperglycemia independently predicted poor outcomes after acute ischemic stroke in the Chinese
population.
Key Words: admission hyperglycemia ,ischemic stroke,death, dpendency,recurrent stroke.
Approximately 40% of patients with acute ischemic stroke have admission hyperglycemia, and the majority of
such patients have DM[1]. Admission hyperglycemia had a significantly higher incidence of poor outcomes after
stroke onset[2]. DM was an independent risk factor for death or dependency in patients with ischemic stroke at 6
months after onset[3]. The hyperglycemia during acute stroke reflects both a spectrum of acute stress and a
spectrum of insulin resistance. The bulk of previous studies exploring the role of hyperglycemia in stroke have
included only westerner. However, it remains unclear whether admission hyperglycemia was associated with
worse outcomes,particularly death, dependency, and stroke recurrence in patients after acute ischemic stroke in
Chinese populations. We investigated the associations between admission hyperglycemia and death,
dependency, and stroke recurrence in patients after acute ischemic stroke onset.
Patients and methods
Patients with acute IS within 3 days of neurologic deficit who were admitted to our hospital between March
2007 through October 2009 were consecutively selected for this study. However, patients with the following
conditions were excluded from this study: nonvascular causes (primary and metastatic neoplasms, postseizure
paralysis, head trauma, etc) that led to brain function deficit, intracerebral hemorrhage by computed
tomography or magnetic resonance imaging，with intravenous thrombolysis treatment, previous history of stroke
and neurological deficit legacy.
In this study,the definition of admission hyperglycemia was prespecified to be serum glucose ＞8.0 mmol/l in
accordance with other studies
[4-6]
. According to the results of admission hyperglycemia , patients were divided into
admission hyperglycemia group and non- admission hyperglycemia group.
Baseline demographic and clinical information were collected upon admission, including gender, age, history of
hypertension,diabetes,dyslipisemia, coronary heart disease, atrial fibrillation, stroke.smoking (current smoker or
experience of regular smoking habit), Alcohol abuse ( current drinker or experience of regular drinking habit),
systolic blood pressure (SBP)and diastolic blood pressure (DBP) levels (mmHg), Glasgow Coma
Scale(GCS)and National Institute of Health Stroke Scale (NIHSS) score. Laboratory assays included total
cholesterol(TC), low-density lipoprotein cholesterol(LDL-C),PPT, international standard rate(INR).
We recorded Urinary tract infection and Oxfordshire Community Stroke Project stroke subtype (OCSP subtypes:
Partial anterior circulation,Total anterior circulation, Lacunar ,Posterior circulation),the days of total hospital
stay and the occurrence of pneumonia or urinary tract infection complications during hospitalization at
discharge.
We assessed the outcomes of all patients through telephone follow-up at 90 days after stroke onset. 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.The outcomes included death (or modified Rankin Scale
[mRS] score=6), dependency (defined by mRS=3to5)[7], favorable outcome(defined by mRS=0 to 1),recurrence
of stroke (aggravated primary neurologic deficit; new signs; or rehospitalization with a diagnosis of ischemic
stroke, intracerebral hemorrhage, or subarachnoid hemorrhage), and the corresponding dates of onset. Poor
outcomes were defined as death or dependency (mRS=3to6)[3]. The telephone follow-up was by two doctors
respectively and was based on a shared standardized interview protocol.
As a primary analysis, admission hyperglycemia group and non-hyperglycemia were compared with regard to
baseline characteristics, stroke recurrence,functional outcome at 90 days, and death. A secondary analysis
examined the association of these outcomes with admission glucose as a continuous measure.
Statistical Analysis
The results are presented as mean±SD or median values with interquartile ranges (25th to 75th) . Univariate
analyses included unpaired t test and Pearsonχ2 test. The associations between admission hyperglycemia and
death, dependency, or recurrence of stroke were analyzed in multivariate logistic-regression models, after
adjusting for potential confounders including age, sex, DM，history of dyslipisemia， history of stroke,smoking,
LDL cholesterol, and other factors.. Significance was established at the P＜0.05 level. Statistical analyses were
performed using SPSS 16.0.
Results
1114 patients with acute IS who consecutively attended our hospital during March 2007 to October 2009.
At 90 days after stroke onset,follow-up information was unavailable for 913 patients with acute ischemic stroke,
who were then included in the present study.
Of the 913 patients, 312(34.17%) were with admission hyperglycemia, of whom 96 (30.8%) had a history of
DM,Compared with stroke patients without admission hyperglycemia, patients with admission hyperglycemia
were older and had a higher proportion of females but had fewer moderate or heavy alcohol drinkers and fewer
smokers. Smoking presented less frequently in patients with admission hyperglycemia compared with patients
without admission hyperglycemia, whereas history of dyslipisemia,history of stroke,LDL cholesterol, total
hospital stay presented more frequently in stroke patients with admission hyperglycemia. We also found stroke
patients with admission hyperglycemia had a significantly longer hospital stay than did those without admission
hyperglycemia. There were no differences in blood pressure, Pneumoni,Urinary tract infection,stroke subtype
between groups. No relationship was observed between baseline serum glucose and baseline NIHSS score and
GCS score(Table 1).
