307 Copyright 2003 Journal of Postgraduate Medicine. Online full text at http://www.jpgmonline.com

Address for Correspondence:Hamidon Bin Basri, MDJabatan Perubatan Fakulti Perubatan UKM, Jalan Yaacob Latiff,Bandar Tun Razak, 56000 Cheras Kuala Lumpur, Malaysia.E-mail: hamidon@mail.hukm.ukm.my

The Impact of Diabetes Mellitus on In-hospital Stroke Mortality

Hamidon BB, Raymond AA

Neurology unit, Department of Medicine, Faculty of Medicine Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia.

Abstract:

BACKGROUND AND PURPOSE: Diabetes mellitus is a strong risk factor for stroke. However, the prognosis in terms of

mortality after a stroke is still unclear, especially in diabetic patients. The main purpose of this study was to compare and

evaluate the features of stroke in patients having diabetes mellitus with those without diabetes mellitus and to identify

factors that influence survival following a stroke. SUBJECTS AND METHODS: In a prospective hospital-based study

consecutive patients with acute ischaemic stroke were enrolled. A single observer, using predefined diagnostic criteria

recorded the demographics, risk factors and the type of stroke and deaths that occurred during the in-patient period.

RESULTS: One hundred and sixty-three patients with acute ischaemic stroke were enrolled in the study. Type 2 diabetes

mellitus was present in 90 (55.2%) patients. Diabetes was a significant independent predictor of mortality (OR 4.88; 95%CI

1.25-19.1). Among the diabetic patients middle cerebral artery (MCA) territory infarct (OR 34.8, 95%CI 4.5-269.4) and

Glasgow coma score (GCS) less than 9 (OR 12.3, 95%CI 3.7-198.1) were independent predictors of mortality.

CONCLUSIONS: MCA infarcts and poor conscious level increase the mortality in diabetic patients with stroke. Mortality is

also significantly related to a high level of blood glucose at admission. (J Postgrad Med 2003;49:307-10)

Key Words: Stroke, Diabetes mellitus, Hyperglycaemia, Mortality.

Original Article

In Malaysia, there is limitedinformation related to the

prevalence and mortality ofstroke. Diabetes mellitus (DM),which confers a two to three-

fold increase in the risk ofdeveloping “first ever” and

recurrent stroke, is one of themost important risk factors

In Malaysia, there is limited information related to the preva-

lence and mortality of stroke. Diabetes mellitus (DM), which

confers a two to three- fold increase in the risk of developing

“first ever” and recurrent stroke, is one of the most important

risk factors. DM has also been reported to be an independent

risk factor for mortality in patients with stroke.1-3 However,

some investigators after performing multivariate analysis have

found that diabetes is not an independent risk factor for the

development of stroke.4 Whether acute diabetic hyperglycae-

mia independently affects patient outcome

is also still debated upon.5 This study was,

therefore, undertaken to determine the ef-

fect of hyperglycaemia on the mortality in

patients with stroke.

Subjects and Methods

The study was undertaken after obtaining sanc-

tion from the institution’s research and ethics com-

mittee. Consecutive patients who were admitted

to the general medical ward, high-dependency ward or the intensive

care unit in a single hospital with a clinical diagnosis of acute stroke

(first ever or recurrent within one week of onset of symptoms) or those

who suffered a stroke in the hospital during the period June 2000 to

January 2001 were enrolled in the study after obtaining an informed

consent. They were managed according to a standardised critical path-

way. The description provided by the World Health Organisation (WHO)

was used to define acute stroke: “rapidly developing clinical signs of

focal (or global) disturbance of cerebral function, with symptoms lasting

24 hours or longer or leading to death, with no apparent cause other

than of vascular origin”.6 A standardised data sheet was used to record

the demographic variables including age, sex and presence of DM. DM

was defined as a fasting plasma glucose level of > 7.8 mmol/l, random

plasma glucose of > 11.1 mmol/l, or the require-

ment of regular hypoglycaemic drug(s). History

of hypertension, hypercholesterolaemia, smoking

and ischaemic heart disease was also recorded.

