Physrev 1921 1 2 295 PDF

THE HEAT-REGULATING MECHANISM OF THE BODY
HENRY G. BARBOUR
From the Departmbt of Pharmacology, Yale University School of Medicine
WATER AND HEAT: Equalization of temperature in living organisms

is best attained through the presence of a mobile constituent which
can circulate freely and rapidly. Water above all other liquids is
fitted for temperature equalization and regulation; for as Lawrence
Henderson (60) points out, it ranks very high as regards three quali-
ties-specific heat, heat of evaporation, and conductivity. The first
favors storage of heat; the second permits of very rapid elimination
when necessary, as when environmental temperature exceeds that of
the body; the third allows rapid equalization of heat within the fixed
tissues of the body, minimizing the possibility of injury from local
overheating within or without.
The recognition of water as the central factor in the regulation of
bodily heat may lend coherence to the following review of some of the
many-sided investigations of the past decade.
HEATREGULATION INTHELOWERANIMALS: Evenamongamphibians
and reptiles is seen an attempt to resist the temperature of the environ-
ment. For instance, in lizards, while the body temperature is a func-
tion of the external temperature, Martin (109) found at medium
environmental temperatures (lO-35°C.) a tendency toward a carbon
dioxid production which is relatively constant. Both above and below
these temperature limits the influence of the environment was more
marked, with approximation of the van’t Hoff law. (Applications of
this law to physiological processes are reviewed by Kanitz (79).)
Krogh (87) finds neither van’t Hoff’s nor Arrhenius’ formula exactly
applicable to metabolism curves. In the frog the nervous influences
which produce tone begin to make themselves felt at ZO”C., for the
rise in metabolism which appears normally at this temperature when
the frog is subjected to gradual heating Krogh finds less marked in
narcosis.
Martin classes the Australian ant-eater (echidna) as a warm-blooded
animal for while the production of heat is directly proportional to the
difference in temperature between animal and environment, its body
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296 HENRY G. BARBOUR
temperature only varies 10°C. within the environmental range of

5-35OC. This indicates that heat loss can be modified although the
animal possesses no sweat glands, exhibits no vasomotor adjustment to
temperature, and does not increase its respirations at high temperatures.
Marsupials are the lowest mammals capable of “heat polypnea.”
Pronounced dependence upon the heat-dissipating mechanism begins
with the higher mammals, e.g., rabbits and cats, the heat production
not being particularly increased until they are submitted to an environ-
ment about 25OC. below their own. Polypnea is well developed but
the loss of heat by sweating varies much with the species; activity
becomes independent of external temperature. The higher mammals
have gained their advantages by a great expenditure of energy, for
Martin states that approximately 800 calories per kilo would be saved
to an animal by allowing its own temperature to fall l°C. instead of
maintaining it by increased heat production. In the carnivora heat
regulation is better developed than in the herbivorous forms; rabbits,
for example, are dependent chiefly upon vasomotor regulation, not pos-
sessing a satisfactory water reserve.
HEAT REGULATION IN MAN: In man the heat-dissipating or ‘( water-
shifting” mechanism, known also as the “physical” regulatory mechan-
ism suffices normally for external temperatures as low as 14-15’.
With cooling below this point, heat production rises rapidly and shiver-
ing movements appear (141). This constitutes the so-called ” chem-
ical” regulation against cold. Young confirms the conclusions of other
observers that cold does not increase metabolism until shivering is
produced. At external temperatures above 30” the intensity of the
metabolism also begins to increase in case the body temperature rises.
The basal metabolism. The normal basal metabolism per square
meter per hour varies with age; DuBois’ chart (99) shows that at birth
this is approximately 30, rising in the first 5 years to over 60, from then
on falling with some irregularity to just below 40 calories at 20 years,
after which it decreases gradually and regularly to about 35 calories at
80 years. DuBois’ height-weight formula gives a satisfactory indica-
tion of the surface area of the human body. From the prediction
tables of Harris and Benedict (57) the metabolism for any adult can be
calculated within a very few per cent on the basis of height, weight,
age and sex. Armsby (3) obtains similar metabolism figures in man,
cattle, horses and pigs. The significance of this metabolism, which is
considerably higher than that exhibited by animals with poor heat-
regulating mechanism, is summed up by Lusk (99) as follows: “The

HEAT REGULATION 297
organism preserves the tropical temperature of its cells at the expense

of a metabolism which is proportional to the skin area of the indi-
vidual.” According to Benedict what determines the basal metabolism
rather than the skin area is ‘I the active mass of protoplasmic tissue.”
Diurnal . variations in body temperature. The diurnal variation in
normal body temperature may be. conservatively placed at l°C. Ad-
justment to inversion of the daily routine by night workers Benedict
(17) found incomplete even after a period of years. In travelling half-
way round the world, Gibson (48) found that the diurnal variations
maintained a parallelism with the daylight. Goldstein (50) describes
as an “interference” curve the diurnal temperature curve of bakers
and night nurses. Upon returning to day work the normal curve
returns in a few days. But in birds, as shown by Hilden and Sten-
baeck (66), the diurnal curve of body temperature can be readily
inverted by reversing the habits of life; owls and other night species
exhibit maximum temperature in the night.
Injluence of age. Imperfections in heat regulation are observed in
the extremes of life. Benedict and Talbot (20) have shown that the
average rectal temperature and heat production are decidedly sub-
normal during the first 3 or 4 days after birth. In old age Munk (121)
has shown that shivering sets in under conditions in which the “phys-
ical” regulation would suffice for younger persons. In doves, Loer (97)
finds the average body temperature highest at 2 to 8 months.
Temperature topography. Benedict and Slack (19) concluded that a
rise or fall in rectal temperature is accompanied by a similar rise. or fall
in temperature of all other parts of the body, aside from the skin.
Moro (119) has shown that the temperature will exhibit the greatest
increase in the axilla or rectum in children according to whether arms
or legs respectively have been active. As a result of marching with a
heavy load, rectal temperatures up to 39OC. were found by Lippmann
(96). The temperature changes were regarded largely as local hyper-
thermias due to marked muscular activity of the lower extremities.
Hirsch, Mueller and Rolly (71) claimed that the liver is always the
warmest part of the body whether during refrigeration, overheating or
infectious fever, or after “heat puncture.” The temperature increase
of muscles after heat puncture was still noticed in the presence of
curare but with or without this drug it was said to lag behind that of
the liver.
Magne (103) states, on the other hand, that during refrigeration
hepatic and intestinal temperatures rise parallel to that of the aorta,

