Neuroscience & Medicine, 2012, 3, 306-313 Published Online September 2012 (
Experimental Hyperthermia during Cardiac Arrest and
CPR Is Associated with Severe Spontaneous Hypothermia
in Mice
Ruediger R. Noppens1,2, Julia Kofler2,3, Richard Traystman2,4
1Department of Anesthesiology, Medical Center of the Johannes Guten berg University, Mainz, Germany; 2Department of Anesthe siology
and Peri-Operative Medicine, Ore gon Health & Science Univer sity, Portland, USA; 3Department of Pathology, University of Pittsburgh,
Pittsburgh, USA; 4University of Colorado Denver, Anschutz Medical Center, Colorado, USA.
Received June 1st, 2012; revised July 1st, 2012; accepted July 10th, 2012
Background: Since genetically engineered mice are becoming more and more av ailable, these an imals b ecome o f high
interest to study physiologic and pathophysiologic pathways of brain ischemia. The aim of this study was to examine
body temperature (Tb), physical activity variation and neurohistopathology in mice exposed to normothermic and hy-
perthermic cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Methods: Male C57Bl/6 mice weighing 22 -
27 g were implanted intraperitoneally with a radio telemeter and subjected to 10 min cardiac arrest followed by cardio-
pulmonary resuscitation. Normothermia (37.5˚C) or hyperthermia (39.0˚C) was induced by controlling peri-cran ial tem-
perature during the arrest period. Results: Hyperthermia during the arrest resulted in a Tb decrease during early recov-
ery to a nadir of 28˚C ± 0.8˚C (mean ± SE) and partially recovered to 34.4˚C ± 1˚C 36 hrs after CA/CPR. With nor-
mothermia during the arrest, Tb depression was less pronounced (nadir of 32.3˚C ± 0.3˚C) and recovered to physiologic
levels within 24 hrs. Coupling of ph ysical activity and body temperature was absent in all animals after CA/CPR. Neu-
ronal injury in the caudoputamen was greater in the hyperthermia group. Conclusions: This study demonstrates that
CA/CPR eliminates normal connectivity between body temperature and physical activity and induces long-lasting hy-
pothermia, the depth of which is related to severity of brain injury. Long term temperature monitoring is required in
survival murine experiments, if body temperature is a study variable.
Keywords: Cerebral Ischemia; Cardiac Arrest; Cardiopulmonary Resuscitation; Hypothermia; Neuroprotection;
Telemetry; Hyperthermia
1. Introduction
It is now well recognized that body temperature strongly
influences outcome from cerebral ischemia. The benefit
of applied cooling in reducing neuronal damage and
neurological deficits after stroke or cardiac arrest is evi-
dent in many animal injury models and in recent clinical
trials [1,2]. Suppression of hyperthermia, should it de-
velop spontaneously, is thought to improve brain his-
tologic and neuro functional outcome after experimental
and clinical focal cerebral ischemia [3,4].
How body temperature is regulated throughout recov-
ery in animal ischemic injury models is unclear and may
be species, brain region and injury specific. For example,
middle cerebral artery occlusion (MCAO) is associated
with severe hyperthermia in rats (e.g. 39.5˚C) but causes
hypothermia in mice (e.g. 33.1˚C) [5-7]. Global cerebral
ischemia produces mild hyperthermia (38.5˚C) in gerbils
but leads to hypothermia in rats (34˚C) and mice (32˚C)
[8-10]. Although the effect of temperature on neuronal
survival has been widely recognized and temperature is
strictly controlled in animal models of brain injury,
changes of body temperature after cardiac arrest and car-
diopulmonary resuscitation (CA/CPR) in mice are not
well described.
The aims of this study were 1) to characterize physi-
ologic body temperature and physiologic activity in
freely moving mice, 2) examine effects of normothermia
and hyperthermia during global brain ischemia in a well
established model of CA/CPR on body temperature and
activity levels during 3-day recovery and 3) to evaluate
neuronal injury in specific brain regions.
