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Physiology of hyperpyrexia

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DATE
NORTHWESTERN UNIVERSITY
PHYSIOLOGY OP HYPERPYREXIA
A DISSERTATION
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
for the degree
DOCTOR OF PHILOSOPHY
DEPARTMENT OF PHYSIOLOGY
BY
STAFFORD LENNOX OSBORNE
EVANSTON, ILLINOIS
APRIL, 1940
P ro Q u e st N um ber: 10101813
All rights r e s e rv e d
INFORMATION TO ALL USERS
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uest.
P ro Q u e st 10101813
Published by P ro Q u e st LLC (2016). C opy rig ht o f t h e Dissertation is held by t h e Author.
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TABLE OF CONTENTS
Statement of the Problem*
I
Introduction*
A* A Brief History of Artificial Hyperpyrexia*
B* The Theory on Which Hyperpyrexia is Based*
II
A Comparison of the Effects of Hyperpyrexis Induced by the External
Application of Heat and by High Frequency Current*
A* The Effects of the Two Methods on Axillary and Rectal Temperature*
1* The Effect of High Skin Surface Temperature on the Sweat Glands*
B* The Effects of the Two Methods on Water Loss*
C* The Effect of Skin Temperature on Heart Rate*
D* General Discussion of the Effects of the Two Methods*
III
IV
V
VI
Temperature Measurements of Various Organs to Tissues During Hyperpyrexia*
The Effect of Hyperpyrexia on Basal Metabolism*
The Effect of Hyperpyrexia on the Electrocardiogram*
The Effect of Hyperpyrexia on the Blood and Circulation*
A* Blood pH*
B* The Specific Gravity of the Blood*
C* Blood Count*
D* The COg Combining Power of the Blood*
E* Non-Protein Nitrogen and Urea Nitrogen of the Blood*
F* Pulse Volume Changes*
G* Hie Influence of Hyperpyrexia on Ascorbic Acid*
VII
VIII
IX
X
The Effect of Hyperpyrexia on Immune Bodies*
The Effect of Hyosoine and Pilooarpine on Axillary Temperature*
The Effect of Hyperpyrexia on Secretion of Digestive Juice*
Summary and Conclusion*
Statement of the Problem
This thesis is concerned with artificially induced hyperthermia
on physiological processes.
Since the subject is very extensive, a
detailed review of the literature will be confined to those sections
of the subject which the author has investigated.
I.
A.
Introduction
A Brief History of Artificial Hyperpyrexia.
Heat in some manner has been used therapeutically for centuries.
It was used even by primitive peoples.
Yet, no one attempted to ascertain
the effect of the application of heat to the body temperature until
1884.
Erasmus Wilson (153) in 1860 described very accurately many of
the readily observable physiological changes induced by heat, but made
no suggestion of the changes in body temperature that must have occurred
during his heat treatments.
Philips (117) in 1884 published his investi­
gations on the therapeutic effects obtained with hot baths as used at
Hot Springs, Arkansas, for the treatment of various diseases.
He carried
out several carefully devised experiments both on patients and himself,
and came to the conclusion that the curative properties were due entirely
to the physiological effects produced by the skillful application of
water at different degrees of temperature.
He noted and recorded an
increase of the oral temperature, increased respiration and pulse rate,
throbbing of the carotids, and an increased apex beat of the heart.
These changes, he stated, were related to the temperature and duration of
the hot bath.
Philips fully appreciated the clinical significance of
his observations.
Twenty-five years later, Hill and Flack (60) published
similar observations.
!Ihey found that immersion up to the neck in a
hot bath (105°F - 110°F) raised the oral, axillary, and rectal tempera­
ture to 102.5°- 104.6°F in fifteen to thirty minutes.
corded blood pressure and alveolar C0£ tension.
They also re­
Ten years later (1919)
a somewhat similar investigation was conducted by Sonntag (141), and
Weichbrot and Jahnel (149) showed that rabbits infected with scrotal
chancres recovered more rapidly, than as a result of the natural evolution
of the disease, when repeatedly placed in boxes, the air of which was
heated to 105.8° F for half an hour*
to 107.6°F.