Hypertension was defined as a previous record of

at least two blood pressure readings of >140/90

mmHg or the requirement of regular intake of anti-

hypertensive drugs. Hypercholesterolaemia was

defined as having a total cholesterol of > 6.5

mmol/l or the requirement of regular anti-choles-

terol drug(s). All study subjects were identified during the first 24 hours

of admission and were observed prospectively by a single observer (first

author). Using predefined diagnostic criteria, the type and time of the

onset of stroke and death that occurred during the inpatient period were

recorded using the standardised data sheet. The subjects were seen every

morning by the observer (or if called) until they were discharged or they

died. The parameters on admission, including the blood pressure, glu-

cose levels, Glasgow coma score and the Barthel activities of daily liv-

ing (ADL) index were recorded. Severe disability was defined as Barthel

308

Variable Diabetes Mellitus Yes (n=90) No (n=73) P value

Age (mean) 61.3 years 63.2 years 0.04Female 56.7% 46.6% 0.21Atrial fibrillation 2.2% 10.9% 0.02Hypertension 82.2% 68.5% 0.04Hypercholesterolaemia 28.9% 34.2% 0.46Smoking 27.8% 28.8% 0.89Ischaemic heart disease 18.9% 10.9% 0.16Lacunar Infarct 63.3% 61.6% 0.82MCA infarct 24.4% 28.8% 0.53PCA infarct 11.1% 8.2% 0.54ACA infarct 1.1% 4.1% 0.22Pneumonia 14.4% 9.6% 0.35Urinary tract infection 6.6% 1.4% 0.09Length of stay 8.03 days 6.73 days 0.02Mean Systolic Blood Pressure 175 mmHg 164 mmHg 0.07Mean Diastolic Blood Pressure 91 mmHg 87 mmHg 0.32Mean random blood glucose 16.0 mmol/l 7.7 mmol/l 0.0001Mortality rate 15.6% 6.8% 0.09

Table 1: Clinical characteristics of ischaemic stroke patientswith and without diabetes (n=163)

Parameters studied Odds Ratio 95% Confidence P valueInterval

MCA infarcts 34.8 4.5 - 269.4 0.001GCS<9 12.3 3.7 - 198.1 0.03Age>75 years 1.10 0.15 - 8.06 0.92Hypertension 1.68 0.28 - 10.13 0.57Smoking 2.89 0.54 - 15.42 0.22Hypercholesterolaemia 1.57 0.31 - 7.93 0.58SBP>220 mmHg 0.32 0.04 - 2.41 0.27DBP> 120 mmHg 0.27 0.02 - 3.46 0.32BI<5 (out of 20) 3.25 0.64 - 16.12 0.15Admission RBS 1.23 1.07 - 1.40 0.002

Table 2: Multivariate analysis of parameters analysed for therisk of mortality in diabetic patients (n=90)

Hamidon et al: The Impact of Diabetes Mellitus on In-hospital Stroke Mortality

J Postgrad Med 2003;49:307-310

The key finding of our study wasthat DM independently predictedstroke mortality for all patients

with ischaemic stroke.

diabetes has the same impact on the cerebral vessels in both

sexes and all type of infarcts. As reported in previous studies,

hypertension was significantly more common in diabetic pa-

tients.9,10 This strengthens the fact that diabetes and hyperten-

sion are closely related.10

The key finding of our study was that DM independently

predicted stroke mortality for all patients with ischaemic stroke.

This was our main primary outcome, which

supported our earlier hypothesis. Diabetic

patients are generally prone to infection and

are less immunocompetent, and usually

have concurrent multiple end-organ dam-

age that ultimately contributes to increased mortality. The det-

rimental effects of diabetes on the outcome of cerebrovascu-

lar disease are in keeping with previous reports that diabetics

have poorer outcome after stroke and coronary artery dis-

ease than those without DM.5,11,12 In comparison with non-

diabetics, diabetics showed significantly higher admission

blood glucose levels (Table 1). Multivariate analysis demon-

index less than 5 (out of 20). Stroke types were classified into ischaemic

or haemorrhagic. Ischaemic stroke subtypes were divided into lacunar

infarcts (infarct size less than 15 mm on brain CT) or territorial infarcts.

The territorial infarcts were further classified as anterior cerebral artery

(ACA) infarct, middle cerebral artery (MCA) infarct, and posterior cer-

ebral artery (PCA) infarct on the basis of the clinical picture and radio-

logical findings. The patients were prospectively observed for the devel-

opment of infection or death. All patients were subjected to CT scan of

the brain before being admitted to the wards. Magnetic resonance

imaging (MRI) of the brain was done if the stroke localisation was in

doubt. Recombinant tissue plasminogen activator (rtPA) was not used

in any of the patients, as it is not a standard treatment at our institution.

The relationship between baseline and clinical variables and DM were

analysed with the chi2 test and t test for categorical and continuous vari-

ables, respectively. The logistic multiple regression model was used for

analysing the risk of developing infection, severe disability and death

among diabetic patients. Odds ratios with 95% confidence interval (CI)

were used to estimate the effects of each factor. All statistical analyses

were performed with the SPSS 11.0 package, with statistical significance

at 0.05 (2-sided).

Results

During the 8-month study period, 163 patients with ischae-

mic stroke were identified. There were 55 cases of intracer-

ebral haemorrhage (not included in the analyses). Diabetes

was present in 90 (55.2%) patients. The total case fatality rate

was 11.7%. The characteristics of the study sample are re-

ported in Table 1.

