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Admission Body Temperature Predicts Long-Term

Mortality After Acute Stroke


The Copenhagen Stroke Study
L.P. Kammersgaard, MD; H.S. Jrgensen, MD, DMSci; J.A. Rungby, MD; J. Reith, MD;
H. Nakayama, MD, PhD; U.J. Weber, MD; J. Houth, MD; T.S. Olsen, MD, DMSci
Background and PurposeBody temperature is considered crucial in the management of acute stroke patients. Recently
hypothermia applied as a therapy for stroke has been demonstrated to be feasible and safe in acute stroke patients. In
the present study, we investigated the predictive role of admission body temperature to the long-term mortality in stroke
patients.
MethodsWe studied 390 patients with acute stroke admitted within 6 hours from stroke onset. Admission clinical
characteristics (age, sex, admission stroke severity, admission blood glucose, cardiovascular risk factor profile, and
stroke subtype) were recorded for patients with hypothermia (body temperature 37C) versus patients with
hyperthermia (body temperature 37C). Univariately the mortality rates for all patients were studied by Kaplan-Meier
statistics. To find independent predictors of long-term mortality for all patients, Cox proportional-hazards models were
built. We included all clinical characteristics and body temperature as a continuous variable.
ResultsPatients with hyperthermia had more severe strokes and more frequently diabetes, whereas no difference was
found for the other clinical characteristics. For all patients mortality rate at 60 months after stroke was higher for patients
with hyperthermia (73 per 100 cases versus 59 per 10 cases, P0.001). When body temperature was studied in a
multivariate Cox proportional-hazards model, a 1C increase of admission body temperature independently predicted a
30% relative increase (95% CI, 4% to 57%) in long-term mortality risk. For 3-month survivors we found no association
between body temperature and long-term survival when studied in a multivariate Cox proportional hazard model
(hazards ratio, 1.11 per 1C; 95% CI, 0.82 to 1.52).
ConclusionLow body temperature on admission is considered to be an independent predictor of good short-term
outcome. The present study suggests that admission body temperature seems to be a major determinant even for
long-term mortality after stroke. Hypothermic therapy in the early stage in which body temperature is kept low for a
longer period after ictus could be a long-lasting neuroprotective measure. (Stroke. 2002;33:1759-1762.)
Key Words: body temperature mortality prognosis stroke

n animal stroke models, body temperature has been studied


extensively over the past 20 years.1 Lowering body temperature through hypothermic therapy has been demonstrated
to be a strong neuroprotective measure.2 4 Elevation of body
temperature has been shown to result in more extensive brain
damage in animal stroke models.5,6 In human stroke, low
admission body temperature seems to improve short-term
survival and neurological recovery, and to result in less
extensive brain damage on computed tomography scans.7 In
addition, low acute body temperature appears to be associated
with less release in humans of glutamate, which is a marker
of ischemia-induced damage to brain tissue.8 However,
whether the association between low body temperature
acutely after stroke and a favorable outcome is only a

temporary phenomenon or low body temperature on admission provides long-lasting improvements remains unknown.
Recently, there have been a few small studies of the
feasibility and safety of hypothermic therapy in patients with
acute stroke,9,10 and this seems to be possible and well
tolerated even in awake stroke patients.11 At least 1 randomized clinical trial of hypothermia in acute stroke patients has
been launched recently by a Danish research team. Furthermore, it is a widely accepted practice to avoid hyperthermia
in the early stages after acute stroke.12
In this study, we sought to evaluate whether body temperature on admission is an independent predictor of long-term
prognosis after stroke. The purpose of the study was 2-fold, as
follows: (1) to determine the relation between admission

Received November 23, 2001; final revision received March 12, 2002; accepted April 2, 2002.
From the Departments of Neurology, University Hospital Gentofte (L.P.K., H.S.J., J.A.R., U.J.W., J.H., T.S.O.), Hellerup, and Bispebjerg Hospital
(J.R., H.N.), Copenhagen, Denmark.
Correspondence to Dr Lars Peter Kammersgaard, Department of Neurology, University Hospital Gentofte, Niels Andersensvej 65, DK-2900 Hellerup,
Denmark. E-mail kammersgaard@dadlnet.dk
2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

DOI: 10.1161/01.STR.0000019910.90280.F1

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July 2002
TABLE 1.