while the muscles show a much greater rise; or with more extreme
degrees of refrigeration the muscle curves show less fall in temperature
th an the other curves. This h.e associates with the augmented activity
of the muscles in regulating against co1.d. Lefevre (91) maintains,
however, that liver and muscle temperatures run parallel during refrig-
eration, and ascribes to the liver 30 per cent and to the muscles 40
per cent of thermogenesis; but Magne attributes to the muscles 70 to
80 per cent.
The ‘I surface temperature” of the body is much less uniform than
is generally supposed. ‘Benedict,, Miles and Johnson (18) find that the
temperature of the skin even with well-clothed individuals exhibits
differences of 4” to 5OC. in various localities.
As an insulator the efficiency of the human skin varies according to
the predominance of fat, corium, or epidermis (157). The epidermis
has the poorest heat conductivity, heat passing through fat and through
corium respectively two and three times as readily. Variations in the
fluid content of its capillaries naturally alters the conductivity of the
living skin.
The heat conductivity of the cranium appears to be relatively good.
Leyton and Sherrington (94) found that in a chimpanzee with a cranial
vault about the thickness of the average human, the application of
local cold (ice bag) or heat over the parietal scalp rapidly affected the
temperature of a thermometer bulb lying under the dura against the
cerebral surface, directly beneath the region of thermal application.
Average body temperature. Precise determination of the average
temperature of the body appears at present impossible. Barr and
DuBois (16) have, however, devised a differential method by which
changes in average body temperature may be determined in a calori-
meter. For a given interval they determine the difference between the
number of calories produced and the number eliminated. This* dif-
ference, when divided by the thermal equivalent, affords the gain or
loss in average body temperature. For example, heat production,
100 calories, minus heat elimination, 60 calories = heat stored, 40
calories. In a 70 kilo man, the thermal equivalent = 58.1. The
40
average temperature gain is therefore - = 0.66’.
58.1
REGULATION AGAINST COOLING : ChemicaZ regulation. In animals
with well-developed physical regulation chemical regulation only
appears as the external temperature descends below 14-15OC. But
many instances may be cited (99) in which external temperatures of

HEAT REGULATION 299
20’ and 25” are no longer borne by animals without an increase in

metabolism, after removal of the protecting cover of hair or feathers.
Rubner (135) showed further the difference made by a protecting
layer of adipose tissue; the same dog when thin has a much higher
metabolism at various temperatures than when fat. For example, at
15” when thin he produced 109 calories per kilo as against 83 calories
when fat.
The older writers, Rubner (135) for example, having contended that
shivering movements were not essential to chemical regulation, Sjoe-
stroem (142) investigated three subjects with and without clothes, in a
Tigerstedt respiration chamber, maintained at external temperatures
varying from 10 to 32OC. He concluded that the increase in oxidations
during shivering movements was directly dependent upon the inten-
sity of the movements; these tremors are instigated reflexly through
the cold nerves. Without shivering movements the variations in
carbon dioxid output bore no relation to the external temperature.
While this makes chemical regulation and shivering appear inseparable
it must be remembered that heat production even in muscle can occur
without external manifestation (68). Exact studies of heat production
in heart and smooth muscle are described by Snyder (143).
In extreme refrigeration such as lowers the body temperature, chem-
ical regulation must break down rapidly, for Storm Van Leewuen (147)
has shown that cooling tends to reduce the reflex irritability of the
spinal cord. This reduction becomes very marked at a body tempera-
ture of 26’ which may explain why this temperature approximates the
lowest compatible with life.
Chemical regulation is largely but not entirely abolished by curare,
for Mansfeld and Lukacs (107) showed that the heat production falls
10 to 15 per cent after severing the sciatic nerves of a curarized dog.
The regulatory influences which are not abolished by curare are said to
take their course through the sympathetic nerves, for when the latter
are cut sciatic section in the curarixed dog no longer reduces the metab-
olism.
The influence of cooling upon metabolism is illustrated by the experi-
ments of Lusk (99), who compared the heat production after giving
glucose dissolved in cold water and in water at the body temperature
to a dog placed in a calorimeter. When warm water was ingested
the computed heat increase agreed with that actually found, but when
cold water was given there was increased oxidation as shown by indirect
calorimetry, in order to provide for the heat lost to the fluid in the
stomach.

The studies of Lusk upon the influence of cold baths show that
heat production may increase by as much as 81 per cent of the normal.
(Schapals (137) has described an increase of 176 per cent in the oxygen
consumption.) The material first burned is sugar, for the respiratory
quotient gradually sinks. In the case of the chemical regulation of the
waking hedgehog, however, Henriques (61), contrary to other authors,
finds the extra heat produced apparently at the expense of fat and not
of carbohydrate; the respiratory quotient remains at about 7.
According to Mansfeld and Pap (107 a) the blood of cooled rabbits
can augment the sugar consumption of the heart.
Physical regulation. Down to environmental temperatures of about
15°C. apparently the so-called physical regulation suffices to maintain
a fairly constant body temperature. The stimulus is from without
(38). By means of this physical regulation the blood, as the most
superficial observation shows, is driven away from the surface of the
body. e It has been customary to assume that this was due simply to a
redistribution of the blood, for example, the internal organs increase
rapidly in volume as well as in temperature under these conditions.
(The various effects of cold baths are reviewed by Matthes (110) .)
It has been noted, however, that hemoglobin, red-blood cell count and
viscosity increase under the influence of a cold environment. Decrease
in blood coagulation time has also been described by Velden (152).
Under our present conceptions such acute changes must be attributed
to alterations in the fluid concentration of the blood.
The effects of cold baths on (‘brain volume” as determined by the
cranial plethysmograph are to cause an increase. How much of this is
due to an increase of the cranial blood supply (120), (148)) how much
to increase in the cerebra-spinal fluid, or how much to actual taking
up of water by the nerve tissue has not been determined.
These cranial volume effects are evidently associated primarily with
increases in blood pressure as shown for example by L. Hill (69), but I
have found in dogs that the cranial volume may continue to increase
during the return of blood pressure to normal. Since this increase in
brain volume is associated with a loss of fluid from the blood the possi-
bility exists of gradual imbibition by the nervous tissue.
REGULATION AGAINST OVERHEATING: The danger of overheating, as
pointed out by L. Fredericq (38), usually arises from within the body
rather than from the environment, which affords the excessive cold
stimuli. In this connection it is interesting to note that Ruffini’s cor-
puscles, the temperature sense nerve endings for heat, are situated in

HEAT REGULATION 301
the deeper layers of the skin, as pointed out by Ebbecke (32), in con-
tradistinction to the cold sense nerve endings (Krause’s bulbs) which
lie at the junction of the epidermis and the cutis Vera.
It is probable, however, that application of heat either to the skin or
to the base of the brain yields similar results (see below).
Filehne (35) has apparently shown that for the initiation of the proc-
esses which regulate against overheating no rise in blood temperature
is necessary. For in a bath up to the neck at 41 to 42OC. , sweating of
the forehead began prior to any change in rectal temperature; plunging
a hand into cold water stopped this sweating at once.
Chemical regulation. Cessation of the chemical heat regulation is
seen in the transition from shivering temperatures to higher ones.
When the external temperature is raised from 26 to 37OC. heat produc-
tion in rats, as shown by A. M. Hill, (67), is reduced by but one-quarter
of the amount which it is reduced when the temperature is raised from
15 to 26’. It is difficult to prove that tlhe heat production is reduced
as a measure against overheating in an individual who is quite inactive
before the heat stimulus is applied. Barbour and Prince (13) SUC-
ceeded in reducing the COz output of rabbits by heating the basal
nuclei and offered evidence indicating that diminished metabolism is
one of the factors reponsible for the temperature fall. At high tem-
peratures Lapicque (89) showed that the metabolism of birds is re-
ducible only to a certain minimum. Hot baths, according to Schapals
(137), appear to increase heat production by 22.5 per cent. The in-
creased heat production in these instances is of course attributable to
the rise in body temperature and has nothing to do with the chemical
regulation,
According to Mansfeld and Pap (107 a) the blood of heated rabbits
can reduce sugar consumption by the heart.
Physical regulation. This defense against overheating involves
evaporation of water from the lungs and skin as well as direct radiation
and conduction of heat from the surface of the body.
Both evaporation and radiation are favored by an increased blood
flow through the skin. According to the older views vasomotor shifts of
blood to the surface at the expense of the interior were chiefly respon-
sible for the increased surface blood flow, but it now appears that the
value of these shifts may be much enhanced by augmented blood
volume, brought about by rapid dilution (6). The water thus made
available serves in the evaporation and radiation processes.