DM was an independent risk factor for mortality, OR 4.88

(95%CI 1.25-19.1). However, there was no significant increase

in the risk of infection, OR 2.1 (95%CI 0.8-5.4). Among the

diabetic population, a multivariate analysis was done for the

risk of mortality. The results are presented in Table 2. The

mean admission random blood glucose level for diabetics who

died was significantly higher than those who survived

(18.71mmol/l vs. 13.95 mmol/l; P=0.001). The influence of

the admission blood glucose on mortality

is presented in Table 2.

Discussion

In this study the prevalence of DM amongst

hospitalised patients with stroke was 55.2%, which is higher

than that reported (13% and 36%) in other studies.7-9 Although

we are not certain about the reason for this difference, it could

be related to differences in the selection of patients, the defini-

tion of diabetes used, methods of measuring glycaemia and

the cohort size. There was no significant difference between

the sexes regarding different types of stroke suggesting that

309

strated that blood sugar level at admission predicted mortality

in these patients. Several large clinical studies have now dem-

onstrated this and shown a two to six-fold increased risk of

death extending across all clinical subtypes of stroke.5,13,14 The

study was also able to identify definite predictors of mortality

in the diabetic group. MCA territory infarcts and poor GCS

were independent risk factors in the multivariate analysis. An-

other key finding was that patients in the diabetic group had a

longer length of stay. This will inevitably translate into higher

overall cost. The longer length of stay might possibly be caused

by the difficulties in controlling the blood glucose during the

hospital stay. This might also be due to complications such as

infection as diabetic patients are generally known to have a

higher risk of developing infection. However, there was no

significant difference in the incidence of infection between dia-

betics and non-diabetics in this study.

A prospective study design and standardized observation

by a single observer afforded strength to the study. The pa-

tients were not followed up after discharge. Deaths within a

few days of discharge might have been missed. This could

constitute a limitation of the study. Many studies have con-

trasting results on diabetes as a predictor of mortality in pa-

tients with stroke. Therefore, a systematic review of the sub-

ject would be the next step. However, the available data ema-

nating from Asia is limited and pertains to local or institutional

reports. As diabetes and hyperglycaemia are associated with

an increased mortality rate, it would be interesting to know

whether acute intervention with strict glycaemic control will

reduce mortality associated with stroke. No large randomised

studies have looked at this aspect and hence, future research

should explore this direction.

References1. Warlow CP. Epidemiology of stroke. Lancet 1998;352:1-4.2. Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Stroke in pa-

tients with diabetes: The Copenhagen Stroke Study. Stroke1994;25:1977-84.

3. Wong KS. Risk factors for early death in acute ischaemic and intrac-erebral haemorrhage: a prospective hospital-based study in Asia.Stroke 1999;30:2326-30.

4. Tuomilehto J, Rastenyte D, Jousilahti P, Sarti C, Vartiainen E. Diabe-tes mellitus as a risk factor for death from stroke: prospective study ofthe middle-aged Finnish population. Stroke 1996;27:210-5.

5. Williams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, et. al.Effects of admission hyperglycaemia on mortality and costs in acuteischaemic stroke. Neurology 2002;59:67-71.

6. Hatano S. Experience from a multicentre stroke register: a prelimi-nary report. Bull World Health Organ 1976;54:541-53.

7. Woo J, Lam CWK, Kay R, Wong AHY, Teoh R, Nicholls MG. Theinfluence of hyperglycaemia and diabetes mellitus on immediate and3 months morbidity and mortality after acute stroke. Arch Neurol1990;47:1174-7.

8. Olson T, Viitanen M, Asplund K, Eriksson S, Hagg E. Prognosis afterstroke in diabetic patients: a controlled prospective study. Diabetologia1990;33:244-9.

9. Megherbi SE, Milan C, Minier D, Couvreur G, Osseby GV, Tilling K,et.al. Association between diabetes and stroke subtype on survivaland functional outcome 3 months after stroke: Data from the Euro-pean BIOMED stroke project. Stroke 2003;34:688-94.

10. Stearne MR, Palmer SL, Hammersley S, Franklin SL, Spivey RS, LevyJC, et.al. Tight blood pressure control and risk of macrovascular andmicrovascular complications in type 2 diabetes: UKPDS 38. Br MedJ 1998;317:703-13.

11. NINDS t-PA Stroke Study Group. Generalised efficacy of t-PA foracute stroke: Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke1997;28:2119-25.

12. Haffner SM, Lehto S. Mortality from coronary heart disease in sub-jects with type 2 diabetes and in non-diabetic subjects with and with-out prior myocardial infarction. N Engl J Med 1998;339:229-34.