They induced temperatures of 104°
They also expressed the opinion that syphilis in man might
be influenced similarly provided such temperatures could be tolerated
safely.
Then in 1926, 1927 and 1928 followed the experiments of Schamberg
and Rule (130).
They found that when the rabbits were immersed daily
in hot water baths they failed to develop specific lesions when inoculated
with virulent treponemas, and experimentally produced testicular syphilomas
and secondary syphilitic ulcers disappeared.
These laboratory results
caused Schamberg and Tseng (131) in 1928 to try the effect of heat on
syphilitic human subjects.
They deviated in their technique from the
usual custom of immersing the patient in the bath for a given period of
time.
They correlated the time in, and the temperature of the bath,
with the patient*s oral temperature.
Their patient*s oral temperature
reached 105° F approximately in 15 to 25 minutes and returned to normal
within 60 to 90 minutes.
Hence, the fever was of short duration.
Mehrtens* and Fouppirt (97) in 1929, followed the hot water bath technique
outlined by Rosanoff (127) in 1928.
Most of these investigations were
made without taking cognizance of work previously done, and while tempera­
tures of 106° F were obtained, they were not maintained for periods longer
than one to two hours.
Mehrtens and Pouppirt, however, made an important contribution
by showing how unreliable and dangerous it is to rely upon oral tempera­
tures.
For the usual clinical oral thermometer they substituted a
rectal thermocouple for recording the rectal temperature.
Previous workers using the hot bath were unable to maintain the
patient*s temperature for an extended period because they failed to take
into consideration the cause of the rapidly falling temperature.
A
fall in temperature naturally occurred when the patient was transferred
from the hot bath to a comparatively cold bed, because there must be
a transfer of heat from the hot patient to the cooler bed until equili­
brium is raaohed.
temperature.
This equilibrium occurred at a much lower and undesirable
This was demonstrated by the author with Merriman (98)
in 1933 by preheating the patient*s bed to a level above that of the
patient on removal from the bath, with the result that the rectal temper­
ature did not drop when he was transferred to the heated bed.
Figure I
shows a typical temperature curve of 104° - 105° F induced by the hot
water bath and maintained for eight hours*
We gave thirty-one treatments
with this method, but in this series we used a rectal thermocouple to
indicate the temperature throughout the entire period.
While Schamberg and Rule were conducting their laboratory experiments
in the years 1926, 1927, and 1928, Neymann and the author were conducting
experiments to produce fever in dogs and human subjects by an entirely
new method —
namely, by means of high frequency current, or, so-called
**Conventional Diathermy.'1 By this method we believed it might be possible
to secure any desired safe temperature and to maintain it for any number
of hours deemed advisable.
This was accomplished.
Studies were also
4
conducted by Helen Hosmer (65) in 1928 on dead and living rats, and
salt solutions, using short radio waves*
a similar machine the same year*
Soiland (140) demonstrated
Thus it can be seen, readily, that
ithe years 1926 to 1928 were productive of much independent and simul­
taneous research.
In addition to those workers already mentioned, the
work of Gosset, Gutmann, and Lakhowsky (52), Schereschewsky (133),
Baldwin and Nelson (3), Kahler, Chalkley and Voegthin (73) should be
referred to*
Kahler and Knollmeyer (74) made use of an electric light cabinet
as early as 1929*
wave diathermy*
1931*
In 1928 Carpenter and Page (27) introduced short
Wilgus and IiUrie (151) used an electric blanket in
In collaboration with Merriman (98) the Indue to therm was intro­
duced in 1933*
In the year 1933 Simpson, Kislig and Sittler (137)
introduced the Kettering Hypertherm which is essentially an air-condi­
tion cabinet*
Today the tendency is to combine air conditioned
cabinets with high frequency current.
B.
The Theory on "Which Artificial Hyperpyrexia is Based.
The use of fever in the therapy of certain diseases is based on
the hypothesis that fever is one of the physiological defense reactions
against disease*
This possibility was not realized until the end of the 19th century.