Basic Clinical Characteristics


37C

Number of patients

37C

179 (45.9%)

P Value

211 (54.1%)

Age, years, SD

73.511.6

74.711.0

0.29

Sex female/male

88/179 (49.2%)

108/103 (51.2%)

0.75

Initial stroke severity, SSS, SD

36.516.8

30.218.2

0.001

Cerebral hemorrhage

14/125 (10.0%)

19/134 (12.4%)

0.63

Unclassified

40/139 (22.3%)

58/153 (27.3%)

0.58

Ischemic heart disease

43/129 (25.0%)

52/145 (26.4%)

0.81

Hypertension

67/106 (38.7%)

60/138 (30.3%)

0.10

Atrial fibrillation

31/146 (17.5%)

46/163 (22.0%)

0.31

Diabetes

25/151 (14.2%)

46/156 (22.8%)

0.04

Intermittent claudication

17/149 (10.2%)

26/161 (13.9%)

0.32

Smoking

76/81 (48.4%)

67/97 (40.9%)

0.18

Daily alcohol consumption

48/148 (30.8%)

53/115 (31.5%)

0.91

Previous stroke

40/136 (22.7%)

55/143 (27.8%)

0.29

Preexisting disability

34/143 (19.2%)

41/159 (20.5%)

0.80
0.16

Blood glucose, mmol/L, SD

7.52.5

7.93.4

3-month survival rate

144/35 (80.4%)

132/79 (62.5%)

0.001

5-year survival rate

72/107 (40.2%)

55/156 (26.1%)

0.006

Test statistics were the Student t test for continuous variables and the 2 test for comparison of
dichotomized variables.

body temperature and long-term mortality in all patients


admitted within 6 hours from onset and (2) to determine
long-term mortality in those of the patients surviving 3
months.

Methods
We included all patients with acute stroke (onset within 6 hours)
admitted consecutively, during a 25-month period from 1991 to
1993, to the stroke unit at Bispebjerg Hospital (Copenhagen,
Denmark). The study is prospective and community-based, as has
previously been described in detail.13 Hospital care is free, and a very
high proportion (88%) of the stroke patients in the area were
admitted to this hospital serving a well-defined catchment area of
nearly 240 000 inhabitants in the city of Copenhagen.14 No selection
of patients was performed with regard to age, severity of stroke, or
medical condition before admission. All treatment, rehabilitation,
and diagnostic procedures were performed within the stroke unit.
Patients were not discharged until the rehabilitation team decided
that no further in-hospital improvement could be expected. Therefore, no referral to other departments or hospitals for further
rehabilitation was necessary.
Stroke was defined according to the World Health Organization
criteria.15 The study does not include patients with transient ischemic
attacks or subarachnoid hemorrhage.
The Scandinavian Stroke Scale (SSS) was used to assess stroke
severity.16 The SSS evaluates level of consciousness; eye movement;
power in arm, hand, and leg; orientation; aphasia; facial paresis; and
gait on a total score from 0 (worst) to 58 (best).17 The score was
recorded on admission, weekly during hospital stay, and at discharge
by the same neurologist (H.S.J.). The long-term follow-up data on
mortality and date of death were obtained from the Danish Central
Registry of Persons where date of death for all residents in Denmark
are recorded through a unique 10-digit identification code containing
information on birth date. Another experienced neurologist (L.P.K.)
who was blinded to data obtained on admission prospectively
recorded the follow-up data. Follow-up was performed during the
year 1999 with December 29, 1999, as censoring date.