2. Material and Methods
2.1. Animals
Male C57Bl/6 mice (22 - 27 g, Charles River, Hollister,
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
Hypothermia in Mice 307
California) were treated according to NIH guidelines for
the care and use of animals in research, and all experi-
mental protocols were approved by the institutional ani-
mal care and use committee. All animals were housed in
a temperature controlled room (22˚C) under a 12:12 hour
dark:light cycle, room lights were turned on at 7:00 AM
and turned off at 7:00 PM. Mice had free access to food
(RMH 1000, 5P07, Purina Mills, USA) and water
throughout the experiment. Surgical procedures were
performed between 7:30 AM and 1:00 PM in all groups.
2.2. Transient Global Brain Ischemia: Cardiac
Arrest and CPR
Cardiac arrest and CPR were performed as previously
described [11,12]. Briefly, animals were anesthetized
(halothane 1% - 3% with supplemental oxygen), the tra-
chea was intubated with a 20-gauge iv catheter and mice
were mechanically ventilated (Mouse Ventilator Mini-
Vent, Type 845, Hugo Sachs Electronic). Temperature
probes were placed into the left temporal muscle and
rectum, and a PE-10 catheter was inserted into the right
jugular vein for drug ad ministratio n. ECG was monitor ed
using subcutaneous needle electrodes placed on the chest
and a common ECG monitor (Hewlett Packard 78353B).
Animals were allowed to stabilize for 15 minutes before
induction of cardiac arrest. Peri-cranial temperature was
controlled by attaching a circulating warm water coil
around the head five minutes before cardiac arrest [11].
One minute before induction of cardiac arrest, body cool-
ing was begun using an alcohol patch placed on the front
side of the body and a water-filled pad placed underneath
which was chilled by running throu gh an ice-wat er bath.
CA was induced by intravenous injection of cold 0.5
M KCl (50 µl) via the jugular catheter and confirmed by
the presence of isoelectric ECG. Anaesthesia and ventila-
tion were discontinued, and the endotracheal tube was
disconnected from the ventilator. Body temperature was
allowed to fall during the arrest to 27˚C, then the cooling
devices were removed.
CPR was initiated at 10 minutes of CA by i.v.injection
of pre-warmed epinephrine (0.3 µg/kg in 0.5 ml saline),
chest compressions (approximately 300/min) and venti-
lation with 100% oxygen. CPR was concluded once ECG
and cardiac contractions confirmed restoration of spon-
taneous circulation (ROSC). Resuscitation efforts were
ceased, and the animal excluded from the study if ROSC
was not achieved by 2.5 minutes of CPR. The circulating
water coil was removed and the body temperature was
raised to physiologic levels (37˚C) in a controlled man-
ner using an electrical warming pad. A radiotelemeter
(22 × 8 mm) was inserted under aseptic conditions into
the peritoneal cavity for measurement of body tempera-
ture (Tb) and spontaneous physical activity (Activity;
Vital View ER-4000, Mini Mitter, USA) 10 min after
ROSC as previously described and adapted for mice [13].
All probes were cleaned with 70% alcohol and rinsed
with normal saline prior to ethylene oxide gas steriliza-
tion before use in animals. Each mouse was singly
housed on an ER 4000 receiver platform and computer
system for data recording. Tb and Activity were sampled
once a minute (VitalView® software, Mini Mitter, USA).
Activity is measured as a relative count by determining
gross motor activity on the receiver platform. This
method does not allow measurement of e.g. a distance
traveled or the moving speed of the mouse.
After 30 minutes, mice were disconnected from the
ventilator and breathing effort and pattern was evaluated .
When a normal respiratory rate (120/min) with sufficient
strength of the breathing musculature was present, the
endotracheal tube and catheter were removed and skin
wounds closed. The animal was returned to its homecage
35 minutes after CA/CPR for continuous monitoring of
Tb and Activity for the following 3 days. Animals not
surviving the 3-day period were excluded from the study.
