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ORIGINAL RESEARCH
published: 04 March 2021
doi: 10.3389/fneur.2021.614266
Frontiers in Neurology | www.frontiersin.org 1March 2021 | Volume 12 | Article 614266
Edited by:
Vincent Thijs,
University of Melbourne, Australia
Reviewed by:
Lars Kellert,
Ludwig Maximilian University of
Munich, Germany
Christian Foerch,
University Hospital Frankfurt, Germany
*Correspondence:
Rainer Kollmar
rainer.kollmar@mail.
klinikum-darmstadt.de
Specialty section:
This article was submitted to
Stroke,
a section of the journal
Frontiers in Neurology
Received: 05 October 2020
Accepted: 12 February 2021
Published: 04 March 2021
Citation:
Lee H, Hedtmann G, Schwab S and
Kollmar R (2021) Effects of a 4-Step
Standard Operating Procedure for the
Treatment of Fever in Patients With
Acute Stroke.
Front. Neurol. 12:614266.
doi: 10.3389/fneur.2021.614266
Effects of a 4-Step Standard
Operating Procedure for the
Treatment of Fever in Patients With
Acute Stroke
Hanna Lee 1,2 , Günter Hedtmann 2, Stefan Schwab 1and Rainer Kollmar 1,2
*
1Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen,
Germany, 2Department of Neurology and Neurological Intensive Care, Darmstadt Academic Teaching Hospital, Darmstadt,
Germany
Background and Purpose: Fever in the acute phase of stroke leads to an unfavorable
clinical outcome and increased mortality. However, no specific form of effective fever
treatment has been established, so far. We analyzed the effectiveness of our in-house
standard operating procedure (SOP) of fever treatment.
Methods: This SOP was analyzed for a period of 33 weeks. Patients with
cerebral ischemia (ischemic stroke, transient ischemic attack) or cerebral hemorrhage
(intracerebral, subarachnoid) and body temperature elevation of ≥37.5◦C within the first
6 days after admission were eligible for inclusion in the analysis. The results of SOP group,
who’s data have been collected prospectively were then compared with a historical
control group that had been treated conventionally 1 year earlier in the same period.
The data of control group have been collected in retrospect. The primary endpoint was
the total duration of the fever for the first 6 days after admission to the stroke unit.
Results: A total of 130 patients (mean age of 78 ±12) received 370 antipyretic
interventions. Sequential application of paracetamol (n=245), metamizole (n=53) and
calf compress (n=15) led to significant reduction in body temperature. In patients who
did not respond to these applications, normothermia could be achieved after infusion
of the cooled saline solution. Normothermia could be achieved within 120 min in more
than 90% of the cases treated by the SOP. The SOP reduced the fever duration in the 6
days significantly, from 12.2 ±2.7 h [95% confidence interval (CI) for mean] in the control
group to 3.9 ±1.0 h (95% CI) in the SOP group (p<0.001). The SOP was rated to be
reasonable and effective.
Conclusion: Our in-house SOP is cost-efficient and effective for fever treatment in stroke
patients, that can be implemented by local health care professionals.
Keywords: acute stroke, standard operating procedure, fever, hyperthermia, fever treatment
Lee et al. Fever SOP in Acute Stroke
INTRODUCTION
Numerous clinical and experimental studies have indicated
the association between elevated core body temperature and
unfavorable clinical outcome in patients with acute stroke (1–
4). In experimental stroke, a temperature decrease of 1–2◦C
in the intraischemic or postischemic brain has been found
to be neuroprotective, while a slight temperature increase
significantly worsens the outcome (5). A clinical study reported
the relative risk of increasement of poor outcome by a factor
of 2.2 for 1◦C increase in body temperature (6). A negative
effect of hyperthermia on functional outcome was demonstrated
even in patients treated with intravenous recombinant tissue
plasminogen activator (rt-PA). Hyperthermia within 3 days
after rt-PA is associated with poor functional prognosis and
survival outcome in patients with acute cerebral infarction (7).
Similar effects of body temperature have been in patients with
intracerebral hemorrhage (8).
Although paracetamol is used frequently in pyretic stroke
patients, it showed limited effect on body temperature and no
effect on the functional outcome compared with placebo (9).