For classification of stroke subtype (hemorrhage or infarction),


computed cerebral tomography was performed with a Siemens
Somatom DR scanner, and the same experienced reader of computed
cerebral tomograms read the scans.
The following prognostic factors were accounted for in the
statistical analyses: age, sex, initial stroke severity, stroke subtype,
ischemic heart disease, hypertension, atrial fibrillation, diabetes,
intermittent claudication, smoking, daily intake of any type of
alcohol (eg, wine, spirits, or beer), previous stroke, preexisting
disability, and admission blood sugar. Diabetes, atrial fibrillation,
ischemic heart disease, preexisting disability, hypertension, and
smoking were defined according to standard criteria.7 Body temperature was obtained immediately after admission to the hospital and
was recorded by tympanic measurements.
Univariately, comparison between patients with hypothermia and
hyperthermia was performed by Students t test for continuous
variables and by 2 test for dichotomized variables. Mortality rates at
60 months were estimated by the log-rank test. Cumulative survival
plots were calculated by the Kaplan-Meier statistics to evaluate
survival for hypothermia versus hyperthermia patients any time
between index stroke and 5 years after onset. To study admission
body temperature as an independent predictor for long-term mortality after stroke onset, a Cox proportional-hazards model was built,
because multiple factors were thought to influence long-term mortality. All variables given in Table 1 were included in the initial
model using the forward procedure including admission body temperature as a continuous variable. Then, unimportant variables were
removed one by one until only variables with a P0.2 remained. The
analysis was then performed using the backward procedure. To
ensure that hazards were proportional throughout the study period for
all dichotomized variables, log-minus-log plots were performed for
each dichotomized variable. The required 2-tailed level of significance for all tests was set at 0.05.

Results
In Table 1, the basic clinical characteristics are given stratified in 2 groups according to admission body temperature.
Hypothermia was present in 45.9% of the 390 patients
included. Patients who were hyperthermic on admission had

Kammersgaard et al

Body Temperature and Prognosis After Acute Stroke

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fibrillation (HR, 0.63; 95% CI, 0.41 to 0.95), and hypertension (HR, 0.67; 95% CI, 0.48 to 0.94) were independent
predictors of survival 3 months after onset.

Discussion

Kaplan-Meier survival plot for hypothermia () vs hyperthermia


(O) on admission.

more severe strokes as compared with hypothermic patients


(SSS score 30.2 versus 36.5 points, P0.001) and more
frequently had diabetes (14.2% versus 22.8%, P0.04). No
differences between hypothermic and hyperthermic patients
were found for the other clinical characteristics considered.
The Figure gives the cumulated survival for all patients
admitted within 6 hours with hypothermia versus hyperthermia calculated by the Kaplan-Meier statistics. At 5 years after
stroke onset, mortality rate among patients with hyperthermia
was 73 per 100 cases versus 59 per 100 cases among those
with hypothermia on admission (P0.001; log-rank test). In
a multivariate model (Table 2) using Cox proportionalhazards analysis (including body temperature as a continuous
parameter), we found that a decrease of admission body
temperature by 1C was an independent predictor of increased long-term survival (hazards ratio [HR], 1.30; 95% CI,
1.04 to 1.63). The covariates admission stroke severity (HR,
1.32 per 10-point-higher SSS score; 95% CI, 1.20 to 1.43),
age (HR, 1.69 per 10-year decrease; 95% CI, 1.43 to 2.00),
atrial fibrillation (HR, 0.66; 95% CI, 0.48 to 0.93), and
admission blood glucose (HR, 1.04 per 1 mmol/L decrease;
95% CI, 0.98 to 1.09) were also in the final model.
In Table 3, the final Cox proportional-hazards model for
3-month survivors is shown. In this model, admission body
temperature was not an independent predictor of long-term
survival (P0.50), when adjusted for other covariates. Instead, covariates such as admission stroke severity (HR, 1.18
per 10-point-higher SSS score; 95% CI, 1.01 to 1.32), age
(HR, 1.85 per 10-year decrease; 95% CI, 1.51 to 2.26), atrial
TABLE 2.