2.3. Experimental Groups
2.3.1. Experiment 1: Measurement of Physiological
Body Temperature Variation and Physical
We first assessed the physiological pattern of body core
temperature and activity variation in healthy mice. Nine
animals were examined in this experiment. A radio-
telemeter was implanted and animals were allowed to
recover 1 week with full access to food and water before
recording of Tb and Activity for 3-days.
2.3.2. Experiment 2: Effect of Normothermia or
Hyperthermia during Brain Ischemia on Body
Temperature Variation, Physi c al Activi ty,
Mortality and Neuronal Survival
To evaluate if Tb and Activity during recovery from
CA/CPR was altered by the level of brain injury, a total
of 26 mice were randomized to receive either nor-
mothermia (peri-cranial temperature during cardiac arrest:
37.5˚C, n = 8), hyperthermia (peri-cranial temperature
39˚C, n = 11) or sham surgery (n = 7, animals followed
the normothermia experimental protocol except receiving
CA/CPR). Radio-telemetric monitoring was performed
for 3-days after CA/CPR.
2.4. Histology
At 3 days post-arrest, mice were deeply anesthetized with
halothane and the brain was perfusion-fixed (10% phos-
phate buffered formalin, as previously described [11].
Tissue analysis was performed by standard hematoxylin
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
Hypothermia in Mice
and eosin histology. For analysis, viable and non-viable
neurons were counted by an investigator blinded to
treatment regimen using light microscopy (100×) in the
CA1 region of hippocampus (bregma –1.5 mm), and ros-
tral and caudal caudoputamen (bregma 0.5 and –1 mm,
respectively). The entire length of the CA1 sector was
counted, and six microscopic fields were evaluated fol-
lowing a distinctive pattern in both levels of the cau-
doputamen. Non-viable neurons were identified by pink
hypereosinophilic cytoplasm and a dark pyknotic nucleus,
and the percentage of neurons that were non-viable was
calculated for each region of interest.
2.5. Statistical Analysis
All data are expressed as mean ± SE. Comparison of
treatment groups for physiologic variables and neuro-
histopathology were performed using one-way analysis
of variance (ANOVA) and post-hoc Tukey test or t-Test
where applicable (Sigma Stat 3.0, SPSS Inc.). A one-way
repeated measures analysis of variance and post-hoc test
(Dunnett’s Method) was used for analysis of body tem-
perature in each group. Fisher’s Exact Test was used for
animal survival analysis. Differences were considered
statistically significant with p < 0.05.
3. Results
3.1. Tb and Activity in Healthy Mice
(Experiment 1)
We observed that higher body temperatures and activity
levels occurred during the dark vs light cycle, indicating
strong circadian rhythm variation (Figure 1). Tb and
activity were highest shortly after light changes in the
housing room. Tb and activity appeared coupled in peri-
ods of high spontaneous activity and correlated well with
increased body temperature (r2 = 0.67).
3.2. Physiologic Parameters (Experiment 2)
Body weight at the day of surgery, CPR time and epi-
nephrine dose were not different between groups (Table
1). All mice were successfully resuscitated after CA/CPR.
As intended, peri-cranial temperature during injury was
higher in normothermia vs hyperthermia groups (p <
0.001), however temperature was equivalent in both in-
jury groups by 30 minutes post-arrest (Table 2). Mortal-
ity was not statistically different between normothermia
and hyperthermia groups (p = 0.49, Table 1).
3.3. Body Temperature and Activity after
CA/CPR (Experiment 2)
Tb and Activity decreased spontaneously during recov-
ery from CA/CPR, and this effect was most striking in
Figure 1. Physiologic body-temperature (a) and activity (b)
in healthy male C57Bl/6 mice. 12:12 hour light:dark cycle
(7 AM:7 PM) is marked as black bars; n = 9, mean SE.
