758
Preservation of Brain Temperature
During Ischemia in Rats
Hiroaki Minamisawa, MD, Pekka Mellergard, MD,
Maj-Iis Smith, PhD, Finn Bengtsson, MD, PhD,
Sten Theander, BSci, Fredrik Boris-Moller, MD, and Bo K. Siesjo, MD, PhD
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Our objectives were to study the loss of heat from ischemic brain and to devise a method of
maintaining brain temperature. Reversible forebrain ischemia was induced by carotid clamping and exsanguination in 30 anesthetized and artificially ventilated rats. Rectal, skull, and
brain temperatures were measured, confirming previous findings that brain temperature falls
by 4-5° C during 15 minutes of ischemia unless measures are taken to maintain head
temperature by external heating. Temperature gradients developed within the ischemic brain,
superficial tissues being cooler than deep ones. These temperature gradients were reversed
when skull temperature was maintained at core body (rectal) temperature by external heating.
With rectal and skull temperatures maintained at 3ff, 37°, 35°, or 33° C, brain temperatures
nonetheless decreased by approximately 1° C during ischemia. This decrease in brain temperature could be prevented by placing the rat in a Plexiglas box with circulating air at
temperatures close to that of the body core and a relative humidity of approximately 100%. We
also found that, unless special precautions are taken, a temperature gradient develops between
the brain and body core duringrecirculation.(Stroke 1990^1:758-764)
B
rain tissues in many mammals maintain a
temperature slightly greater than that of the
arterial blood circulating within the tissue.1-3
In terms of heat exchange, therefore, brain tissue
normally serves as the source and blood as the sink.
However, the temperature of blood supplying brain
tissue may be lower than the body core temperature,
especially in animals that use the mechanism of
countercurrent heat exchange between an arterial
rete and the venous sinuses draining the mucous
membranes of the nose and mouth.4-7 Furthermore,
brain temperature is not uniform. For example,
superficial tissues with their supplying arterial vessels
lose heat to their surroundings by conduction, radiation, evaporation, and convection. Since evaporation occurs mainly from mucous membranes in, for
example, the nasal and oral cavities, even deep
tissues may lose heat to their surroundings. As a
From the Laboratory for Experimental Brain Research (H.M.,
M-L.S., S.T., B.K.S.) and the Departments of Neurosurgery
(P.M.), Clinical Pharmacology (F.B.), and Anesthesiology (F.BM.), Lund University Hospital, Lund, Sweden and the Second
Department of Internal Medicine (H.M.), Nippon Medical School,
Tokyo, Japan.
Supported by Swedish Medical Research Council grant 14X-263
and United States Public Health Service grant 5. RO1 NS-07838.
Address for reprints: Professor Bo K. Siesj6, Laboratory for
Experimental Brain Research, Lund University, S-221 85 Lund,
Sweden.
Received August 10, 1989; accepted January 11, 1990.
result of heat loss, there is often a temperature
gradient between the deep and superficial tissues.8-12
Heat loss is a function of the efficacy of insulation by
bone, muscles, skin, and hair,1314 a function of the
temperature and movement of ambient air,15-17 and a
function of the humidity of the ambient air.1819 Brain
temperature also depends on regional blood flow and
the temperature of the nasal mucosa.20"24 Normally,
the surroundings are cooler and have a lower vapor
pressure than body tissues, favoring heat loss.
Since it retards or interrupts the arterial blood
supply, ischemia upsets temperature regulation. In
centrally located brain tissues temperature may rise,
at least transiently, reflecting the failure of arterial
blood to remove metabolic heat.3 However, superficial tissues cool, and in small mammals such as rats
this cooling can be fast and can rapidly cause centrally located brain tissues to cool also. Thus, forebrain ischemia lasting 15-20 minutes is accompanied
by a striatal temperature decrease of 4-5° C.25
Previous as well as more recent results25"31 have
demonstrated that even small changes in brain temperature (1-3° C) significantly alter ischemic brain
damage or the cerebral metabolic response to ischemia. This makes it imperative that experiments on
ischemia are conducted with brain temperature
under tight control. In fact, unrecognized differences
in tissue temperature may explain many of the discrepant results reported in the literature.
Minamisawa et al Ischemia and Brain Temperature
Our study had two objectives. First, we wished to
explore the factors that determine heat loss from
ischemic brain and to assess temperature gradients
within the brain. Second, we wanted to devise a
method, preferably one not too complicated, for maintaining brain temperature during ischemia at any level.