A few previous studies have suggested that a lower admission


body temperature is associated with a better short-term
outcome. We found only 1 study looking at prognosis beyond
the first few months after onset in relation to body temperature.18 In this study hyperthermia raised the risk of 1-year
mortality by a factor of 3.4 relative to normothermic patients.
However, in this study no validated measure for admission
stroke severity was used, and the study was retrospective,
based on medical records.
For all patients included in the present study, we found
significantly higher mortality rates among patients with
hyperthermia as compared with hypothermic patients. But
this could be explained by the more severe strokes for
patients with hyperthermia on admission, because stroke
severity was not adjusted for in the Kaplan-Meier analysis.
Therefore, we had to evaluate the relative mortality risk
adjusted for differences in admission stroke severity and risk
factor profile. In the multivariate survival analysis, admission
body temperatures were entered as a continuous variable
rather than as a dichotomized variable to detect the independent predictive impact of differences in body temperature.
For all patients, we found a 1-degree difference in admission
body temperature to correspond to a 30% difference in the
relative risk of long-term mortality. However, it may be that
this relation is only due to a temporary effect early after
stroke, resulting in a sustained favorable mortality rate for
patients with a low admission body temperature. This may be
the case as the survival curves are converging after 2 to 3
months, and we failed to show admission body temperature
per se to be associated with survival for those patients still
alive 3 months after stroke. Nevertheless, this study only
studied the spontaneous relationship. It may be that if body
temperature is kept low for a longer period of time acutely
after admission, a more robust and long-lasting effect will
emerge.
The explanation for the possible neuroprotective effect of
low body temperature in acute stroke remains largely speculative. However, most studies point toward a slowing down of
the neurodegenerative processes in the penumbra.19 The
penumbra consists of a hypoperfused zone of neurons surrounding the initial necrotic area, which are still alive but
without the ability to perform normal activity.20 These neu-

Cox Regression Analysis (Final Model) for All Patients (n294): Overall 2 <0.0001

Variable

Covariate

Coeff (b)

SE (b)

Hazards Ratio

95% CI

Survival

Temperature (per 1C decrease)

0.23

0.11

0.03

1.30

1.041.57

Blood glucose (per 1 mmol/L decrease)

0.04

0.02

0.09

1.04

0.981.09

Severity (per 10-point increase)

0.03

0.004

0.0001

1.32

1.201.43

Age (per 10-year decrease)

0.05

0.009

0.0001

1.69

1.432.00

Atrial fibrillation

0.41

0.17

0.01

0.66

0.480.93

Hypertension

0.12

0.16

0.23

0.89

0.631.12

Coeff (b) denotes regression coefficient; SE, standard error.

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TABLE 3. Cox Regression Analysis (Final Model) for Patients Surviving 3 Months After Stroke Onset
(n234): Overall 2 <0.0001
Variable
Survival

Covariate

Coeff (b)

SE (b)

Hazards Ratio

95% CI
0.821.52

Temperature (per 1C decrease)

0.11

0.16

0.50

1.11

Blood glucose (per 1 mmol/L decrease)

0.04

0.04

0.34

1.04

0.961.12

Severity (per 10-point increase)

0.02

0.006

0.005

1.18

1.011.32

Age (per 10 years decrease)

0.06

0.01

0.0001

1.85

1.512.26

Atrial fibrillation

0.47

0.21

0.03

0.63

0.410.95

Hypertension

0.40

0.18

0.02

0.67

0.480.94

Coeff (b) denotes regression coefficient; SE, standard error.

rons are at risk of degenerating if reperfusion is not established within a reasonable time. If temperature is decreased in
the penumbra, a subsequent slowing down of the neurodegenerative processes may result. This means that the time
window for reperfusion to be established will be widened,
and more neurons in the penumbra will be able to survive and
regain their function.
The present study suggests that the neuroprotective effect
of low body temperature go beyond the first few weeks after
stroke onset. We speculate that a slowing down of the
degenerative processes in the penumbra resulting in smaller
brain lesions causes the long-lasting effect of decreased body
temperature. The current results may suggest that if hypothermia proves to be an efficient therapy in acute stroke
patients, this is likely to have long-lasting implications for
mortality. Trials on hypothermia applied deliberately in acute
stroke patients are warranted.