Thus, the current recommendations for fever treatment in stroke
are rather unspecific and have a questionable impact on fever
burden and outcome (10).
Some non-pharmacological techniques to reduce fever
include physical methods such as high flow transnasal air or
external cooling devices (11). They are effective, but highly
expensive and require sometimes invasive procedures. Most
importantly, they are associated with side effects such as
shivering, which warrant more aggressive pharmacological
management (12).
An in-house standard operating procedure (SOP) was
previously presented in a pilot study, which was applied over a
relatively short period of time and demonstrated its satisfactory
antipyretic effect in stroke patients (13). This SOP included
a sequence of 4 pharmacological and physical interventions,
instead of a single-drug approach. Based on the former results,
we have expanded our clinical investigation with an increased
number of patients over a longer period of time.
We report the effects of our SOP regarding frequency of fever,
fever duration and neurological outcome. These results were
compared to a historical control group which has been treated
without adherence to a standardized protocol.
METHODS
Standard Operating Procedure
This 4-stage SOP contains a sequence of 4 pharmacological
and physical interventions instead of a monotherapy
(Figure 1). The SOP was implemented in April 2017 and
represents the local standard of care since this timepoint.
The data included for this investigation of the SOP were
analyzed for a period of 33 weeks, from May to December
2017. This SOP was eligible for the patients with brain
ischemia (ischemic stroke, transient ischemic attack) or
cerebral hemorrhage (intracerebral, subarachnoid) and body
temperature elevation of ≥37.5◦C in the first 6 days after
FIGURE 1 | The SOP includes a sequence of four antipyretic interventions
with close measurement of body temperature.
admission. They were diagnosed by brain imaging and clinical
examination. The primary endpoint was defined as the total
duration of fever during the first 6 days after admission to the
stroke unit.
In stage 1, patients are treated by a single infusion of 1.000 mg
paracetamol and, in stage 2, by a single infusion of 1.000 mg
metamizole, through a peripheral or central intravenous catheter.
In cases of limited effects of these antipyretics, external cooling
by calf packing is applied for 60 min at stage 3 and finally
an intravenous application of 500 ml of cooled (4◦C) saline
solution (0.9% NaCl) is administered via 30 min at stage 4.
The last stage is suitable for patients without clinical signs
of congestive heart failure or dyspnea (NYHA III or IV).
Body temperature measurement is performed 60 min after
each stage. Body temperature >37.5◦C after completion of
the final step results in return to stage 1. The treatment is
limited to a maximum of 4 complete cycles within 24 h. All
patients receive continuous non-invasive cardiac monitoring,
including ECG, oxygen saturation, respiratory rate, heart
rate and arterial blood pressure. Routine laboratory tests are
performed on admission (gamma -glutamyl transpeptidase,
glutamic oxaloacetic transaminase, glutamic acid pyruvate
transaminase, C-reactive protein (CRP), blood count and
electrolytes) at least once during the following 6 days in
the Stroke unit. In both the SOP and control group, the
screening for body temperature was performed with an electronic
tympanic thermometer (Genius 2 Tympanic Thermometer;
Tyco Healthcare Group, Mansfield, Massachusetts, USA) at 4-h
intervals. In case of fever the temperature was measured every
hour in both groups.
The body temperature before and 60 min after each stage
of antipyretic intervention as well as the duration of the
body temperature of ≥37.5◦C per day were measured.
We recorded the time from the initiation of the antipyretic
treatment to the attainment of normothermia or early relapse
Frontiers in Neurology | www.frontiersin.org 2March 2021 | Volume 12 | Article 614266
Lee et al. Fever SOP in Acute Stroke
TABLE 1 | Baseline characteristics of patients.