Table 1. Body weight, CPR duration, Epinephrine dose and
Animal survival.
Experimen tal Group
ShamNormothermia Hyperthermia
Body Weight [g] 24.8 ± 0.6 24.6 ± 0.5 25.8 ± 0.7
CPR Duration [sec] 59 ± 8 61 ± 8
Epinephrine [µg] 7 ± 0.4 9 ± 0.7
Epinephrine[µg/g/BW] 0.3 ± 0.02 0.3 ± 0.02
Animal Survival 77
Normothermia: 37.5˚C during CA/CPR; Hyperthermia: 39˚C during CA/
CPR. Mean ± SE.
the hyperthermia group (Figure 2(a)). Tb fell during
early recovery in the hyperthermia group and reached a
nadir of 28˚C ± 0.8˚C (p < 0.001 as compared to baseline
values). Tb partially recovered to 34.4˚C ± 1˚C at 34 hrs
post CA (p < 0.001 as compared to baseline valu es), then
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
Hypothermia in Mice 309
again decreased. Phases of high activity levels were not
accompanied by a significant increase of Tb. Although
Tb remained low at all times, spontaneous activity was
evident by 8 hours, increased steadily then again declined
40 hours after CA/CPR (Figure 2(b)). A physiologic
activity variation, as observed in sham operated animals,
was absent during the observation period. In the nor-
mothermia group, Tb was also depressed for hours after
CA/CPR, but the nadir for Tb depression was less
(32.3˚C ± 0.3˚C), and full recovery of Tb did occur. Dur-
ing the first 12 hours activity was higher than in th e other
groups, followed by a decrease in the following observa-
tion period. Nevertheless, the normal coupling of Tb and
spontaneous activity was lost and physiologic variation
was absent in the normothermia group. Despite high
spontaneous activity during the first post-arrest day, Tb
remained low (32.8˚C ± 0.5˚C at 10 hours).
3.4. Neurohistopathological Injury
(Experiment 2)
Neuronal injury was similar in the hippocampal CA1
region in normothermia and hyperthermia groups (Fig-
ure 3). Mice subjected to hyperthermic cardiac arrest had
a higher percentage of injured neurons at the caudal and
rostral level of the caudoputamen than normothermic
cardiac arrest mice (p < 0.001 and p < 0.05, respectively).
Injury was greater in both groups at the caudal caudopu-
tamen than at the more rostral level.
4. Discussion
This study demonstrates that mice undergoing hyper-
Table 2. Body temperature and Peri-Cranial Temperature
at Baseline, end of Cardiac Arrest period, and 10 and 30
min after Restoration of Spontaneous Circulation (ROSC).
Experimental Group
Sham Normothermia Hyperthermia
Rectal Temperature (˚C)
Baseline 36.8 ± 0.1 36.5 ± 0.1 36.6 ± 0.1
10 min Cardiac
Arrest 33.4 ± 0.1 27.3 ± 0 .2 26.8 ± 0.3
10 min ROSC 34.8 ± 0.1 30.6 ± 0. 4 29.5 ± 0.5
30 min ROSC 36.8 ± 0.1 37.2 ± 0.2 36.6 ± 0.3
Peri-Cranial Temperature (˚C)
Baseline 34.7 ± 0.3 34.6 ± 0.2 34.5 ± 0.2
10 min Cardiac
Arrest 37.5 ± 0 37.5 ± 0*** 39 ± 0.1
10 min ROSC 35.6 ± 0.1 31 ± 0.1 31.2 ± 0.4
30 min ROSC 34.6 ± 0.2 34.8 ± 0. 1 34.7 ± 0.1
Figure 2. Body core temperature (a) and Activity (b) in the
housing cage after cardiac arrest and CPR. BI: Brain In-
jury; Mean ± SE.
thermia during CA/CPR have loss of post-ischemic tem-
perature regulation, spontaneous severe hypothermia as
well as uncoupling of spontaneous activity and body
temperature. Normothermia during brain injury resulted
in a milder form of spontaneous hypothermia and a loss
of circadian temperature regulation. Hyperthermia during
CA/CPR resulted in greater neuronal injury in caudopu-
tamen, suggesting that spontaneous marked hypothermia
during recovery is related to the severity of brain injury.