That the peripheral flow is increased in warm environments was

shown in the case of the arm by Hewlett, Van Zwaluwenburg and
Marshall (63). Stewart has demonstrated the same fact for the blood
flow through the feet by the use of his limb calorimeter.
The vasomotor shifts which bring more blood to the surface have
been extensively studied, for example, by Mueller and Veiel (120), who
indicate the volume changes in the limbs, abdominal organs and brain,
under the influence of hot and cold environments, by the following
scheme:
ABDOMINAL LIMBS AND
STIMULI BRAIN
ORGANS SURFACE
Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . + + -
Heat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . - - +
Strassburger’s (148) experiments in which the brain volume was also

studied show similar effects of cold and heat, although in the latter
case the diminution in brain volume is sometimes preceded by a tem-
porary increase. The role of the blood pressure is but a temporary
one, as shown by L. Hill (69). The origin of the fluid which dilates
the peripheral vessels is by no means definitely determined. Obviously
there is loss of fluid from the abdominal organs and from the brain
region. (The muscles require further study.) In my own experi-
ments on dogs showing that external heat diminishes the percentage of
total blood solids, the volume of the brain became simultaneously
diminished.
The conception of an augmented blood volume as the response to
external heat accords with many of the older observations on blood
cell content and hemoglobin. (Consult Matthes (110) .)
Light upon the heat-regulating mechanism from this angle is shed
by the recent work of Kestner and his collaborators upon the effects of
exercise. They have shown that marked exertion with sweating dilutes
the blood, as indicated by diminished hemoglobin content and red
blood cell count. Gross and Kestner (52) showed further that this
stream of fluid into the blood is associated with an increased rather
than a decreased protein content.
Quite recently Cohn, (27) as well as Eckert, (33) has published
results indicating that this protein-salt-solution which flows out of the
tissues (apparently the muscles are the important stores) is not the
result of muscular exertion; for the phenomena are absent when the
muscles are tetanized in animals, and in man when the climatic condi-

HEAT RECULATIOX 303
tions under which the exercise is carried out are such that sweating
does not occur. Furthermore sweating procedures such as electric-
light heat baths in the entire absence of muscular activity do produce
this flow of protein-salt-solution from the tissues into the blood.
The conclusion is that this dilution of the blood is a response to stim-
ulation by heat Whether the sweating mechanism is the one that is
primarily set into action through the temperature-sense nerve endings
and the central nervous system, and the water thus lost from the blood
replaced by a fluid-regulating mechanism of some sort which over-
compensates, or whether the heat directly affects this fluid-regulating
mechanism without first drawing off water through the sweat glands
has not been determined.
The temporary decrease in white blood cells under the influence of
dry heat described by Murphy and Sturm (122) may be another expres-
sion of blood dilution.
Under some conditions fluid may be drawn into the blood and then
lost by excretion without any dilution of the blood being detected.
This is indicated in the experiments of Young, Breinl, Harris and
Osborn (161), who found under t)ropical conditions of heating asso-
ciated with a considerable rise of body temperature, that the blood
(as determined by hemoglobin tests) became somewhat concentrated.
Conditions of overheating, brought about by raising the temperature
of the environment, result in a 50 per cent diminution of the flow of
gastric secretion excited by sham feeding with Liebig’s meat extract
(36). It does not appear in these experiments whether the blood was
concentrated or diluted at the time of inhibited gastric secretion.
As regards regulation by evaporation of water from the surfaces of
the body Soderstrom and DuBois (144) found that in normal men,
age 20 to 50, the average secretion of water through the skin and air
passages is 29 grams per hour; 24 per cent of the heat produced is thus
lost. In boys and old men the amount is a little more.
Osborne (127) has shown that the expired air is probably satura,ted
with moisture under all conditions. The heat output by the lungs
can only vary with changes in their ventilation; heat polypnea will be
referred to later on.
Galeotti and Macri (44) have shown that the insensible perspiration
averages 0.12 gram per square decimeter per hour on the anterior
region of the forearm of normal persons at 23°C. While it is claimed
that this may become totally inhibited when the temperature of the
environment is considerably reduced, it of course becomes increased
by heating.

Montuori (116) finds that overheating cats seems to diminish the

osmotic pressure of the blood, thus favoring sweat secretion; this may
be inhibited by injection of hypertonic NaCl. He claims that lowering
of the osmotic tension is an added stimulus to the nerve centers which
control sweat secretion. The secretory factor in sweating is empha-
sized by Kittsteiner (83), who states that the sweat glands in the
human arm produce a very marked secretion pressure, often over 25
cm. of mercury, -much higher than the local blood pressure under the
conditions.
Before leaving the question of increased blood flow in warm environ-
ments it may be pointed out that with very high environmental tem-
peratures it would be of advantage to have a diminished blood flow
through the skin rather than an increased blood flow, thus protecting
the body to a certain extent in a manner precisely similar to that in
which it is protected against excessive cold. Put in another way,
increased surface blood flow promotes poikilothermia because it facili-
tates the conduction of heat either to or from the body. In this con-
nection Berti (22) has shown that very high temperature may produce
vasoconstriction; under conditions of extremely high temperature there
is also a tendency to increase the coagulability of the blood, the
greater viscosity probably hindering the flow through the surface (152).
Climate and heat regulation. The value of evaporation of water from
the surface of the body as a method of absorbing heat in environmental
temperatures above 37 or 38OC. is illustrated by the work of Haldane
(54) and in numerous observations upon heat stroke. The climatic
factors most concerned are temperature, humidity and wind rate.
The loss of heat by evaporation, calculated by L. Hill’s katather-
mometer, is taken as the difference between the heat lost in a given
time by the wet bulb and dry bulb respectively. Under varying con-
ditions Winslow (156) has shown that the changes in this instrument
are an approximate index of bodily comfort. This appears to be
another way of stating that they indicate the extent of the strain being
put upon the heat-regulating mechanism.
Comfort and health, according to E. H. Hunt (72), can readily be
obtained in dry heat where for long periods the air temperature is
above that of the body. Of course this requires copious water drink-
ing, sometimes up to 6 liters per diem, but man is provided apparently
with a large reserve of water (stored mainly in the muscle), and SO
readily available that the percentage of the water in the blood is not
appreciably diminished even when several liters have been lost by