13. Weir GJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an in-dependent predictor of poor outcome after acute stroke? Results of along term follow-up study. Br Med J 1997;1:1303-6.

14. Gray CS, O’Connell JE, Lloyd H. Diabetes hyperglycaemia and re-

covery from stroke. Geriatr Gerontol Int 2001;1:2-7.

RECEIVED 27-06-03

REVIEW COMPLETED 24-07-03

ACCEPTED 24-09-03

Hyperglycaemia in Acute Stroke

In addition to the long-term detriments of chronic hyperglycaemia, elevated blood glucose levels during acute stroke may

augment brain injury. The majority of animal studies support this hypothesis.1 Numerous studies have shown an associa-

tion between elevated glucose levels during acute stroke and worse clinical outcomes.1 The results of the correlation

studies should be viewed with caution because the cause-and-effect relationship between admission hyperglycaemia and

clinical outcome cannot be determined from these studies. Statistical analysis may be imperfect and it may not be possible

to adjust for all the important confounding factors. Hyperglycaemia during acute stroke, with and without diabetes mellitus,

is likely in part a stress reaction and also may be a marker for more severe insulin resistance and greater comorbidities.

Also, it is frustrating and discouraging that a definite mechanism for the possible exacerbation of cerebral infarction by

hyperglycaemia has not been determined. Knowing this would help in the design of an optimised clinical efficacy trial.

Despite the methodological limitations inherent in correlation studies and the lack of an identified molecular mechanism,

sufficient evidence has accumulated to justify randomised trials to lower hyperglycaemia in acute stroke.2 Further support for

clinical trials comes from randomised trials showing that tight glycaemic control in acute myocardial infarction3 and in post-

Expert Comments

Hamidon et al: The Impact of Diabetes Mellitus on In-hospital Stroke Mortality

J Postgrad Med 2003;49:307-310

310

surgical ventilated patients4 improves outcome. If this applies to acute stroke, then many patients might benefit.

The important questions to address in clinical trials include: how late after stroke-onset could hyperglycaemia-lowering

treatment begin and still improve outcome? How much reduction in the glucose level is needed to improve outcome?

Does this treatment benefit patients with and without diabetes mellitus? What factors identify patients with greatest benefit

from tight glycaemic control?

At this time one can only speculate, based on the available evidence: 1. The cerebral penumbra either recovers or

becomes an infarcted tissue within the first 24 hours, hence benefit from intervention seems unlikely beyond this time.

2. The correlation analyses suggest a linear relationship between admission glucose and outcomes,5 so if effective, the

benefit may increase with the extent of glucose reduction in a linear fashion. Like with blood pressure, serious complica-

tions could develop with excessive lowering of hyperglycaemia. 3. There is more evidence correlating admission hyperg-

lycaemia with worse outcomes in non-diabetic subjects, perhaps because most subjects in the studies are non-diabetic.

However, it would be premature to exclude diabetic subjects from randomised clinical trials based on the available corre-

lation studies. 4. If found beneficial, multiple factors may predict benefit, one being cerebral reperfusion. A hypothesis that

hyperglycaemia is only harmful during acute stroke if there is reperfusion, is supported by animal and human studies and

could be considered as reperfusion injury.6

Because of lack of evidence from randomised trials, and the added labour and risk involved with tight glycaemic

control during acute stroke, it is not the standard practice at this time. The ongoing clinical trials will clarify if and when

tight glycaemic control during acute stroke is beneficial, how it can be achieved effectively and safely, and which patients

benefit most.

Bruno A, MD

Department of Neurology,

Indiana University School of Medicine,

Indianapolis, IN 46202, USA.

E-mail: abruno@iupui.edu

References

1. Bruno A, Williams LS, Kent TA. Plasma glucose during acute cerebral infarction: is it important? Stroke Review 2003;7:31-6.

2. Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS. Glucose potassium insulin infusions in the treatment of acute stroke

patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke Trial (GIST). Stroke 1999;30:793-9.

3. Malmberg K, for the DIGAMI (Diabetes Mellitus IGIiAMISG: Prospective randomised study of intensive insulin treatment on long term

survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512-5.

4. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients.

N Engl J Med 2001;345:1359-67.

5. Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, et al, NINDS rt-PA Stroke Study Group. Related Articles, Links Admission

glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59:669-74.

6. Kent TA, Soukup VM, Fabian RH. Heterogeneity affecting outcome from acute stroke therapy: making reperfusion worse. Stroke 2001;32:

2318-27.

Hamidon et al: The Impact of Diabetes Mellitus on In-hospital Stroke Mortality

J Postgrad Med 2003;49:307-310