A corollary of the present observations is that long term
temperature monitoring is required in survival murine
experiments, if body temperature is to be controlled as a
study variabl e.
We observed that body temperature and physical ac-
tivity varied in a circadian rhythm under basal conditions,
a phenomenon that has been described in mice and which
differs amongst mouse strains commonly used as ex-
perimental models in neuroscience [14,15]. In mouse,
physiologic temperature ranges from mild hypothermia
during periods of low activity to hyperthermia during
high activity. However, circadian fluctuations are imme
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
Hypothermia in Mice
Figure 3. Neuronal injury after cardiac arrest and CPR. A:
CA 1 field of the hippocampus; B: rostral caudoputamen; C:
caudal caudoputamen. *p < 0. 05, **p < 0.01. Mean ± SE.
diately ablated, and not restored, in animals that sustain
injury from global cerebral ischemia. In murine models
of focal ischemia, hyperactivity has been described pre-
viously and its level has been associated with severity of
brain injury [16,17].
The depth of spontaneous hypothermia induced by
CA/CPR, even in the presence of persistent physical ac-
tivity, is surprising. Spontaneous hypothermia after
CA/CPR has been described in a rat model of asphyxial
cardiac arrest, with recovery to control values by 36 hr
ROSC [8]. In another study, rats developed moderate
hypothermia (32˚C) five hours after CA/CPR and recov-
ered within eight hours to normal body temperature [18].
The depth of hypothermia was less in these studies, and
recovery more rapid, than we observed in our mouse
model of CA/CPR. Other rat models of brain ischemia
have also been associated with spontaneous temperature
changes during recovery. The four-vessel occlusion
model in rat causes mild hypothermia in brain [19].
However, results are inconsistent in studies examining
temperature changes in the two-vessel occlusion model
of brain ischemia. One study reports a period of hyper-
thermia lasting up to three days and a loss of circadian
temperature variation after the insult [2 0]. In a later stud y
using the same model of brain ischemia, no post-
ischemic temperature changes could be demonstrated
[21]. In a modified model of two-vessel occlusion, a brief
two hour period of mild hypothermia was followed by
recovery to normothermia within six hours after the in-
sult [22]. In a model of two vessel occlusion in C57Bl/6
mice, spontaneous hypothermia occurred after the in-
sult[10]. In agreement with our results in the normother-
mia during CA/CPR group, the lowest body temperature
in this study was 32˚C and recovered to physiologic lev-
els within 24 hours after brain ischemia [10]. Spontane-
ous hypothermia in patients, especially in pediatric pa-
tients has also been reported anecdotically, however this
finding has not been systematically evaluated [23]. In
part, the lack of attention to endogenous temperature dys-
regulation is due to ongoing interest in therapeutic cool-
ing after CA/CPR or traumatic brain injury. Mild to mo-
derate hypothermia post arrest remains to date the only
successful neuroprotective strategy applied to humans
and is used increasingly in intensiv e care units for select-
ed patients [1,2]. In contrast, post-injury hyperthermia
worsens outcome and increases neuronal injury [24,25].
The hyperthermia during CA/CPR group in our study
exhibited severe hypothermia in the first hours of recov-
ery, with only incomplete recovery during the 3-day ob-
servation period. The mechanism for initiation/mainte-
nance of spontaneous hypothermia is not clear. However,
it is unlikely that low physical activity was responsible
for low temperature in this set of experiments. Mice ex-
hibited high activity levels in the first 12 hours post ar-
rest, yet body temperature failed to rise to basal levels.