HEAT REGULATIOX 305
sweating. Hunt warns against undue or needless use of the stored

water under tropical conditions, in cases where the intake is restricted,
because if the reserves are extensively drawn on replacement seems to
require many hours.
Murschhauser and Hidding (124) showed the effects of environ-
mental moisture upon heat production in a number of series of guinea
pigs. In a dry environment increasing the temperature from 21 to
35’ reduced the COz production by 18 per cent. When saturated air
was breathed, however, CO2 production was increased by 6.1 per
cent under the same conditions. In the first case chemical regulation
was found necessary at 21” on account of the dry moving air. In the
case of moist air actual overheating of the body took place at 35”
because of the inability to give off heat by evaporation.
Lee and Scott (90) found that muscles taken from cats which had
been exposed for 6 hours to a temperature of 33”C., with average humid-
ity of 90 per cent, exhibited only 76 per cent of the efficiency shown by
muscles taken from animals exposed to a temperature of 21°C. with
52 per cent humidity. Muscular efficiency therefore shows a certain
parallelism with the need for heat production.
Young (160) found in white men a high metabolism during the hot
season in tropical Australia. The increased heat production was
attributed to the ordinary activities of life which had preceded the
experiment and which in the hot, moist weather, produce a greater
increase in body temperature than in the cool season. (See also
Aron (4) .)
On the other hand, de Almeida (2) believes that the usual 39 calories
per square meter per hour are not produced in the minimal basal
metabolism of native white men in the tropics. He finds the heat
production averaging from 29.5 to 31.5 calories and attributes this to
an adaptation of the heat-regulating mechanism to the lessened need
for heat.
Other details relating to climatic effects upon heat1 regulation are set
forth in an interesting fashion by Lusk (99).
Effects of uncompensated overheating. When the regulation against
overheating fails and the body temperature rises to any considerable
extent, there results an increased metabolism (137), (123). Upon this
would depend the tendency to acidosis which has frequently been
described by the older investigators and apparently confirmed by the
finding of Hill and Flack (70) that the alveolar CO2 tension is reduced,
sometimes almost to 3 volumes per cent. But Haggard (53) finds this
PHYSIOLOGICAL REVIEWS, VOL. 1, NO 2

306 HENRY G. BARBouR
reduction unaccompanied by compensatory changes in the C02-com-

bining power of the blood. Hence he assumes that the C, is lowered.
Haggard’s experiments were performed on himself in baths giving oral
temperatures above 40°C.
Koizumi (84) describes acidosis in thermic fever.
Talbert (149) finds that the sweat result!ing from overheating is more
acid than that due to muscular activity. The acidity of the urine is
also increased. Kittsteiner (83) has shown that heating a portion of
the skin increases the percentage of nitrogen and sodium chloride of
the sweat there secreted. High (as well as subnormal) body tempera-
tures are unfavorable to certain syntheses such as the formation of
et,hereal sulphates and of glycuronates, as shown by Hiizu (65).
Many of the physiological effects of overheating the body are
described by Heymans (64), who varied the body temperature by
heating or cooling an artificial carotid-jugular anastomosis.
Fatal termination of overheating an organism is due to the accumu-
lation of acid, according to Mayer (ill), who has shown this to be true
for lower forms of life such as corals, anemones, etc. Those forms
having the highest CO2 output and therefore the greatest accumulation
of acid in the- tissues are the most sensitive to heat.
NERVOUS CONTROL OF HEAT REGULATION: Undoubtedly temperature
regulation is intimately interwoven with the balance of other physi-
ological factors, such as the blood content of water, colloids, various
ions and metabolites, red and white cells, etc. Many of these factors,
however, probably maintain a high degree of constancy in animals
which are poikilothermic. Temperature regulation therefore depends
on something further. It occurs in fact only in those species which
have a highly developed nervous system.
The existence of a thermostat-like nervous mechanism at the base of
the brain is indicated by the demonstration that warming of the region
of the corpus striatum in rabbits reduces the rectal temperature, while
cooling has the opposite effect (6). The vasomotor mechanism of the
ears was studied particularly in this connection; warming of this region
causes dilatation while cooling causes constriction.
The anatomical region subjected to the temperature stimuli in these
experiments was selected because it has given the best results in the
much-discussed ” heat-puncture” experiments.
Kahn (78) had shown that warming the carotid blood in dogs results
in manifestations of increased heat output, namely, peripheral vaso-
dilatation and increased secretion from the sweat pads in the feet.

HEAT REGULATION 307
Similar effects have been demonstrated by Moorhouse (118). The

brain therefore shares with the temperature sense nerves a sensitivity
to thermal stimuli.
Barbour and Prince (13), in further experiments on the warming and
cooling of the heat centers, showed that the carbon dioxid output
varied in the same direction as the temperature changes. O’Connor
(126) has since brought forward experiments showing, according to his
interpretation, that shivering in cats and rabbits placed in baths at
various temperatures, depends rather on the temperature of the brain
than on that of the skin. For example, when the bath was being
warmed up, one animal ceased shivering at 29.6’ rectal temperature,
the brain temperature having been brought up to 31” by warming the
carotid vessels. But later the same animal continued to shiver until
the rectal temperature was as high as 34” as long as the brain was
kept cooler than 31.2’. The significance which this author attaches to
the skin temperature is the determination of the “extra oxygen” con-
sumed during shivering; this is said to be proportional to the extent to
which the skin temperature is exceeded by that of the brain.
The effects upon the rectal temperature of warming and cooling the
corpus striatum in rabbits have been confirmed by many observers, for
example, by Moore (117) as well as Hashimoto (58). In both cats and
rabbits the same effects have been described by Prince and Hahn (131).
Observers who have failed to demonstrate them have neglected certain
precautions such, for example, as the omission of anesthetics. Further
demonstration of the significance of the base of the brain in heat regu-
lation is seen in experiments with fever and with drugs, which will be
referred to below.
Hashimoto (58) has found in rabbits that the effects of thermal
stimuli upon the brain can be augmented by making a second puncture
on the opposite side. But if heat is the stimulus through one side and
cold through the other, the stimulus on the left side seems always to
prevail. Under such circumstances one ear is hot and the other cold.
It is suggested that the left “heat center” is the most strongly devel-
oped, like the speech center in man.
Decerebrntion experiments. Further evidence of the importance of
the brain for heat regulation is seen in its failure when the entire cere-
brum or certain of its parts have been removed. The extent of the
decerebration operation necessary to produce poikilothermic rabbits
has been defined with a fair degree of exactness by Isenschmid and
Krehl (74). They found in a series of animals that the power to resist

environmental temperatures fails suddenly when the transection is

located at a point just anterior to the center of the optic thalamus.
Similarly Citrone and Leschke (26) have described in the same loca-
tion a “mid-brain” puncture by which the connections of the brain
which are of importance for heat regulation are severed from the
periphery.
Rogers (132) has shown that the power of heat regulation is lost in
decerebrate pigeons when the optic thalamus has been injured. In
such experiments as these it has been shown not only that the animals
fail to regulate against changes in environmental temperature but also
fail to respond to many drugs and infectious agents. For example,
Barbour and Deming (8) have demonstrated a reversal of antipyrine
action in decerebrate rabbits. This was confirmed by Isenschmid (73),
who has extended the work to include the effects of salicylates and
other drugs. Increased heat production can be thus elicited in the
absence of central inhibition.
Experiments on cord section. The importance of the central nervous
system to heat regulation is well demonstrated by experiments in which
the cord has been severed at various levels. It had been recognized
clinically for a great many years that lesions of the spinal cord, par-
ticularly in the cervical region, were associated with marked disturb-
ances of heat regulation, but the fact remained unexplained that in
some of the cases hyperthermia ensued while others were associated with
fall of temperature. Gardiner and Pembrey (45) concluded from
clinical study that the general effect of lesions of the spinal cord, bar-
ring complications such as infection, was to deprive t,he patient of heat-
regulating power in proportion to the extent of the paralysis. (See
also Kennaway and Pembrey (82).) The hyperthermias could then
be ascribed to restriction of the heat output by excessive use of
blankets, etc.
Freund and Strasmann (43) investigated the “regulation range” of
environmental temperature in three series of animals; normals, those
with section of the fourth to eighth segment of the cervical cord, and
those with section of the dorsal cord. Normal rabbits withst,ood
environmental temperatures of 6 to 31*C. with no essential change in
body temperature. Dorsal cord rabbits regulated poorly outside of
the limits 18 to 31”. Cervical cord rabbits were, however, practically
poikilothermic since in, environments varying from 19 to 33’ their
body temperat,ure showed an equally wide range, varying c from 28 to
42*C.