SOP group n=130 Control group n=74 P-value*
Clinical features
Age, years (±SD) 78 ±12 76 ±15 0.426
Females, n(%) 71 (55) 41 (55) 1
Median NIHSS day 1 (±SD) 9.25 ±7.11 6.78 ±6.34 0.016
Median NIHSS on day of discharge (±SD) 6.34 ±6.62 5.91 ±7.50 0.68
White blood cell count at baseline >10.000/µL, n(%) 43(33) 16 (22) 0.115
CRP at baseline >5 mg/L, n(%) 62 (48) 37 (50) 0.864
GOT at baseline, U/L (±SD) 36.7 ±42.3 27.3 ±14.3 0.023
GPT at baseline, U/L (±SD) 24.1 ±18.2 21.6 ±18.0 0.346
GGT at baseline, U/L (±SD) 55.2 ±73.4 60.4 ±106.1 0.707
Cardiovascular risk factor profile
Atrial fibrillation, n(%) 55 (42) 22 (30) 0.103
Arterial hypertension, n(%) 109 (84) 68 (92) 0.157
Hyperlipidemia, n(%) 82 (63) 48 (65) 0.917
Active smoking, n(%) 7 (5) 4 (5) 1
Diabetes Mellitus, n(%) 50 (38) 25 (34) 0.606
Persistent foramen ovale, n(%) 7 (5) 4 (5) 1
History of stroke, n(%) 31 (24) 21 (28) 0.584
Coronary artery disease, n(%) 21 (16) 12 (16) 1
History of myocardial infarction, n(%) 9 (7) 4 (5) 0.773
Peripheral artery disease, n(%) 4 (3) 4 (5) 0.465
Type of cerebrovascular disease
Transient ischemic attack, n(%) 10 (8) 8 (11) 0.618
Ischemic stroke, n(%) 107 (82) 56 (76) 0.340
Intracerebral hemorrhage, n(%) 10 (8) 6 (8) 1
Subarachnoid hemorrhage, n(%) 2 (2) 4 (5) 0.193
Detected infections
Pneumonia, n(%) 27 (21) 9 (12) 0.174
Urinary tract infection, n(%) 18 (14) 11 (15) 1
Other infection, n(%) 15 (12) 15 (20) 0.194
NIHSS, National Institutes of Health Stroke Scale; CRP, c-reactive protein; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvate transaminase; GGT, gamma-glutamyl
transpeptidase. SD, standard deviation.
*p-values from t-test for continuous variables, Pearson’s Chi-squared test with Yates’ continuity correction for categorical data and Fisher’s Exact Test for Count Data in case of counts
lower than five.
of fever as well. Here, “Early relapse” is defined as temperature
increase within 24 h after achieving normothermia. Finally,
the length of stay on the stroke unit and the NIHSS score
points (National Institutes of Health Stroke Scale) on discharge
were documented.
Control Group
The historical control group consisted of 74 patients
who had been treated at the Stroke Unit of Darmstadt
Academic Hospital for 16 weeks, from May to September
2016, 1 year earlier in the same period, which is exactly
half of the time period of the study group. The patients
were diagnosed with brain ischemia (ischemic stroke,
transient ischemic attack) or cerebral hemorrhage
(intracerebral, subarachnoid) and with a body temperature
of ≥37.5◦C within the first 6 days after admission.
Fever in the control group was treated according to the
recommendations of the European Stroke Organization
guidelines without application of the formerly described SOP
(14,15).
Data Management and Evaluation
Every single implementation of the SOP in patients with body
temperature of ≥37.5◦C was recorded daily by the nursing
staff and by physicians of the Stroke Unit. The data of SOP
group were collected prospectively, while the data of control
group were collected retrospectively. Data was investigated after
pseudonymization of the patient chart.
Statistical evaluations were created with R Version 3.5.2
(16). For normally distributed data, mean values and standard
deviations were calculated. We assumed that populations had
different variances, and used one-tailed Welch’s t-test (17). For
count data, absolute and relative frequencies are given.
Frontiers in Neurology | www.frontiersin.org 3March 2021 | Volume 12 | Article 614266
Lee et al. Fever SOP in Acute Stroke
TABLE 2A | Prevalence of fever with number of patients in SOP and control
groups.
Total Duration of first fever (days)
1 day 2 days 3 days 4 days 5 days
SOP group (n, %) 64 (50%) 36 (28%) 21 (16%) 5 (4%) 4 (3%)
Control group (n, %) 34 (46%) 22 (30%) 8 (11%) 8 (11%) 2 (3%)
TABLE 2B | Days of fever onset.