Prior to that time it was believed that fever was a symptom to be cornbatted.
In 1876 Rozeriblum (129) purposely inoculated psychotic patients
with relapsing fever with favorable results.
This type of fever therapy
was revived in 1914 by V. Wagner-Jauregg (147) who used malaria*
Soon
the use of other foreign substances was recommended, such as tuberculin,
typhoid vacoine, and suspensions of sulphur in oil, in the treatment
of general paresis.
Most of the clinicians who used these forms of
treatment explained their action by vague references to crossed protein
immunity, increased leucocytosis, increased production of antibodies,
and by the direct and spirocheticidal effect of these drugs, vaccines
and diseases.
Thus, the effects of non-specific protein therapy were
confused with the effects of fever.
When a foreign substance was
injected one could not say whether the beneficial effects, if some
occurred, were due to fever or to foreign protein.
The author’s investigations were undertaken to ascertain the effects
of fever per se on various diseases and physiological processes.
Of
course, it was realized that the application of heat to the skin or to
the tissues may, if the temperature rises sufficiently, release autogenous
protein or nitrogenous substances which may act as foreign proteins*
However, it was believed that a sufficient fever maintained for an
adequate period might,
1)
2)
3)
4)
5)
Kill certain organisms such as treponema pallidum,
Increase the rate of antibody production,
Cause a leucocytosis,
Increase the blood flow through a diseased part,
Increase the metabolism of cells which in turn would
augment the processes concerned in resistance and repair.
That an
electrical current would produce effects in the body other than the
production of heat was not seriously considered.
Evidence which supports the foregoing points will be presented
later in this thesis.
- 6 -
II.
A Comparison of the Effects of Hyperpyrexia Induced by the
External Applications of Heat and by the Use of High
Frequency Current.
Intr oduc ti on t
It is quite evident, from the history of hyperpyrexia, that many
methods have been utilized during the last few years for the production
of artificial fever in man.
Broadly speaking, all of the techniques
for the production of artificial fever by physical agents can be classi­
fied under two general methods*
One method uses external heat, which
can be applied by ’’electric blankets” —
cabinets using hot airy nebular
spray cabinets, ’’conditioned air” cabinets, radiant energy cabinets
using either infrared generators or incandescent lamps, and hot water
baths.
The production of the fever is dependent upon the patient being
in a heated environment.
The deeper tissues of the body are slowly
heated by the conduction of heat from the heated surface tissues.
other method
The
uses the high frequency electric current to generate
heat in the tissues themselves, independent of any external application
of heat, for the purpose of producing fever.
In both methods it is
necessary to retard heat loss from the body as effectively as possible
so that the patient’s temperature can be maintained at a requisite
level.
In addition, the desired temperature plateau is reached with
a minimum loss of time*
The methods of retardation of heat loss have
evolved from the ordinary hospital bed, using rubber sheets, and many
blankets, to the use of an outdoor heavily insulated sleeping bag (47),
and finally to the air-conditioned cabinet.
Whether a patient reacts differently to the two methods of pro­
ducing fever is a question worthy of consideration.
Unfortunately, very
- 7 -
few investigations comparing these two methods have been ma.de to provide
objective evidence bearing on the question*
clinical method was on trial*
This is natural for a new
The question as to whether clinical
results could be secured was a far more important question than the uhow,!