References
1. Maher J, Hachinski V. Hypothermia as a potential treatment for cerebral
ischemia. Cerebrovasc Brain Metab Rev. 1993;5:277300.
2. Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg
MD. Small differences in intraischemic brain temperature critically
determine the extent of ischemic neuronal injury. J Cereb Blood Flow
Metab. 1987;7:729 738.
3. Busto R, Dietrich WD, Globus MY, Ginsberg MD. Postischemic
moderate hypothermia inhibits CA1 hippocampal ischemic neuronal
injury. Neurosci Lett. 1989;101:299 304.
4. Meden P, Overgaard K, Pedersen H, Boysen G. The influence of body
temperature on infarct volume and thrombolytic therapy in a rat embolic
stroke model. Brain Res. 1994;647:131138.
5. Corbett D, Thornhill J. Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioral
outcomes following cerebral ischemia. Brain Pathol. 2000;10:145152.
6. Kim Y, Busto R, Dietrich WD, Kraydieh S, Ginsberg MD. Delayed
postischemic hyperthermia in awake rats worsens the histopathological
outcome of transient focal cerebral ischemia. Stroke. 1996;27:
2274 2280.

7. Reith J, Jorgensen HS, Pedersen PM, Nakayama H, Raaschou HO,


Jeppesen LL, Olsen TS. Body temperature in acute stroke: relation to
stroke severity, infarct size, mortality, and outcome. Lancet. 1996;347:
422 425.
8. Castillo J, Davalos A, Noya M. Aggravation of acute ischemic stroke by
hyperthermia is related to an excitotoxic mechanism. Cerebrovasc Dis.
1999;9:2227.
9. Schwab S, Spranger M, Aschoff A, Steiner T, Hacke W. Brain temperature monitoring and modulation in patients with severe MCA
infarction. Neurology. 1997;48:762767.
10. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W.
Moderate hypothermia in the treatment of patients with severe middle
cerebral artery infarction. Stroke. 1998;29:24612466.
11. Kammersgaard LP, Rasmussen BH, Jrgensen HS, Reith J, Weber U,
Olsen TS. Feasibility and safety of inducing modest hypothermia in
awake patients with acute stroke through surface cooling: a case-control
study: the Copenhagen Stroke Study. Stroke. 2000;31:22512256.
12. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a
significant clinical concern. Stroke. 1998;29:529 534.
13. Jrgensen HS, Nakayama H, Raaschou HO, Olsen TS. Effect of blood
pressure and diabetes on stroke in progression. Lancet. 1994;344:
156 159.
14. Jrgensen HS, Nakayama H, Raaschou HO, Olsen TS. Recovery of
walking function in stroke patients: the Copenhagen Stroke Study. Arch
Phys Med Rehabil. 1995;76:2732.
15. Stroke1989. Recommendations on stroke prevention, diagnosis, and
therapy: report of the WHO Task Force on Stroke and Other Cerebrovascular Disorders. Stroke. 1989;20:14071431.
16. Multicenter trial of hemodilution in ischemic stroke: background and
study protocol: Scandinavian Stroke Study Group. Stroke. 1985;16:
885 890.
17. Lindenstrm E, Boysen G, Christiansen LW, Hansen BR, Nielsen PW.
Reliability of the Scandinavian Neurological Stroke Scale. Cerebrovasc
Dis. 1991;1:103107.
18. Wang Y, Lim LL, Levi C, Heller RF, Fisher J. Influence of admission
body temperature on stroke mortality. Stroke. 2000;31:404 409.
19. Hakim AM. Ischemic penumbra: the therapeutic window. Neurology.
1998;51(3 suppl 3):S44 S46.
20. Olsen TS, Larsen B, Herning M, Skriver EB, Lassen NA. Blood flow and
vascular reactivity in collaterally perfused brain tissue: evidence of an
ischemic penumbra in patients with acute stroke. Stroke. 1983;14:
332341.

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