Onset of fever SOP group (n, %) Control group (n, %)
Day 1 46 (35.4%) 30 (40.5%)
Day 2 59 (45.4%) 28 (37.8%)
Day 3 23 (17.7%) 13 (17.6%)
Day 4 2 (1.5%) 3 (4.1%)
RESULTS
Patient Characteristics
N=1,034 patients in total were treated at the Stroke Unit of
the Darmstadt Academic Hospital during the 33-week study.
767 patients of them were diagnosed with “acute ischemic
stroke,” “intracerebral hemorrhage,” “transient ischemic attack”
or “subarachnoid hemorrhage.” 130 (16.9%) of 767 patients
had a body temperature of ≥37.5◦C within the first 6 days
after admission and were included in the study. A total of n
=370 antipyretic interventions were applied. All patients were
Caucasians; the mean age was 78 ±12 years, 55% were female.
Mean NIHSS score on first day was 9.25 ±7.11. “Acute ischemic
stroke” was diagnosed in 107 patients (82%), “transient ischemic
attack” in 10 patients (8%), “intracerebral hemorrhage” in 10
patients (8%), “subarachnoid bleeding” in 2 patients (2%) and
“venous sinus thrombosis” in 0 patients (0%).
Table 1 shows the patient characteristics of the SOP group
and the control group including age, sex and NIHSS score on
admission and discharge.
Prevalence of Fever and Infections
There was no significant difference in prevalence of fever between
the SOP and control groups (Table 2A). The number of days on
which fever was overall detected showed no significant difference
between SOP and control group. In most cases fever started on
day 1 and 2 after admission. No patient developed the first fever
period on day 5 and 6.
Table 2B shows the contribution of the first fever onset. In the
control group, there were slightly more patients developing fever
on day 1 than on day 2. In the SOP group, fever occurred on day
2 in most patients.
An increase in body temperature to ≥37.5◦C with the
indication for antipyretic treatment was detected for 370 times
in SOP group (Table 3). On admission, 48% of patients (n=
62) had CRP values >5 mg/dl. Thirty three percent of patients
(n=43) had leukocyte counts >10.000/µl. During treatment,
an infectious focus was identified in 46% of patients (n=60)
(Table 1).
The percentage of patients in the control group with elevated
CRP levels on admission was 50% (n=37), leukocytosis was 22%
(n=16). A focus of infection could be identified in 47% of
patients (n=35) (Table 1).
Antipyretic Effects of the SOP
Paracetamol was given the most (n=225), followed by
metamizole (n=49), calf packing (n=15) and infusion of
cooled saline (n=55). A significant reduction of the mean
body temperature measured 60 min after each intervention could
be observed (Table 3). A tendency toward a decrease body
temperature was observed after infusion of cooled saline (n=55).
Normothermia was achieved in 62% of cases after infusion of
cooled saline, which represents the last step of the SOP.
Normothermia could be achieved by application of the second
bolus of paracetamol in 13 of the remaining 20 patients who
still had a body temperature of >37.5◦C after completion of first
round of the SOP.
After the patients reached normothermia, early relapse
occurred in 54% of cases within 24 h. The shortest median time to
early relapse was 0.9 ±3.2 after first application of calf packing,
while the longest median time to early relapse was 6.0 ±8.5 h
after second infusion of cooled saline. The mean NIHSS score of
the SOP group on discharge was 6.34 ±6.62 (the mean NIHSS
score on admission was 9.25 ±7.11), while the mean NIHSS score
of the control group was 5.91 ±7.50 (the mean NIHSS score on
admission was 6.78 ±6.34).
Most importantly, the SOP had a significant effect on primary
endpoint. The primary endpoint was defined as the total duration
of fever during 6 days after admission. The fever duration has
been reduced significantly, from 12.2 ±2.7 h (95% confidence
interval for mean) in the control group to 3.9 ±1.0 h (95% CI)
in the SOP group (p<0.001). We could observe a mean daily
duration of fever of 2 ±0.6 h in the SOP group, while it was 5.4
±1.8 h in the control group (Figure 2A). The mean duration of
body temperature >37.5◦C in the SOP group was considerably
shorter in all days compared to the control group. No patients in
the SOP group had a body temperature >37.5◦C on day 6.