and uwhyM of the various methods in use*
Most investigators were too
busy perfecting their own particular method to experiment with other
^nethods*
Most investigators were quite satisfied that their own parti­
cular method was the method of choice*
The Symptomatic Reactions of the Patient to the Two Methods of Producing
Fever
After one has used the two methods on a number of subjects, it
becomes evident that the two methods differ quantitatively in regard to
the reactions produced*
Ihen heat is externally applied, the subject
is more restless, delirium is more frequently encountered, and vascular
collapse and heat stroke is more likely to occur*
This is a clinical
impression based on over 300 treatments in which the external heating
method was used and on a very large number given with the internal
heating method*
These observations stimulated the author to attempt to ascertain
the explanation*
To do this the response of a number of physiological
processes to fever produced by the two methods was studied*
A*
The Effect of Heat Applied by the Two Methods on Axillary and Rectal
Temperature *
Normally the axillary temperature is below that of the rectum*
When
heat is applied to the skin, the skin temperature is obviously raised*
For this reason it was considered advisable to determine the axillary
and rectal temperature changes when fever is produced by the two methods*
- 8 -
A review of the literature showed that Neymann and Osborne (ill)
itpublished axillary and rectal temperature curves of a fevr individual
patients, but they furnished no data from which a comparative study
icould be made*
Wo other reference or comparative study of these tempera­
tures could be found*
Method:
The rectal and axillary temperatures were recorded by
a aBrown” or ’’Leeds and Northrup” potentiometer or by a ’’Cenco*1 theme lo,meter*
These instruments were accurately calibrated and had a tempera­
ture lag of two minutes or less*
In the majority of instances the
axillary temperature bulb was so placed that the e xternal heat from the
apparatus did not affect it.
A light plaster bandage maintained constant
contact of the thermometer bulb with the skin of the axilla during the
entire treatment*
The pear-shaped rectal insert was introduced and
passed beyond the external anal sphinoter*
The temperatures were
recorded on a moving roll of chart paper*
Results:
In Table I is recorded the data secured from the mean
of twelve patients with external heat*
In Table II are recorded the
data secured for the mean of eight patients with internally produced
heat.
In Figure 2 the temperature curves are shown.
The entire fever
curves are not given because the relationship between axillary and
rectal temperature is maintained until normal values return*
It is to be noted that when internal heat in the form of high
frequency current is used for raising the body temperature, this normal
temperature gradient is maintained from the start to the finish of the
treatment.
Conversely, with the use of external heat, a reversal of
this normal temperature gradient is present during the induction of the
fever*
When the fever plateau has been reached, then the normal
temperature gradient reasserts itself, and does not change again
provided the patient is well insulated*
Conclusions
Pever produced by high external temperatures causes
reversal of the normal heat gradients of the body during the induction
period, but once the fever plateau has been reached, the normal tempera­
ture gradient reasserts itself during the remainder of the fever bout
unless it becomes necessary to reapply the heat due to a falling rectal
temperature•
1*
The Effect of High Skin Surface Temperature on the
Sweat Glands*
It was thought that a high skin surface temperature might cause
paralysis of the sweat glands and in this manner precipitate heat stroke*
Therefore, we conducted a series of experiments to evaluate the validity
of this point*
Methods;
Both hands of six normal individuals were thoroughly
washed and then immersed in distilled water to thoroughly rinse them*
One hand was then placed in a constant temperature bath maintained at
a temperature of 116° P*
The hand was immersed for a variable period
of from ten to twenty minutes.
Both hands were rinsed again thoroughly
in separate basins of distilled water*
was evaporated to equal volumes*
The water from both these vessels
A sample from each was then tested
with AgNOg for the detection of chloride as an index of the amount of
prespiration*
Next the entire contents of both vessels were evaporated
to 20 cc. volume, made up to 50 cc* by the addition of distilled water,
and once again tested for the presence of chlorides*
A second experiment was made by placing the entire arm in a so-called
HBakerM which maintained a hot dry temperature of 160° F for two hours*
- 10
The heat
was
intense
enough to oause some slight tissue damage.
arm was then removed from the ttBakerw.
The
The treated arm showed a much
greater degree of perspiration than the control arm,
Resultss
In each instance these experiments showed that the
heated arm perspired a far greater extent than the control.
There cer­
tainly was no seat gland paralysis of the ,fbaked” arm.