Furthermore, multivariate logistic-regression analyses (Table 3) suggested that, after adjusting for potential
confounders, admission hyperglycemia was an independent risk factor for death or dependency at 90 days (odds
ratio=1.442; 95% CI,1.051 to 1.998), but had no significant association with stroke recurrence at 90 days(odds
ratio=1.427; 95% CI, 0.914 to 2.230) after onset.
Discussion
In this study, we prospectively and systematically investigated the associations between admission
hyperglycemia and outcomes of acute ischemic stroke. Human studies have largely been observational, and
most of them show an association between hyperglycemia and inferior clinical outcomes from acute ischemic
stroke[8-11]. The higher the glucose level during acute ischemic stroke, the worse the outcomes are. Some studies
suggest a linear decrease in favorable outcomes as blood glucose increases [12] . One study found that during the
initial 48 h of acute ischemic stroke, maximum glucose of 155 mg/dL was the best cutoff for predicting
outcome[13] . Hyperglycemia is more likely to be present and persist during hospitalization in Hispanic patients
than in African American and White patients. These disparities may explain the disproportionate mortality rates
among Hispanic and African American and White patients after AIS [14].To our knowledge, this study is the first
investigated the associations between admission hyperglycemia and outcomes in patients after acute ischemic
stroke onset in the Chinese population.
Admission hyperglycemia in 34.17% of our population with acute ischemic stroke, which is consistent with the
prevalence range of 21% to 44.4%( Approximately 40%), a suggested in the literature.Follow-up information at
90 days after stroke onset was available in 81.9% (913/1114) of all enrolled patients at admission. The main
variables, such as NIHSS score,GCS score at admission and OCSP subtyes were comparable between patients
with and without admission hyperglycemia 90 days follow-up information, indicating that the analyzed
population was a good representation of the patients enrolled in our registry.
Some findings suggest that patients with acute lacunar strokes (small subcortical infarcts caused by occlusion of
small penetrating arterioles) have better outcomes with hyperglycemia
[4]
. In our study, we did not find this
phenomenon.Our results indicated that patients with admission hyperglycemia were more likely to have a
history of DM,dyslipisemia,stroke,smoking, which contrasts with the majority of previous studies.
Complications of urinary tract infection and Pneumonia were not different between the two groups.
In our study, admission hyperglycemia was significantly associated with death or dependency (mRS=3 to 6) in
patients at 90 days after stroke onset, whereas the occurrence of stroke showed comparable results between the
2 groups.
The potential confounding factors adjusted for in the multivariable logistic-regression analysis were selected as
either confirmed effect factors for stroke outcomes in previous studies.Our findings confirmed that admission
hyperglycemia remained an independent predictor for poor outcomes in stroke patients,even after adjusting for
DM, in contrast with the previous studies[13, 15] reporting no significant outcome differences between patients
with and without admission hyperglycemia when adjusted for admission glucose levels. Our findings highlight
the concept of the clinical significance that early identification and treatment of admission hyperglycemia
should be emphasized to improve the outcome of ischemic stroke in the Chinese population.
Acute ischemic stroke patients with diabetes and hyperglycemia have a more intense procoagulant state
compared with nondiabetic patients. This is related to glucose levels and provides a potential mechanism for the
observed worse prognosis in such patients after acute stroke[17].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 Ca2+, and cellular edema[16].
Our results confirm the notion that poststroke hyperglycemia is a predictor of death,worse functional outcome,
in acute IS patients. This association remains true regardless of stroke subtype or severity and in patients with
and with-out diabetes. 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.
Table 1. Clinical Characteristics of Patients With or Without Hyperglycemia After Ischemic Stroke
Without Hyperglycemia
With Hyperglycemia
（n=601）
（n=312）
Sex,male
392（65.2%）
181（58.0%）
0.033
Age（median）y
67（57-75）
67（60-75）
0.034
History of Hypertension
325（54.1%）
169（54.2%）
0.979
History of DM
33/568（5.5%）
96/216（30.8%）
0.000
History of Dyslipisemia
24（4.0%）
57（18.3%）
0.000
Coronary heart disease
30（5.0%）
23（7.4%）
0.145
Atrial fibrillation
32（5.3%）
13(4.2%)
0.443
History of stroke
74(12.3%)
61(19.6%)
0.003
Smoking
222/380（36.8%）
85/227（27.2%）
0.004
Alcohol abuse
140/461（23.3%）
58/254（18.6%）
0.102
158.42±27.10
162.00±27.46
160(140-176)
160(144-180)
89．81±15.58
89.44±14.22
90(80-100)
89.5(80-97.75)
NIHSS score（median）
6（3-9）
6（3-10）
0.370
GCS score （median）
15（15-15）
15（15-15）
0.581
Total cholesterol (mmol/L)
4.71±1.32
5.21±1.14
0.086
LDL cholesterol(mmol/L)
2.82±0.81
3.04±0.89
0.000
PTT sec.