HEAT REGULATION 309
Freund (39) ascribes this marked difference between the effect of the
lower cervical and the upper thoracic operation to the severance of
sympathetic paths leading to the abdominal viscera. More recently
he has shown that by performing in addition to the dorsal cord opera-
tion a double vagotomy just below the diaphragm, animals become
poikilothermic to essentially the same extent as those with cervical
cord section. This is probably dues to the severance of sympathetic
fibers. If instead, the dorsal cord operation be supplemented either
by removal of the stellate ganglion or bv section of the eighth cervical
and first dorsal roots a similar loss of heat regulation will ensue.
Freund and Grafe (40) have made extensive studies of the metab-
olism of animals with various cord operations. Dorsal cord section
plus double vagotomy was found to increase the total metabolism, and
especially the protein loss. In explanation the removal of central
inhibitions is suggested. After such an operation infectious agents,
including trypanosomes, swine-pest bacilli, or hay infusion, increase
neither metabolism nor body temperature. This argues against a
toxogenic protein decomposition in infectious fevers.
Hari and Janney (56), however, have failed to find that cord opera-
tions increase the total metabolism. They state that metabolism
becomes diminished by one-quarter or more by cervical section, while
below this no effect is produced except possibly a slight increase.
Hannemann (55) states that in frogs the gaseous exchange is increased
by decerebration.
Investigations on the brain. Since Ott’s (128) time many have
attempted a more accurate localization of anatomical “heat centers.”
(See Liljestrand and Frumerie (95), also Jacobj and Roemer (75).)
The results in general have been inconclusive, although the best results
from “heat puncture” have usually resulted when the basal nuclei
were involved. The last-mentioned authors regard irritation, disten-
tion or hyperemia of the walls of the lateral ventricle as the essential
cause of heat puncture hyperthermia. They find that corrosives such
as phenol or mercury when introduced into one of the lateral ventricles
also produce hyperthermia.
The subthalamic region was successfully punctured by Barbour and
Wing (15) in experiments where the needle was passed through the
orbital fossa instead of from above and the relation of this to Isen-
schmid and Krehl’s (74) and Citron and Leschke’s (26) operations
appears to make this point of considerable significance. These facts
suggest coordination between heat regulation and the pituitary

gland. Leschke (93), however, ascribes the disturbances in the water

balance associated with diabetes insipidus to mid-brain injury rather
than to disturbance of the pituitary. (Compare Jungmann’s (77)
“salt puncture.“) Karplus and Kreidl (81) have described at the base
of the optic thalami a center for the sympathetic nervous system
whence, for example, pupillary dilatation can be obtained by electrical
stimulation. This region bears relations therefore both to the vaso-
motor and fluid-regulating mechanisms of the body.
Furthermore the mid-brain bears a definite relationship to the
respiratory center. Garrelon and Langlois (46) as well as Nicolaides
and Dontas (125) describe a “polypnea center” in this region. The
latter find that if the medulla be separated from the brain heat polyp-
nea cannot occur, although the ordinary respiratory regulation persists.
It is possible that there is some psychic control over heat regulation,
for Courtier (29) states that a suggestion of heat is followed within a
few minutes by a lowering of the surface temperature, the converse
occurring upon a suggestion of cold.
Fraenkel (37) states that heat-regulatory powers are poorly devel-
oped in neuropathic children.
Although Moore (117) is probably justified in doubting the infalli-
bility of the old “heat puncture” operation as a means of producing
fever the weight of evidence which has now accumulated indicates
that the processes essential to heat regulation in mammals are largely
coordinated at the base of the brain.
HEAT REGULATION AND THE ENDOCRINE GLANDS: Gautrelet and
Thomas (47) pointed out that heat regulation becomes much disturbed
by removal of the adrenals. Elias (34) finds “heat puncture” inde-
pendent of these glands. Freund (39) was able to produce fever in
dry-fed rabbits with epinephrin but not in those receiving green fodder.
The relation of epinephrin “‘fever” to the water balance is therefore
evident.
Cushing and Goetsch (31) have drawn an analogy between hiberna-
tion and hypopituitarism and have suggested that other glands of
internal secretion are probably without function during hibernation.
As regards the thyroid, this conjecture has recently been confirmed by
Adler (I), who observed very marked degenerative histological changes
in this gland in hibernating bats and hedgehogs. Furthermore he
finds that protein-free thyroid extracts will awaken hibernating hedge-
hogs, increasing both metabolism and body temperature. Thymus,
adrenals and phenyl-ethyl-amine all gave a similar result. Thyroid

HEAT REGULATION 311
extract is similarly effective after antipyrine injections in hibernating

hedgehogs, but only partially so after quinine injections.
Mills (115) had shown previously that a warm environment increases
the colloid matter of the thyroid gland in normal guinea pigs. This
increase is accompanied by a flattening of the epithelial cells.
Karelkin (80) found that thyroidectomieed animals regulate poorly,
being hypersensitive to external heating and cooling, as well as to pyret-
its and antipyretics.
Mansfeld (105) has emphasized the relationship between heat regu-
lation and the well-known control of the thyroid over oxidations. The
increased protein destruction in fevers has been ascribed by Mansfeld
and Ernst (106) to the thyroid.
Loewi and Weselko (98) have found “ heat puncture” less effective
after thyroidectomy. They state further that after this operation
there occurs no increased sugar combustion by the heart such as
described by Mansfeld (105) for animals with intact thyroids.
Mansfeld and Pap’s (107 a) experiments indicate that the internal
secretion of the thyroid controls the increase and decrease of sugar
consumption by the heart after cooling and heating respectively.
FEVER: Fever may be defined as any condition of positive heat
balance not due solely to food, exercise or environment.
Heat production in fever. Infectious and neurogenic fevers are
chiefly attributable to partial failure of the heat-eliminating mechanism
in ordinary environments. There is little evidence that increased heat
production is primarily at fault; for increases due to feeding, exercise,
etc., greatly exceed those seen in fever. In the case of “chills,” how-
ever, such as those of malaria, (16) heat production is probably of impor-
tance, but even here there is no evidence that it precedes the tempera-
ture rise. Coleman and DuBois (28) found the same coincident
increase of temperature and heat production in typhoid fever In
tuberculosis the metabolism is increased very little above the normal.
(McCann and Barr (112) and experiments of the author.) In ana-
phylactic and other fevers Leschke (93) and others found the high
temperature even associated with a diminished heat production.
Porcelli-Titone (130) also found great variation in the heat produc-
tion in fevers according to the infectious agent used. Under some
conditions it was even reduced 20 per cent. There were also wide
variations in individual animals.
A toxogenic heat production in fever is denied by Freund and Grafe
(40) for they find upon the introduction of infectious agents in poikilo-