Materials and Methods
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We used 30 male Wistar rats (M0llegaard's Breeding Center, Copenhagen, Denmark) weighing 300350 g. The rats were fasted the night before the
experiments but were allowed free access to tap
water. Anesthesia was induced with 3.5% isoflurane
(Abbott Laboratories Ltd., Kent, England), and the
rats were then tracheotomized and connected to a
Starling-type ventilator delivering 1.5% isoflurane
and 30% N2O in O2. Catheters were inserted into the
tail artery and vein of each rat to allow blood pressure
recording, blood sampling, and infusions. The common carotid arteries were isolated via a neck incision,
and a silicone catheter was advanced into the inferior
caval vein via the right jugular vein to allow later
withdrawal of blood. A pair of needle electrodes were
inserted into the temporal muscles for electroencephalographic (EEG) recording.
Following these procedures each rat received 50
IU heparin; 30 minutes passed before induction of
reversible forebrain ischemia. The ventilator was
adjusted to maintain PaOj and Paco2 at 90-115 and
35-40 mm Hg, respectively; arterial pH was thus
kept at approximately 7.4. Mean arterial blood pressure was maintained at 100-120 mm Hg. Blood glucose concentration was measured. During the experiments the rats were immobilized with 0.3-0.6 mg i.v.
d-tubocurarine.
We used copper-constantan thermocouples to
measure temperature. Each thermocouple was calibrated in a temperature-controlled water bath to
<0.1° C error at 37° C before each experiment. Rectal and esophageal temperatures were measured with
a type A-RM 4 thermocouple (Ellab, Copenhagen,
Denmark) inserted 5 cm into the rectum or into the
esophagus to a position directly behind the heart.
Arterial temperature was measured using a thermocouple constructed at the electronic workshop of
Lund University Hospital and placed in the abdominal aorta via a cannula in the femoral artery. Skull
temperature was measured with a type A-K3 thermocouple (Ellab) placed subcutaneously on the
bregma. Brain temperature was measured using a
type A-K19 needle thermocouple with an outer
Teflon guide (Ellab). This thermocouple had thin
plastic coating all but the distal 0.15 mm of the
metals. When in place, the Teflon guide covered all
but the distal 2 mm of the thermocouple. The diameters of the plastic-coated thermocouple and the
Teflon guide were 0.2 and 0.8 mm, respectively. To
check the sensitivity of this thermocouple to changes
in the surrounding temperature, we stereotactically
guided the thermocouple within a very strictly
temperature-controlled water bath covered with a
759
Teflon membrane at the same room temperature as
the rat experiments. As expected, the distal 0.15 mm
of the thermocouple was the actual temperaturemeasuring site, but the temperature readings were
influenced slightly by the temperature around the 2
mm plastic-coated part of the thermocouple. However, the Teflon guide gave very good insulation so
changes in temperature around the guide did not
influence the temperature readings, the temperature
resolution being 0.1° C.
For measuring the temperature gradient, a burr
hole 2.5 mm in diameter was drilled with its center 5
mm lateral to the bregma for measuring caudoputaminal temperature. A second burr hole was made
4.5 mm lateral and 4.5 mm posterior to the bregma
for measuring thalamic temperature. The dura was
carefully lifted and punctured with a thin needle. The
thermocouple was then stereotactically inserted into
the left caudoputamen or thalamus to a depth of 5
mm from the cortex. The skin above the burr hole
was sutured before the beginning of temperature
measurements.
The temperature of each rat was maintained close
to the desired level by either the use of a 55-W
heating lamp placed above its head and a heated
operating table or by the use of a Plexiglas box
constructed for the experiments. The box measured
60x40x50 cm (length x width x height) and had no
bottom so that it could be placed around the operating table. The box had small windows that could be
opened, permitting all manipulations of the rat to
take place without removing the box. It was equipped
with a heating fan and a small water bath, a thermocouple at the level of the experimental animal, and a
device for measuring humidity. The box also contained insulated inlets and outlets for cables and
respiratory tubings.
The model of ischemia has been described in
detail.32 Isoflurane was discontinued, and 1 minute
later both common carotid arteries were clamped,
followed by exsanguination to a blood pressure of 50
mm Hg. Cerebral ischemia was confirmed by cessation of EEG activity. At the end of the ischemic
period, recirculation was instituted as the carotid
clamps were removed and the blood was reinfused.
When blood pressure was restored, 0.5 ml of 0.6 M
sodium bicarbonate was injected intravenously to
counteract systemic acidosis.