Figure 2B shows the difference in the duration of the first
fever between study and control groups in a 4-h interval. Fever
lasted significantly longer in the control group than in the SOP
group. In 90% of the patients in the control group, fever lasted
longer than 12 h. In 90% of the patients in the SOP group the
fever lasted up to 4 h (Figure 2B).
Drug Administration
The maximum daily dose of 4 g/day was never exceeded during
paracetamol administration in both OP and control group. The
mean daily doses were similar in the control group with 1.03 ±
0.49 g/day and SOP group with 1.06 ±0.52 g/day. Similar results
were observed for metamizole administration. The mean daily
dose of metamizole in the control group was 0.83 ±0.41 g/day
and 1.53 ±1.10 g/day in SOP group.
A total of 60 patients (46%) in the SOP group underwent
antibiotic treatment during the treatment on the stroke unit.
Frontiers in Neurology | www.frontiersin.org 4March 2021 | Volume 12 | Article 614266
Lee et al. Fever SOP in Acute Stroke
TABLE 3 | Effects of sequential antipyretic interventions (n=370) in 130 febrile patients.
Antipyretic
intervention
Numbers of
intervention, n
Median
temperature
before
intervention,
◦C (±SD)
Median
temperature
after 60 min ◦C
(±SD)
Normothermia
achieved, n(%)
Early relapse
(<24 h), n(%)
Median time to
relapse, h
(±SD)
Antibiotic
treatment, n
(%)
P1 225 38.0 ±0.3 37.2 ±2.1 168 (75) 46 (27) 2.1 ±4.8 38 (17)
M1 49 38.2 ±0.5 37.6 ±0.5 27 (55) 12 (44) 2.4 ±4.8 6 (12)
CP1 15 38.4 ±0.6 38.2 ±0.6 2 (13) 1 (50) 0.9 ±3.2 3 (20)
CS1 55 38.1 ±0.4 37.5±0.7 34 (62) 12 (35) 2.2 ±4.5 8 (15)
P2 20 38.0 ±0.4 37.5 ±0.4 13 (65) 7 (54) 2.8 ±4.2 2 (10)
M2 4 38.0 ±0.3 37.5 ±0.4 3 (75) 1 (33) 3.0 ±6.0 0 (0)
CS2 2 37.8 ±0.1 37.4 ±0.1 2 (100) 1 (50) 6.0 ±8.5 1 (50)
CP2 0 0 0 0 0 0 0
P1, Paracetamol first bolus; M1, Metamizole first bolus; CP1, first application of calf packing; CS1, first infusion of cooled saline; P2, Paracetamol second bolus; M2, Metamizole
second bolus; CP2, second application od calf packing; CS2, second infusion of cooled saline. Data are means ±standard deviation and absolute number N and relative frequency in
%, respectively.
FIGURE 2 | (A) Mean duration of body temperature >37.5◦C in hours per day
after admission to the stroke unit in the SOP group and in the control group, *p
<0.01, **p<0.001 by ttest. (B) Distribution of duration of first fever in the
SOP and control group.
A total of 35 patients (47%) in the control group underwent
antibiotic treatment during the treatment on the stroke unit.
Safety Aspects
Eight patients in the SOP group (6.1%) and five patients in
the control group (6.7%) died during their stay in hospital.
The admission diagnosis in nine patients was ischemic stroke,
in four patients intracerebral bleeding. Eight patients died of
multimorbidity and palliative therapy, one patient of sepsis
caused by endocarditis, two patients of malignant infarction
in palliative approach and two other patients of pulmonary
embolism and pneumonia.
DISCUSSION
In this study we investigated the effects of an in-house SOP for
temperature treatment, which is implemented in an acute phase
in patients with acute ischemic stroke or cerebral hemorrhage.
This in-house SOP includes a sequence of pharmacological and
physical interventions, since we considered an escalation therapy
to be more effective for fever reduction than monotherapy. A
few years ago, a pilot study on this SOP indicated significant
effects on fever after acute stroke (13). In more than 90%
of cases treated per SOP, normothermia was achieved within
120 min. Compared to conventional treatment, fever burden was
significantly lower within the first 4 days after admission (p<
0.001). However, the number of patients was rather small and
there has been no follow-up investigation on this SOP so far.