thermic animals that with the failure to increase the temperature is

associated an unchanged heat production.
The production of infectious fever does not seem to require the
presence of glycogen in the liver, which distinguishes it fundamentally
from “heat puncture” fevers (133).
Heat elimination in fever. The failure of heat elimination to keep
pace with heat production during the temperature rise can be deduced
from the fact that the surface of the body becomes paler and the per-
spiration diminished; furthermore if the blood flow through the periph-
ery be measured, this likewise is found decreased.
Hewlett (62) for example, has shown that the rate of blood flow
through the arm becomes much diminished during the onset of-fever
thus accounting for the tendency against an increase in heat elimination.
Stewart (146) also emphasizes the importance of reduced blood flow in
fever. The blood is assumed to be sent to help the affected organs.
He regards the rise of temperature as a result of the vasoconstriction.
Soderstrom and DuBois (144) found that typhoid patients with a
rising temperature have a diminished water output. With falling
temperature vaporization affords an abnormally high percentage of
the calories eliminated.
Barr and DuBois (16) warn us that the skin temperature (which of
course is associated with the flow of blood through the skin) is not
necessarily a criterion of the slow or rapid elimination of heat, for it
is possible for the sharp bend in the gradient of heat output to occur
at some deeper level in the body, where the flow of blood is more rapid.
The total amount of heat radiated in a given time to the colder super-
ficial layers of the body and thence to the air could thus be as great as
that radiated from a hot skin through which much blood is flowing.
Deficient heat elimination in fever has been emphasized by Balcar,
Sansum and Woodyatt (5), who show that by dehydrating a dog with
intravenous injections of concentrated dextrose solution, very high
temperatures may be produced, attributable to concentration of the
blood and lack of water available for giving off heat.
Concentration of the blood is a marked symptom in influenza as
shown by Underhill and Ringer (150), who compare this condition to
poisoning with lethal war gases. In both cases loss of fluid from the
blood prognosticates a temperature rise and a change for the worse, the
intravenous introduction of fluids often saving the patient’s life.
Parallel to the initial temperature rise in coli fever in dogs, Barbour
and Howard (12) have demonstrated a concentration of the blood sim-

HEAT REGULATION 313
ilar to that seen with cold baths. During this concentration Barbour
and Freedman (9) observed a marked reduction in the salivary response
to pilocarpine. This accords with the reduced gastric secretion in
fever noted by Meyer, Cohen and Carlson (114).
hTervous. regulation in fever. In fever it is said that the body ther-
mostat is “set at a higher level.” A normal temperature becomes
apparently interpreted as “cold” by the temperature centers, while
one of 40’ perhaps feels “neutral.” Similarly the skin nerves seem
hypersensitive to cold, or hyposensitive to heat, whence the subjective
“ chill.”
This alteration in sensitivity on the part of the nervous apparatus
might be attributed to a depressing action of toxins upon the nervous
system. In accord with this idea Head and Riddoch (59) note in all
febrile conditions a diminished responsiveness of the severed spinal
cord. Storm Van Leeuwen (147) finds that 38OC. is the optimum
condition for the transmission of reflexes through the cord. They dis-
appear entirely at 42”. Furthermore because of the production of
polypnea by a central action Nikolaides and Dontas (125) state that
the effect of antipyretics on the heat center is one of stimulation.
Because of the effects of “ stimulating” the base of the brain mechan-
ically, electrically, etc., it has been said that the heat centers are “stim-
ulated” in fever. If one explains fever by the dual heat center theory
of Hans Meyer (113) one may say that the ” cooling center” is depressed
while the “heating center” is stimulated. Grafe (51) has attributed
fever to the supposed irritating action of the decomposition products of
bacteria or of the injuredtissues upon the heat centers. By the intra-
cerebral introduction in properly sensitized animals of Xb to ia the
necessary intravenous dose of serum, Hashimoto (58) has produced
anaphylactic fever.
That the nervous mechanism is essential to some fevers is shown by
the failure of infectious agents to act after mid-brain section (26), (76)
and after cord section (40), (142).
Water and salt balance in fever. It has been pertinently objected, how-
ever, that some fevers can be produced in the absence of the heat-
regulating mechanism, notably the sugar dehydration hyperthermia of
Woodyatt (5). This investigator rejects the neurogenic theory of
fever and advances the idea that the central fact to which a positive
heat balance must be attributed is a deficit of free water in the body.
Water regulation he admits, however, may in part be under vasomotor
nervous control.

According to Woodyatt, in ordinary febrile diseases the symptom of

fever is due to a deficit of free-water resulting from an abnormal tend-
ency on the part of the colloids of the body to bind water. The pro-
vocative poison leads to changes which increase the hydration capaci-
ties of the cell colloids. With the return to normal body temperature,
as for example in the crisis of pneumonia, (136), (lOI), (100)) there is
a notable release of water or, more exactly, of salt solution from the
tissues.
Evidently anhydremia promotes excessive sparing of heat. Accept-
ing the water balance as the central factor in fever, we are never-
theless obliged to correlate its behavior with that of the nervous
heat,-regulating mechanism.
In the infectious fevers some such process as the following probably
takes place. As the provocative poison reaches the tissues (perhaps
the muscles in particular) catabolic changes are initiated which increase
the affinity of the tissues for water. This general demand upon the
blood for water tends to reduce the blood volume, especially at the
expense of the surface blood. The skin immediately becomes cooler,
and this arouses the nervous regulation against cold, thus exaggerat-
ing the processes of vasoconstriction and hemo-concentration. This
continues until the blood becomes warm enough for the nervous centers
to interpret the temperature as comfortable or neutral.
Without the brain there is apparently no infectious fever, and unless
the water loss from the blood be extreme, as in Woodyatt’s (5) sugar
dehydration, the nervous mechanism is undoubtedly involved in the
production of fever.
In “heat puncture” fevers and the like, the original catabolic proc-
esses are in the brain tissue itself. They must result in imbibition,
which increases the intracranial pressure. This initiates a vicious
circle in which the tendency is toward a continually increasing pressure,
for the external cerebral vessels become compressed and the catabolic
processes which incite imbibition are augmented by the anemia thus
produced (25). Increased intracranial pressure, as Moore (117)
points out, seems to incite heat sparing processes and these presumably
include the tendency of the tissues to deprive the blood of water.
PHARMACOLOGY OF HEAT REGULATION: Pyretics. Chemical agents
may produce fever in a variety of different ways. As a general thing,
as with infectious fevers, the controlling factor is presumably anhy-
dremia. The fate of the water varies with the different drugs.

HEAT REGULATION 315
Diuretics produce anhydremia, by causing loss of water presumably