Disoussiont
Wiggers (150) states,
MIn exposure to high external temperatures, as exemplified
by hot
baths, the temperature gradient is either decreased
or,
in the
case of
temperatures higher than those of the body, it is
actually reversed, so that heat passes from the surrounding
medium to the body. The reactions which occur consist of dilata­
tion of skin vessels, partly through local axon reflexes or by
direct action, partly through action of an increased temperature
on nervous centers* Heat tends to increase the formation of
vasodilator substances in tissues (H substances); these cause
dilatation of capillaries and venules directly, and relaxation
of arterioles by axon reflexes. At still higher temperatures
the increase in such instances becomes so great that endothelial
permeability is reduced.n
Luchsinger (90) reported that when the hand is held in water at
a temperature of from 45° to 50° C (113° - 122° F), the unheated hand
will begin to sweat in response to exercise much sooner than the heated
hand.
Our subjects oould not tolerate a temperature higher than 116° F,
and there was no practical reason why higher temperatures should be
employed.
Conclusions}
Paralysis of the seat glands from the direct effect
of external heat is certainly not the cause of heat stroke.
- 11 -
FIGURE 1.
I06°1F
1-------- 1
i
-------- 1
-------- ■
-------- 1
---------1
-------- -
150
777/ 77-
(t)
1
2
3
^
5
6 - 7 8 9
hours
o
------ <>
o
0 O <)
o
@
o
O (1 o o
rl
1
H
respiration />-win
Hyperpyrexia by means of a Hot Water Bath*
Bath temperature 110° F*
Patient*s rectal temperature 103° F in fifteen minutes#
Note high pulse rate.
- 12 -
FIGURE
2m
Jnternai heat
External heal
5130-
^5'
f
,15'
)30'
15
^
'
J5l
30'
1^5'
—
------
|3h E ___ i30' [W_K_.|I5'.__ 30
Comparison of External and Internal Heating Methods on
Jdcillary and Reotal Temperatures*
Temperature gradient normal with internal heat*
Temperature gradient reversed with external heat*
,
'
,<£
EXTERNAL HEAT
AXILLARY AND
RECTAL
TEMPERATURES
TABLE I
Axillary
Temp* °P.
Rectal
Temp. °P.
Time
Minute s
Time
Hours
97.6
99.3
100.5
101.3
102.3
98.1
98.5
99.0
99.7
100.9
0
15
30
45
60
1
102.6
103.3
103.6
104.0
101.5
102.7
103.2
103.8
15
30
45
60
104.3
104.6
104.6
104.7
104.2
104.7
104.9
105.2
15
30
45
60
104.9
105.4
104.4
104.9
105.4
105.7
105.7
105.5
15
30
45
60
Average of 12 treatments
2
3
4
INTERNAL HEAT
AXILLARY AND RECTAL TEMPERATURES
TABLE II
Axillary
Temp. °P.
Reotal
Temp. °P.
97.6
98.1
98.6
99.5
100.1
98.9
99.1
99.6
100.5
101.3
0
15
30
45
60
101.1
101.5
102.2
102.6
101.9
102.5
103 .3
103.5
15
30
45
60
103.1
103.5
103.7
103.7
103.8
104.1
104.3
104.5
15
30
45
60
104.1
104.2
104.2
104.2
104.7
105.0
105.1
105.0
15
30
45
60
104.4
104.5
104.6
104.5
105.0
105.2
105.3
105.3
15
30
45
60
Time
Minutes
Average of 8 treatments
Time
Hours
1
i
2
3
4
5
15
B*
The Effect of External and Internal Heat on Water Balance*
Introductions
"While most workers in the field of hyperpyrexia state that
patients lose weight during treatment, no attempt was made to ascertain
the actual weight loss until 1934 when Neymann and Osborne (111) pub­
lished some limited data*
In 1938 Gibson and Kopp (50) presented a valuable paper regarding
blood volume and water balance during hyperpyrexia treatment.
The same
year Kopp and Solomon (83) published their article "Shock Syndrome in
Therapeutic Hyperpyrexia•"
For the first time these two papers gave
ample evidence to account for the more frequent occurrence of "shook11,
or "vascular collapse", when high external temperatures are used to
produce artificial fever.