Rectal, skull, and caudoputaminal temperatures
were measured in all rats. In one rat the rectal,
esophageal, and abdominal aortic temperatures were
also measured simultaneously. The rats were divided
into seven groups. One rat was subjected to 20
minutes and the other 29 to 15 minutes of ischemia.
Experiments in the first five groups (n=4 in each)
were performed in room air (temperature 20-22° C,
relative humidity 10-20%). In one group no attempt
was made to control the temperature of the rat's
head; in one of the four rats (subjected to 20 minutes
of ischemia) the temperature at different depths in
the brain were measured by moving the stereotacti-
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I I I I I
3 6 9
15/0
- ISCHEMIA 1
10
15
20 25
- REPERFUSION -
30 Mln
FIGURE 1. Graph of mean±SEM rectal ( A ) , caudoputaminal (o), and skull (•) temperatures during and following 15
minutes of reversible forebrain ischemia in four rats in which
rectal temperature was maintained at 37° C while head was
allowed to cool spontaneously.
cally guided thermocouple through the parenchyma
in 1-mm steps. In the other four groups rectal and
skull temperatures were kept at 33°, 35°, 37°, or 38° C
during ischemia using the heating lamp and the
heated operating table. Heating was discontinued
during recirculation. In two of the 16 rats (one at 33°
and the other at 37° C) brain temperature gradients
were measured as described above. Experiments in
the two remaining groups took place in the Plexiglas
box at a relative humidity of either 10-20% (n=5) or
approximately 100% (n=5). In both groups, the box
was opened for 5 minutes at the start of recirculation
but closed at all other times. At the lower humidity,
ambient air temperature was kept at 37° C, and the
head of two rats and the body of one were wrapped
in aluminum foil; in the two remaining rats the
inspired air was heated to 37° C. At the higher
relative humidity, ambient air was kept at 35° C in
one rat, at 37° C in three rats, and at 39° C in one rat.
Values presented are mean±SEM. Due to the
nature of the experiments, no other statistical calculations were made.
Results
Blood pressure, Pao2, Paco2, arterial pH, and
blood glucose concentration were kept within normal
physiologic limits in all rats before and after ischemia. No differences in the variables were observed
among the groups.
In the rat in which rectal, esophageal, and abdominal aortic temperatures were measured simultane-
I— ISCHEMIA
FIGURE 2. Graph of mean±SEM rectal ( A ) , caudoputaminal (o), and skull (•) temperatures during and following 15
minutes of reversible forebrain ischemia in rats. Rectal and skull
temperatures were controlled by external heating to 38° C (top,
n=4), 37° C (middle, n=4), or 35° C (bottom, n=4) during
ischemia. At start of recirculation, heating was discontinued.
ously, rectal temperature adequately reflected the
central body core temperature. The maximum difference between the rectal and esophageal/abdominal
aortic temperatures was 0.3° C.
In one group, spontaneous changes in brain temperature during and immediately after ischemia were
measured. The results are shown in Figure 1. Immediately following induction of ischemia, skull and
caudoputaminal temperatures began to fall, and they
continued to fall in parallel during the entire ischemic period. These results confirm those of Busto et
al,25 who noted an equally extensive reduction in
brain temperature during ischemia. Skull temperature
was 0.5°-1.0° C lower than caudoputaminal temperature. After 15 minutes of ischemia, skull temperature
had fallen to <32° C and caudoputaminal temperature to approximately 32° C. When recirculation was
instituted rectal temperature fell transiently, probably
Minamisawa et al Ischemia and Brain Temperature
761
37
FIGURE 3.
35
o
34
o
o
5 33
I 32
©
31
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10
15
20/0
10
15
i I iI I I I I
I I i I i i
Ischamla
Graph of rectal ( A ) ,
brain (o), and skull ( • ) temperatures during and following 20
minutes of reversible forebrain
ischemia in one rat in which
head was allowed to cool spontaneously. —1 to —5, depth in
millimeters from brain surface at
which temperature gradient was
measured. After 8 minutes of
ischemia, thermocouple placed
in caudoputamen 5 mm below
brain surface was withdrawn in
1-mm steps. For each step toward
brain surface temperature fell,
neocortex (-1) being 0.7°C
cooler than caudoputamen (—5).
After 18 minutes of ischemia,
thermocouple was lowered into
thalamus (—5) and gradient between superficial and deep structures was confirmed.
36
20Mln
il
Rsperfudon
because the reinfused blood had cooled. At the beginning of reperfusion, skull and caudoputaminal temperatures rose very rapidly. After 10 minutes of recirculation, caudoputaminal temperature approached its
preischemic level while skull temperature remained
approximately 1° C below its preischemic value.