chiefly through the kidneys. Spiro (145) discusses this in connection
with the purines, especially theophyllin, which he finds concentrates
the blood. This explains Isenschmid’s (73) finding that caffeine
increases the body temperature of animals deprived of their heat
centers.
Mandel (104) observed that in fever there is often a relationship
between the rise in temperature and the appearance of purine bases in
the urine. Xanthin and caffeine, in his experiments, both caused
febrile temperatures, which could be neutralized by sodium salicylate.
Besides caffeine and the other purines, salts, sugars and other diuretics
increase the body temperature.
The numerous studies on salt fever in infants, beginning with those
of Finkelstein, led to the placing of emphasis on the water balance.
Peteri reduced the transitory fever of the new-born by giving fluids by
mouth, agreeing with Heim and John in speaking of this as a desicca-
tion fever. (See Balcar, Sansum and Woodyatt (5).)
Rolly and Chrjstiansen (134) state that intravenous injections of
3 per cent but not of normal saline solutions always increase the tem-
perature in rabbits.
Wideroe (154) has obtained varying degrees of fever as a result of
injecting different salts and attributes the differences to the individual
ions. Sodium appeared to be the least effective of the kations; chlo-
rides and bromides always caused a temperature rise.
Fever-inducing cathartics, among which Berrar (21) studied aloin,
promote a loss of water by way of the alimentary canal.
In curarized animals Freund and Schlagintweit (42) found the
susceptibility to fever from sodium chloride as well as from aloin
retained.
Sympathetic poisons, epinephrin, tyramine, and other amines, espe-
cially beta-tetrahydronaphthylamine (I’ B-tetra”) as well as ephedrin,
all produce fever. In the case of epinephrin, at least in many species,
water is lost from the blood to the liver cells and the lymph circulation
as has been shown by Lamson (88).
Cramer (30) attributes B-tetra fever to over stimulation of the
‘I thyroid-adrenal” apparatus and claims that it fails to appear in a cool
environment. He likens it to heat-stroke.
Hashimoto (58) found that the fever curve induced by sympathetic
poisons or by large amounts of cocaine could not be influenced by
heating or cooling the basal nuclei, although after small doses of cocaine

it could be influenced. On the other hand, application of cold as well

as of heat to the heat centers was able to exert an influence upon
fevers produced either by killed typhoid bacilli or by anaphylaxis or
sodium chloride. From these experiments he concluded that the
sympathetic and cocaine fevers should be attributed to direct chemical
stimulation of the ‘I heating centers” with secondary automatic inhibi-
tion of the “cooling centers” of Hans Meyer, while the infectious and
salt fevers are an expression of increased irritability of the heat centers.
In interpreting such results, one must consider that the failure or
success in influencing the fever curve may be after all purely a quanti-
tative matter, dependent on the strength of the opposing influence
irrespective of the mechanism.
Isenschmid (73), with B-tetra, increased the gas exchange of rabbits
after operative destruction of the heat centers.
In the thermogenic action of cocaine muscular activity is prominent,
but I find also that the blood may become very concentrated. Isen-
schmid states that the thermogenic action of cocaine occurs in the
absence of the heat centers.
Adler (1) finds that the hibernating hedgehog, from which the central
heat regulating mechanism has been excluded by operation, responds
to injection of certain hormones, of epinephrin, and of proteinogenous
amines by a considerable increase in body temperature. This increase
occurs also in hibernating hedgehogs after paralysis of the sympathetics
by ergotoxin. It is also observable after both procedures. The tem-
perature rise under all of these conditions is not as great as when the
“heat centers,” or the sympathetics are intact.
These effects must probably be explained by the redistribution of
water by the sympathetic stimulants. The case is one in which the
nervous system contributes to fever but is not essential.
Githens (49) finds that ergotoxin raises the temperature of cats and
rabbits. It is effective in the latter after curare but not after decapi-
tation or ether. I t is therefore assume d to act through the heat
centers. Curiously enough, in rats, mice, and pigeons it depresses the
temperature.
Hemolytic fever and the like probably result from the action of
decomposition products of the blood cells exerting an influence upon
the tissues similar to that produced by the agents of infectious fever.
Yamakami (158) has shown that temperature curves due to the injec-
tion of distilled water are parallel to those resulting from the injection
of hemoglobin, etc.

HEAT REGULATION 317
Bock (23) has noted that the introduction of indifferent particles,

such as finely divided paraffin, into the blood stream, increases the
body temperature. This may be brought about by some diminution
in the blood flow through the periphery. Other pyretic substances
include hematoxylin and related compounds (151) and liquid paraffins
(138).
Depressants. Drugs which are usually classed as depressants in
general reduce the body temperature in all cases where the environ-
mental conditions are normal. This is seen particularly in the case of
alcohol and the general anesthetics as well as with morphine. These
substan ces usually favor blood dilution and peripheral dilatation.
The inhibiting influence of morphine upon the fluid-regulatin
mechanism of the body has been demonstrated by Bogert, Mendel and
Underhill (24). This may account for the influence of this depressant
in rendering animals poikilothermic.
An example of depression of the chemical regulation by drugs is
seen in the work of Magne (lO3), who showed that shivering move-
ments are inhibited by apomorphine.
Magnesium salts were shown by Schultz (139) to be antipyretic
even in subnarcotic doses. Calcium, although it antagonizes mag-
nesium narcosis, seems to enhance the antipyretic action.
Ethylenediamine is also antipyretic in subdepressant doses. Toler-
ance to this effect is readily acquired (11).
Chlorine in high concentrations behaves like a depressant drug in
rendering animals poikolothermic although low concentrations produce
hyperthermia at ordinary temperatures (6). The temperature changes
produced by the lethal war gases are parallel to the blood concentra-
tion; the latter seem to account for the former (150).
Attempts to influence the body temperature by heating and cooling
the brain during general anesthesia are usually unsuccessful (58), thus
confirming the conjecture that anesthetics inhibit the function of the
heat center.
O’Connor (126), however, has increased the blood flow through the
limbs of cats anesthetized with chloretone or Verona1 by heating the
brain to a temperature still subnormal, or the skin up to normal body
temperature The former experiment might be interpreted as showing
hypersensitivity to warmth.
Wideroe (154) showed that during ether narcosis no salt hyper-
thermia can be produ .ced. These depressants are known to have
antidiuretic properties thus f avorin g an increased water content of

the blood. Since they as a rule increase the blood sugar this fact
may be brought into relation with their antipyretic action, as will
appear below.
Antipyretics. Substances which reduce the temperature in febrile
and similar states but not in normal conditions unless the dosage be
excessive are termed antipyretics.
Acetyl-salicylic acid in doses reducing fever temperature by l°C.
increased heat elimination in my series of cases by 38 per cent. Simi-
larly, a decrease in elimination was observed during the return to fever
temperature. The heat production was but little altered. Antipy-
reties therefore act chiefly upon the heat-dissipating mechanism.
Barbour and Herrmann (IO) have contributed evidence bearing on the
mechanism of the increase in heat elimination. Salicylates, antipyrine
and quinine, in dogs under normal conditions, tend to increase slightly
the body temperature and blood solids. In coli fever these drugs
dilute the blood, thus accounting for the fall in temperature. All
these substances increase the blood sugar which (by osmosis) may
account for the blood dilution in febrile cases, in which the water
reserve of the tissues is increased at the expense of the blood.
Antipyretics inhibit adrenalin glycosuria, but Mansfeld and Purjesz
(108) have shown that this is a renal effect; thus an antidiuretic effect
favoring increased blood sugar and blood volume is obtained.
Dextrose, intravenously given, as shown by Barbour and Howard
(12), resembles the antipyretics in that it reduces the temperature in
fever, causing the blood to become more dilute than under normal
conditions. This supports the contention that blood sugar plays a
role in antipyretic action. Barbour and Baretz (7) found that acacia
similarly tends to dilute the blood in fever and to reduce the tempera-
ture, which it does not do in normal animals.
Wiechowski (155) showed that antipyrine and similar substances
relax the brain vessels in fever but not in normal animals.
Notwithstanding the central action of antipyretic drugs Yamamoto
(159) noted no appreciable difference in the amounts of salicylic acid
and acetyl-salicylic acid present in brain tissue in rabbits, although the
latter drug is much more powerful than the former.
According to Piccini (129) antipyrine, phenacetine and acetanilid
all diminish the total oxygen of the arterial blood.
Hashimoto (58) noted certain differences between antipyrine and
salicylates on the one hand and quinine on the other. The antipyretic
effect of the former could be increased by the heat stimulus to the