Both of these papers are valuable contribu­
tions, because they tend to clarify some of the hitherto obscure physiologic
changes occurring during the course of artificial fever*
In the following experiments, water intake was correlated with
urinary output and weight loss*
Methodt
All patients were placed on a fixed fluid intake for 24
hours previous to the day of treatment*
Before treatment the patient
was weighed on an accurate and sensitive scale in the nude*
The patients
were subjected to the same degree and duration of fever, namely, at
least six hours at 103*5 °F plus an additional two hours at 105*8 °F*
The water intake, as well as fluid loss during treatment such as urine
or vomitus, when present, was measured.
at the termination of the treatment*
The patient was weighed again
Fourteen experiments were made
on patients undergoing treatment by means of high frequency current*
Thirty-one experiments were made on patients undergoing treatment by
- 16 means of external heat applied in the form of electric blankets, or
the so-called "Hyperpyrexator" which is similar to the "Kettering
Hypertherm11 in principle and operation#
The environmental temperature
of the patients that received diathermy was approximately between 100°
and 110° F, with high relative humidity#
The environmental temperature
of the electric blanket was between 120° to 130° F* and the Hyperpyrexator
^between 130° to 160° F#
!!
j;
Total weight loss was calculated from the amount of weight loss
ii
ji
jlduring treatment, plus the weight gained by fluid intake and minus the
weight lost through fluid output*
This represented the total fluid
lost by the body in an attempt to regain its normal temperature#
The
water was lost chiefly through evaporation from the skin and lungs#
Weight loss during treatment was recorded as the actual weight difference
before and after treatment and without regard to the water intake or
output•
Resuitss
Complete data are found in Tables III and IV#
The
average total weight loss was found to be 5.4 kgms# when external
heat was used, and 3*9 kgms* when internal or diathermy heating was
used, a difference of 1#5 kgms#
The mean weight loss during treatment
was 2.010 kgms. with diathermy and 1#9 kgms# with external heat —
difference of 0#142 kgms*
a
These data were subjected to statistical
analysis and these differences were found to be significant*
The
statistical data is summarized in Table V#
The group treated with external heat averaged a fluid intake
of 3.8 liters per treatment, while the diathermy group averaged 1.5
liters.
In other words, the fluid intake for the externally heated
group was greater by 157 per cent*
The average urine output was 190
cc* for the group having external heat and 89 oo* for the diathermy
groups, or a difference of 13 per cent#
- 17 -
WEIGHT LOSS COMPLETE DATA
EXTERNAL HEAT
TABLE III
Experiment
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Means
cr +
Intake
Water
CO •
Output,
Urine
or
Vomitus
Kgms# Weight
Gain by
Fluid Intake
Kgms. Ibight
Loss During
Treatment
Total Weight
Loss Kgms.
3550
4350
3250
3155
4670
5430
4600
4420
7630
6060
5745
6990
10680
4150
4510
1440
1310
910
375
630
630
895
4050
2140
1650
3100
2360
1660
2425
3560
11605
365
140
120
120
30
150
500
75
65
160
295
125
90
285
300
120
150
205
120
990
240
255
450
300
255
3.185
4.210
3.130
3 .035
4.690
5.400
4.600
4.270
7.130
5.985
5.680
6.830
10.385
4.150
4.335
1.350
1.025
3.610
0.255
0.480
0.425
0.775
3.060
2.900
1.650
2.845
1.900
1.360
2.425
3.560
11.350
1.275
1.162
3.516
2.466
0.822
1.162
2.268
1.816
0.425
2.126
1.162
0.992
0.681
1.984
1.928
2.240
2.610
2.610
3.289
3.147
3.204
2.778
2.211
2.610
1.247
0.709
1.588
1.843
1.332
0.850
-
4.460
5.372
6.646
5.501
5.492
6.562
6.868
6.086
7.555
8.111
6.842
7.822
11.066
6.134
6.313
3.690
3.636
3.220
3.544
3.627
3.629
3.553
5.271
5.510
2.897
3.554
3.488
3.203
3.757
4.410
10.655
3836
190
-
1.868
5.431
0.206
0.38
-
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- 20
Discussion*
From, this data it would appear that the principle
difference between these two methods lies in the large amount of fluids
demanded by the body when high environmental temperatures are used*
With
externally applied heat the fluid demand was 157 per cent greater,
while the urine output increased only 13 per cent*
In a previous com-
1
munication, it was stated that there is a greater total weight loss
•
•
•
with diathermy but a more complete and critical study of our data shows
that an error was made (ill).