Normothermia during CA/CPR mice also showed early
hyperactivity at periods when their lowest temperatures
were observed. The hyperthermia during CA/CPR group
presented body temperatures during early recovery simi-
lar to body temperatures that have been described in tor-
por. Topor is a temporary hibernation-like state that has
been previously shown during times of food restriction
[14,26]. In contrast to topor, which is characterized by a
state of motor inactivity, animals in this study showed a
high level of activity in the early phase of recovery with-
out a corresponding increase of body temperature.
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
Hypothermia in Mice 311
A limitation of our study is that hyperthermia during
CA/CPR was used to induce more severe brain injury.
The temperature manipulations in our model may have
contributed to post-arrest temperature dysregulation.
However, a milder form of spontaneous hypothermia,
albeit in a milder form, has also been described in other
mouse models of global ischemia without intra-ischemic
hyperthermia [10]. Therefore, we believe that the tem-
perature dysregulation in our model is a direct result of
increased neuronal injury and only indirectly related to
the experimental temperature manipulation. We did not
specifically monitor weight changes or food and water
intake in our animals. However, we noted that most mice
in the hyperthermia group did not appear healthy at the
end of the 3-day observation period. Some of these ani-
mals might not have survived much longer than four days
after cardiac arrest and CPR. Several reasons for the poor
health of these animals exist, e.g. multi organ failure,
which might have been responsible for body temperature
and decreased activity two to three days after the insult,
but is unlikely responsible for the Tb and activity altera-
tions during the early recovery period.
The present study does not determine the potentially
complex mechanisms underlying spontaneous post-
ischemic hypothermia. However, the data underscore the
need for long term monitoring of body temperature in
mouse brain injury models and emphasize the extreme
change that occurs in temperature regulation. It is well
recognized that temperature in recovering animals is in-
fluenced by multiple factors, including method of tem-
perature measurement, anesthetic regimen and injury
model [6,8,27,28]. Furthermore, the neuroprotective po-
tential of a number of pharmacologic agents such as
MK-801, NBQX or Magnesium has been linked to tem-
perature [29-31]. Therefore, interactions with brain in-
jury induced spontaneous hypothermia and investiga-
tional neuroprotective drugs must be considered.
No guidelines exist on how body or brain temperature
in small rodents after brain ischemia should be measured
or controlled. Several techniques have been published,
including the use of heating devices such as infrared
lamps or the use of incubators used in human medicine
[8,32]. In a recent review, MacLellan et al recommended
tight temperature measurements of the brain and body
during surgery as well as during recovery after brain
ischemia for at least one day [33]. Telemetry probes are
strongly recommended for measuring temperature in
conscious rodents because this technique allows repeated
measurements without stressing the animal by handling
as is necessary with rectal measurements. It is also im-
portant that the use of a temperature controlled environ-
ment does not obviate the need for frequent temperature
measurements since experimental animals could present
with either hyper- or hypothermia after brain ischemia.
Heating as well as cooling devices must be po sitioned in
such a way that animals are exposed uniformly. The use
of infrared lamps is discouraged as they impose a risk of
non-uniform heating and overheating of an impaired
post-ischemic animal.
In conclusion, the present results demonstrate severe
spontaneous hypothermia after CA/CPR in mice, which
is partially spontaneously reversible. However, future
studies will be necessary to determine which mechanisms
are involved. Our results also underline the necessity for
monitoring body temperature in survival murine studies
since temperature is a major factor influencing outcome.
5. Acknowledgements
This study was supported by National Institutes of Health,
grants NS 46072, NS 20020 and NS 33368. None of the
authors has a financial interest to disclose.
Experiments were conducted at Oregon Health & Sci-
ence University, Department of Anesthesiology and Peri-
Operative Medicine, Portland, Oregon, USA.
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Experimental Hyperthermia during Cardiac Arrest and CPR Is Associated with Severe Spontaneous
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