HEAT REGULATION 319
basal nuclei or could be completely counteracted by the cold stimulus

within half an hour. On the other hand, during quinine action the
heat and cold applications were both quite ineffective. He interprets
this as a confirmation of the old idea that the quinine effect is not
brought about through the heat centers but through direct metabolic
inhibition. This, however, could be equally well interpreted as show-
ing that quinine has a depressant action upon the brain similar to that
exhibited by the anesthetics. Hashimoto himself demonstrated such
an action in the case of morphine.
He finds further that convulsive and medulla poisons (picrotoxin,
santonin, veratrin, and digitalin) reduce body temperature and subse-
quent heating the centers may produce a still further fall, but cooling
produces no rise. These results lead him to conjecture that such
poisons do not depress the “heating center” directly, but stimulate
the antagonistic parasympathetic “cool centers” (said to reside in the
medulla) primarily and directly. Camphor, of which the point of
attack as a convulsive poison lies in the cerebrum, behaves like an
antipyretic in that cooling and heating of the centers is able to affect
the camphor temperature fall, whence it is concluded that the anti-
pyretic effect of camphor like that of antipyrine is through the “heating
centers” and not as with picrotoxin in the “cooling centers.”
Krauss (86) has shown that the antipyretic effect of nitrites is greater
after “heat puncture” than in normal animals.
Magyary-Kossa (102) has pointed out the antipyretic effect of car-
bon dioxid (by inhalation or asphyxial procedures). It is seen in nor-
mal as well as in febrile conditions.
HEAT REGULATION AND CARBOHYDRATE METABOLISM: When the
environmental temperature is varied Freund and Marchand (41) as
well as Silberstein (140) have described corresponding changes in the
blood sugar content which becomes less with heat and greater with
cold. These effects might be attributed partly to dilution and concen-
tration respectively of the blood.
Kramer and Coffin (85) found hyperglycemia in dogs exposed to cold
for a day or more although not for briefer periods; Lee and Scott
noticed that the blood sugar of animals which have been exposed to
environments of 33*C. with average humidity of 90 per cent is only
94 per cent of the normal amount.
As described by Lepine (92), while extreme refrigeration causes the
blood sugar to increase and then disappear, reduction of an animal’s
temperature only to, say 36”C., gives a more lasting hyperglycemia.

According to Freund and Marchand (41) an environment sufficiently

warm to raise a rabbit’s own temperature will also give hyperglycemia.
They observed the lowest blood sugar content at environmental tem-
peratures between 30’ and 34OC. But nervous control of temperature
is independent of the blood sugar for heat regulation was found intact
in phloridzinized dogs.
In fevers Lepine (92) has investigated the blood sugar content and
usually finds it little altered. In cases where there is hyperglycemia
he attributes it to an irritating effect of fever toxins upon the fourth
ventricle. Freund and Marchand (41) showed fairly constantly an
increase in the blood sugar content in fever but this was of such a
degree as may well be accounted for by blood concentration.
The effect of dextrose administration or injection upon the body
temperature appears to depend largely upon whether it results in dilut-
ing or concentrating the blood. During the stage of dilution it cer-
tainly acts as an antipyretic in fever (12). When however it produces
marked dehydration it raises the temperature (5).
Fever and antipyretics exert little effect upon the respiratory quotient.
BODY TEMPERATURE IS REGULATED BY WATER-SHIFTING, BUT UNDER
NERVE CONTROL: As the organism finds itself in an increasingly
favorable environment it inclines toward an attitude of outspread
relaxation; but upon the approach of unfavorable conditions a tend-
ency to assume a spherical form is seen. These facts are well illus-
trated in single cell organisms. Their purposefulness is obvious when
the unfavorable condition happens to be temperature.
Of the two extremes of temperature man’s chief enemy is the cold,
and must become more so with the passing of time if the physical fate
of the world be correctly predicted. Besides the voluntary assumption
of a drawn-together position to protect against cold, the water reserve
of the body is withdrawn from the surface to the better insulated parts.
With warm environments however the water is not only brought to
but poured freely over the surface of the outspread body.
In general the higher the development of the animal the greater
becomes the capacity for dissipation of heat, while the mechanism for
saving or dispersing it becomes correspondingly more complex, as is
seen for example in the water-shifting role of the nervous system.
The shock of cold is akin to that of the emotions, asphyxia, etc.,
hence Cannon’s (25) ideas concerning the nerve-adrenal complex may
be applied to the heat regulating mechanism, for the shock of cold will
undoubtedly discharge epinephrin into the blood, blanch the skin and

HEAT REGULATION 321
drive water out of the circulation. (Lamson’s (88) epinephrin poly-

cythemia.)
Whether or not the adrenal secretion is of significance, the part
played by the nervous system is essential.
OC Blood
39 /
I
I
38 20
37 18
36 16
3ti 14
10
Fig. 1. Effects of cool (20°C.) bath upon dog with and without nervous heat
regulation. Upper two curves, normal dog; lower two curves, dog after section
of sixth cervical cord segment; continuous lines, temperature; broken lines, blood
solids.
Note that normal dog keeps temperature from falling by means of blood con-
centration. Cord section dog is poikilothermic because blood concentrating
mechanism is broken down.
This mechanism is illustrated by experiments I have recently per-

formed with E. Tolstoi (14). In the accompanying figure the upper
two curves illustrate the behavior of a normal dog in a cool bath (20°C.).
The body temperature (continuous line) is maintained,-even raised
slightly; this is accomplished by blood concentration (the broken line
represents the blood solids). In the two lower curves are seen the
behavior under the same treatment of a dog with spinal cord severed

at the sixth cervical segment. The body temperature falls steeply

because the blood fails to become concentrated. The connection between
the temperature sense nerve endings and the water shifting mechanism
has been severed.
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THE HEAT-REGULATING MECHANISM OF THE BODY

WATER AND HEAT: Equalization of temperature in living organisms

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temperature only varies 10°C. within the environmental range of

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organism preserves the tropical temperature of its cells at the expense

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20’ and 25” are no longer borne by animals without an increase in

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That the peripheral flow is increased in warm environments was

Strassburger’s (148) experiments in which the brain volume was also

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Montuori (116) finds that overheating cats seems to diminish the

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sweating. Hunt warns against undue or needless use of the stored

PHYSIOLOGICAL REVIEWS, VOL. 1, NO 2

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reduction unaccompanied by compensatory changes in the C02-com-

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Similar effects have been demonstrated by Moorhouse (118). The

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environmental temperatures fails suddenly when the transection is

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gland. Leschke (93), however, ascribes the disturbances in the water

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extract is similarly effective after antipyrine injections in hibernating

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thermic animals that with the failure to increase the temperature is

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According to Woodyatt, in ordinary febrile diseases the symptom of

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Diuretics produce anhydremia, by causing loss of water presumably

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it could be influenced. On the other hand, application of cold as well

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Bock (23) has noted that the introduction of indifferent particles,

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basal nuclei or could be completely counteracted by the cold stimulus

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According to Freund and Marchand (41) an environment sufficiently

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drive water out of the circulation. (Lamson’s (88) epinephrin poly-

This mechanism is illustrated by experiments I have recently per-

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at the sixth cervical segment. The body temperature falls steeply

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(68) HILL,A. V. Journ. Physiol., 1912, xliv, 466.

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