Therefore, we analyzed the effects of a newly introduced SOP
in our department with an increased number of patients and an
extended period of time compared to the former investigation.
A total of 130 patients treated by the SOP over a total period
of 33 weeks were included in the analysis. These patients had
developed a body temperature of ≥37.5◦C in the first 6 days
after admission to the stroke unit. A historical control group
consisted of 74 patients who had been treated 1 year earlier
according to the recommendations of the European Stroke
Organization guidelines (14). The incidence of fever was similar
between SOP and control group. However, there was a significant
difference in the duration of fever periods in hours between both
groups. The sequential application of paracetamol, metamizole,
calf packing and infusion of cooled saline in the SOP group
resulted in a significant reduction in body temperature 1 h after
Frontiers in Neurology | www.frontiersin.org 5March 2021 | Volume 12 | Article 614266
Lee et al. Fever SOP in Acute Stroke
each implementation. This showed a remarkable difference in the
fever burden compared to the historical control group treated
with a monotherapy of paracetamol. The period of fever in the
SOP group was considerably shorter at each day compared to the
control group. Paracetamol and metamizole never exceeded the
allowed maximum daily dose in both SOP and control group.
Previous studies investigated the effects of paracetamol and
other medications as a monotherapy on neurological outcome
and fever after acute stroke (9,10,18–21). None of them
showed improved neurological outcome followed by antipyretic
medication. This is also the case in our investigation. However,
we have been able to show that fever as the major target parameter
could be significantly lowered in a meaningful time period. The
PAIS study showed that treatment with a daily dose of 6,000 mg
of paracetamol lowered body temperature by 0.3◦C (95% CI:
0.1–0.5) (19). This minimal impact on fever could easily explain
why the neurological outcome could not be improved by the
named approach. In contrast, our SOP could represent a powerful
strategy for a large randomized trial to investigate effect on
effective fever treatment on neurological outcome, since our SOP
influences body temperature effectively.
Non-pharmacologic techniques often show reduction of fever.
For example, transnasal cooling has been demonstrated its
effectivity with temperature decrease by an average of 1.21◦C
(SD 0.46) within 1 h (11). However the side effects such as
shivering, discomfort and steep increases in blood pressure raise
serious concerns regarding the safety of its use in stroke patients
(11,12). In our study, we report efficacy of sequential use of
two pharmacological and two physical treatments without any
vital side effect, such as arterial hypertension or shivering. In
addition, the use of SOP does not require invasive monitoring
or procedures, which can be therefore considered to be more
feasible and cost-efficient.
One limitation of our study is the lack of permanent
temperature monitoring. Each temperature measurement in the
patients was carried out manually using a tympanic thermometer.
This could delay the detection of the fever manifestation,
although the temperature was measured by the nursing staff every
4 h. For more accurate temperature measurement, permanent
temperature monitoring should be used (22). The lack of
precision of measurement with a tympanic thermometer was also
cited in a previous study (13). The rate of calf packing was less
compared to cold infusions indicating that nursing stuff favors
short application modes such as infusions. Therefore, further
studies should focus on sequences of medication and iv cooling
and potentially not include time consuming calf packing.
Moreover, this observation is not a randomized controlled
study and therefore data has to be interpreted with caution.
Temperature-lowering effect of the antibiotic treatment
was already described in an earlier study (23). Prophylactic
or early calculated antibiotic treatment must also be
discussed further.
CONCLUSION
The presented 4-stage SOP is a cost efficient and effective
method for fever treatment in stroke patients, that can be easily
implemented in everyday clinical practice. Further studies should
investigate this approach in a randomized fashion.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Ethics Committee of the State Chamber of
Physicians of Hesse in Germany. Written informed consent for
participation was not required for this study in accordance with
the national legislation and the institutional requirements.
AUTHOR CONTRIBUTIONS
RK contributed to the study design. HL performed data
acquisition and analysis. RK, GH, and SS supervised the research.
HL and RK wrote the article. SS and GH approved the final
manuscript. All authors contributed to the article and approved
the submitted version.
ACKNOWLEDGMENTS
The present work was performed in fulfillment of the
requirements for obtaining the degree Dr. med.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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Frontiers in Neurology | www.frontiersin.org 7March 2021 | Volume 12 | Article 614266