30.32±5.31
30.15±5.14
0.400
INR
1.19±0.79
1.16±0.51
0.120
Pneumonia
65（10.5%）
35（11.2%）
0.726
Urinary tract infection
20（3.3%）
11（3.5%）
0.876
Total hospital stay, median (IQR), d
13（11-16）
15(13-17)
0.000
PACI
58（9.7%）
28（9.0%）
TACI
352（58.6%）
179（57.4%）
LACI
100（16.6%）
59（18.9%）
POCI
91（15.1%）
46（14.7%）
Characteristic
P value
Risk factors
Systolic blood pressure (median)(mmHg)
0.104
Diastolic blood pressure (median)(mmHg)
0.729
OCSP subtypes
0.854
Data are presented as the mean value ± SD , median values with interquartile ranges (25th to 75th) or the number (%) of
patients.
Table 2—Outcome at 90 days in hyperglycemic and nonhyperglycemic patients with unadjusted and
adjusted RRs (after multivariate logistic regression)
Without Admission
With Admission
hyperglycemia
hyperglycemia
601
312
Outcomes variable
n
RR(95%CI)
p
Unadjusted
Adjusted
Outcomes at 90 days
0.
Stroke recurrence
106（16.5%）
1.547(1.041-2.
1.427(0.914-2.
62（19.9%）
101
299)
230)
Excellent
332(55.2%)
144(46.2%)
0.009
0.694(0.528-0.914)
0.750(0.551-0.962)
199（33.1%）
136（43.6%）
0.002
1.561(1.179-2.067)
1.442(1.051-1.998)
outcome(mRS 0-1)
Death or dependency
(mRS5-6)
References
[1]
Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. Decreased mortality by normalizing blood glucose after acute ischemic stroke.
Acad Emerg Med. 2006. 13(2): 174-80.
[2]
Bruno A, Liebeskind D, Hao Q, Raychev R. Diabetes mellitus, acute hyperglycemia, and ischemic stroke. Curr Treat Options Neurol. 2010.
12(6): 492-503.
[3]
Jia Q, Zhao X, Wang C, et al. Diabetes and poor outcomes within 6 months after acute ischemic stroke: the ChinaNational Stroke Registry.
Stroke. 2011. 42(10): 2758-62.
[4]
Uyttenboogaart M, Koch MW, Stewart RE, Vroomen PC, Luijckx GJ, De Keyser J. Moderate hyperglycaemia is associated with favourable
outcome in acute lacunarstroke. Brain. 2007. 130(Pt 6): 1626-30.
[5]
Alvarez-Sabin J, Molina CA, Montaner J, et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissueplasminogen
activator--treated patients. Stroke. 2003. 34(5): 1235-41.
[6]
Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke
patients treated with intravenous thrombolysis. Diabetes Care. 2009. 32(4): 617-22.
[7]
Quinn TJ, Dawson J, Walters MR, Lees KR. Exploring the reliability of the modified rankin scale. Stroke. 2009. 40(3): 762-6.
[8]
Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. Decreased mortality by normalizing blood glucose after acute ischemic stroke.
Acad Emerg Med. 2006. 13(2): 174-80.
[9]
Bruno A, Williams LS, Kent TA. How important is hyperglycemia during acute brain infarction. Neurologist. 2004. 10(4): 195-200.
[10]
McCormick MT, Muir KW, Gray CS, Walters MR. Management of hyperglycemia in acute stroke: how, when, and for whom. Stroke. 2008.
39(7): 2177-85.
[11]
Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke. 2008. 39(10): 2749-55.
[12]
Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002.
59(5): 669-74.
[13]
Fuentes B, Castillo J, San JB, et al. The prognostic value of capillary glucose levels in acute stroke: the GLycemia inAcute Stroke (GLIAS)
study. Stroke. 2009. 40(2): 562-8.
[14]
Gentile NT, Seftchick MW. Poor outcomes in Hispanic and African American patients after acute ischemicstroke: influence of diabetes and
hyperglycemia. Ethn Dis. 2008. 18(3): 330-5.
[15]
Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke
patients treated with intravenous thrombolysis. Diabetes Care. 2009. 32(4): 617-22.
[16]
Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrainischemia in rats. Stroke.
1993. 24(1): 111-6.
[17]
Gentile NT, Vaidyula VR, Kanamalla U, DeAngelis M, Gaughan J, Rao AK. Factor VIIa and tissue factor procoagulant activity in diabetes
mellitus afteracute ischemic stroke: impact of hyperglycemia. Thromb Haemost. 2007. 98(5): 1007-13.