In the next four groups, both rectal and skull
temperatures were kept constant during ischemia.
Results for three of the groups are displayed in
Figure 2. Brain temperature, as measured in the
caudoputamen, fell by approximately 1° C during
ischemia. This decrease in brain temperature was
similar regardless of whether rectal and skull temperatures were kept at 33° C (data not shown), 35°, 37°,
or 38° C. Skull temperature fell very rapidly during
the first 5 minutes of recirculation and continued to
fall more slowly during the entire observation period,
to 2-3° C below rectal temperature. Caudoputaminal
temperature, on the other hand, increased rapidly to
the rectal temperature immediately upon recirculation. In the group heated to 35° C, caudoputaminal
temperature remained close to rectal temperature
during recirculation. In the groups heated to 37° or
38° C, after 10-15 minutes of recirculation caudoputaminal temperature again fell to 1-1.5° C below
rectal temperature.
In the rat in which the skull was allowed to cool
spontaneously during 20 minutes of ischemia, caudoputaminal temperature reached 32.3° C after 9 minutes
of ischemia The thermocouple was then withdrawn
from the caudoputamen in 1-mm steps. This procedure
disclosed a temperature gradient within the brain, the
neocortex being 0.9° C cooler than the caudoputamen
(Figure 3). The thermocouple was then inserted
through the second burr hole into the thalamus, and
37
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o
e
a
E
35
10
I Ii
lichimlt
15/0
i l l
5
i
i i
i I i
10 Mln
ij
I Raparfuslon
FIGURE 4. Plot of temperatures in brain (o) of one rat in which
rectal (A) and skull (•) temperatures were maintained at 37° C
during 15 minutes of reversible forebrain ischemia. —1.5 to —5,
depth in millimeters from brain surface at which temperature
gradient was measured. Temperature gradient between brain
surface and deep structures was reversed compared with Figure 3,
superficial structures being warmer, in both caudoputamen (A)
and thalamus (B). After 30 minutes of recirculation without
heating, temperature gradient was again reversed between superficial and deep structures in thalamus (C).
762
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Vol 21, No 5, May 1990
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FIGURE 5. Graph of mean±
SD rectal (A), caudoputaminal
(o), and skull (•) temperatures
during and following 15 minutes
of reversible forebrain ischemia
in three rats placed in Plexiglas
box with air temperature of
37° C and relative humidity of
approximately 100%. Brain temperature was kept at desired level
throughout ischemic period. Box
was opened at start of recirculation and closed again 5 minutes
later.
36.0-
-3
0
3
9 1 2
18/0
3
Ischemia
after 18 minutes of ischemia the temperature gradient
was confirmed by the same procedure.
This same procedure was also performed in two
rats in which skull temperature was controlled during
ischemia. In these rats a temperature gradient of
approximately 0.5° C was seen. When the head was
heated, however, the temperature gradient was
reversed compared with when the head was not
heated, the deep structures being cooler than the
brain surface (Figure 4). During recirculation, when
heating was discontinued, the temperature gradient
was again reversed, with the thalamus being up to
0.25° C warmer than the neocortex (Figure 4).
In two groups experiments were performed with the
rats in the Plexiglas box. Keeping the air around the
rat at 37° C with normal (approximately 10-20%)
relative humidity did not prevent the decrease in brain
temperature previously described. This decrease
could not be prevented by wrapping the rat's head or
body in aluminum foil or by heating the inspired air to
37° C. However, when the relative humidity was
increased to approximately 100% it was possible to
keep rectal, skull, and caudoputaminal temperatures
at the desired level without any decrease in brain
temperature (Figure 5). This was shown with ambient
air heated to 35°, 37°, and 39° C.
Discussion
Our major findings are as follows. First, if no
measures are taken to maintain the temperature of
the skull during ischemia, brain temperature falls
rapidly, with relatively small intracerebral gradients.
Second, when the head is heated by a lamp so that
the subcutaneous skull temperatures are maintained
12
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Reperluslon
at 38°, 37°, 35°, or 33° C, at identical body core
temperatures intracerebral temperatures nonetheless decrease by approximately 1° C. Third, if the
brain is recirculated and skull heating is discontinued, the temperature gradient between the brain and
body core changes with time. During recirculation
this gradient first decreases, then increases. These
changes probably reflect postischemic changes in
blood flow, encompassing an initial hyperemia and a
later hypoperfusion. Fourth, even when the body is
placed in a box with circulating air at a temperature
close to that of the brain, brain tissue loses heat
during ischemia. In all probability, the decrease in
brain temperature is due to evaporative heat losses
since it is abolished by increasing the relative humidity to 100%.
Two factors favor heat loss from the brain. First,
since the skin (which normally represents the outer
temperature zone) is cooler than deep organs, there
is a gradient favoring conductive heat loss to the
surroundings.16'33'34 Second, even when the temperature of the skin is the same as that of the surroundings, heat is lost by evaporation. Evaporation may
occur from all skin surfaces; however, it is more
marked from the mucous membranes of the nasal
and oral cavities due to their wet condition and their
large surface area.18-20
To our knowledge, the first authors to recognize
that the brains of ischemic animals cool were Hirsch
et al,35 who reported that brain temperature could
fall to 33° C during ischemia and that the rate of
decline increased when the skull was exposed (duration of ischemia unknown). These authors devised
two methods for preventing the decrease in brain
Minamisawa et al Ischemia and Brain Temperature
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temperature: external heating of the head or enclosing the animal in a glass box, the air of which was
heated to within 1-2° C of body temperature. They
reported that, with the latter method, temperature
differences between rectum and brain could be kept
to ±0.15° C.26 However, they did not report increasing differences with longer ischemic periods, nor is
the humidity of the air in their box known.
Heat loss from ischemic brain is facilitated by the
reduction in blood flow to extracerebral cranial tissues that occurs in all models of forebrain and global
ischemia. Predictably, when ischemia is focal, as
when a major intracerebral blood vessel is obstructed
or when intracranial pressure increases, the maintained circulation to extracerebral tissues reduces the
heat lost from the ischemic tissue.
For many years36 and before we published a model
of recovery from forebrain ischemia,32 it has been our
practice to prevent heat losses from ischemic brain by
placing a lamp some distance from the brain. Previously, we used a standard placement of the lamp, one
that maintained intracerebral temperatures at approximately 37° C,32 but during the last few years we have
used a thermistor placed on the skull to guide placement of the lamp. We now report that even with these
precautions, intracerebral temperatures fall by
approximately 1° C during 15 minutes of ischemia. In
fact, even when the entire animal was placed inside a
box maintained at body temperature, brain temperature fell. Since this decrease could be prevented by
increasing the relative humidity of the warm air, our
results prove that evaporative heat losses contribute to
brain cooling during ischemia. In addition, our results
demonstrate that deep-to-superficial temperature gradients during spontaneous cooling of the head could,
at least in part, mask the true differences in susceptibility to damage of different neuronal populations. For
example, hypothermia is cerebroprotective, and since
the neocortex has the lowest temperature in this
model of ischemia, the vulnerability of neocortical
cells to ischemia may have been underestimated compared with deeper structures. We will report experimental results supporting this contention elsewhere.37
Although local heating of the head may seem to be
a simple and adequate method of maintaining brain
temperature at any level, two problems can be identified. First, as has been discussed, intracerebral
temperatures are not exactly those of the body core
or a subcutaneous site on the skull. Second, it seems
likely that local heating can cause an error opposite
that arising from uncontrolled cooling, that is, brain
damage that is worse on the surface than deep within
the tissue. As discussed above, this issue can be
studied using animals placed in a heated box at the
desired temperature and a high relative humidity.
Previous as well as more recent results indicate that
postinsult hypothermia may ameliorate brain damage
due to trauma or transient ischemia.30-38-41 This possibility, coupled with the knowledge that temperature
differences of only 1-2° C significantly alter the density of ischemic damage,25-28 justifies exploration of
763
factors determining postischemic brain temperatures.
Our present results clearly show that although brain
temperature increases immediately after recirculation
is initiated (presumably because of reactive hyperemia), the difference between brain and blood temperatures subsequently increases. We tentatively interpret this to be the result of reduced blood flow,
allowing blood in the superficial arteries of the brain
to cool before entering the tissue. Very likely, evaporative heat losses from mucous membranes contribute
to postischemic brain cooling.
Clearly, in view of the possibility that postischemic
brain temperatures modulate the final damage
incurred, it seems highly justified that factors determining brain temperature during and after ischemia
be better defined.
Acknowledgment
The authors wish to thank Birgit Olsson for skillful
work with the illustrations as well as secretarial
assistance.
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KEY WORDS
• rats
brain temperature regulation • cerebral ischemia
Preservation of brain temperature during ischemia in rats.
H Minamisawa, P Mellergård, M L Smith, F Bengtsson, S Theander, F Boris-Möller and B K
Siesjö
Stroke. 1990;21:758-764
doi: 10.1161/01.STR.21.5.758
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