In their paper on shock during therapeutic fever, Kopp and
jSolomon (83) presented some interesting data on shock reactions which
(Occurred while using the MKettering Hypertherm1’, or externally applied
'j
i
heat*
They found a reduction in the volume of the blood plasma ranging
from 10 to 32 per cent in spite of a large fluid intake by mouth.
Approximately 66 per cent of the body weight is water* In a person
’1
weighing 70 kilos,, the water is distributed approximately as follows*
In the plasma, 3 kilos; in the lymph vessels and tissue spaces, 14 kilos;
in the cells, 26 kilos.
'When water is lost, that in the tissue spaces
is probably called on to conserve the plasma volume.
When the plasma
volume is decreased, that indicates impoverishment of the water in the
tissue spaces which bathes the cells*
To what extent the cells become
dehydrated is unknown*
Oibson and Kopp (50) recently published a comparative study on
j
total blood and plasma volumes while using the Hypertherm, diathermy
and radiant heat cabinets*
These data give further confirmation that
low environmental temperatures produce less change in the blood volume
than do high external temperatures.
It is unfortunate that these
investigators used the most unsatisfactory diathermy application known
- 21 ;i
1:o raise body temperature - namely the belt and cuff technique*
is an ideal method for producing vascular collapse.
did not last long attests to its danger*
This
That this method
A belt was placed around the
waist, one around each thigh, and one around each lower leg*
The current
■j
ijflow thus was in series with the largest blood vessels in the abdomen
||
ISand legs, and was prone perhaps to cause splanchnic dilatation*
However,
in spite of this, diathermy shows less change than the other methods
during the induction of the fever*
Fijoan (110) recently reported that if the environmental tempera­
ture is low, and the alkalosis mild, that the hematocrit change is minimal
and within 7 per cent of the original value.
Theoretically the degree
of change in the hematocrit value occurring during fever closely parallels
the degree of tissue dehydration, because the blood tends to maintain its
(composition in the face of great odds*
During hyperpyrexia absorption of fluid from the gastro-intestinal
Jj
(tract appears to be either delayed or impaired regardless of the method
jused for producing fever, but it may be much more marked when external
«heat is used*
If fluids are given without regard to this physiologic
disturbance, vomiting and nausea are very apt to result due to marked
!distention of the stomach.
Hartmann and Major (56), experimenting on
dogs and using a Hypertherm, found that unless their animals were
given repeated intravenous infusions of dextrose and saline solution,
they did not survive the treatment*
The permeability of the lymphatic capillaries has been found by
Hudack and McMaster (67) to be increased when the temperature of the
part is raised.
The edema of the hands rather frequently seen after
hyperpyrexia is indicative of the altered capillary permeability.
Krogh (85) has shown that agents which cause capillary dilatation will
also cause edema or stasis, or both, when applied in sufficient strength
High external temperatures, it would seem, might be an ideal dilator
of the capillaries at least in the skin*
Gibson and Kopp (50) state
that the loss of 5 cc* of tissue fluid per hour per kilogram of body
weight is the limit of safety*
It should be pointed out that changes in environmental temperature
and humidity cause activity of the autonomic nervous system which makes
adjustments to meet the exigencies of the situation*
Hhen the demand
on this system is too great or too sudden, a breakdown may occur*
Kopp and Solomon (85) state that "shock phenomena occurred only when
the patients were in the Hypertherm where the wet bulb temperature
approximates 135° F, and never in the diathermy carbon lamp machine,
where it is about 105° F*”
In view of the foregoing, then, it would seem quite significant
that the externally heated group in our series required 157 per cent
more fluids than the diathermy group*
A great deal more work must have
been required for the body to evaporate so much water from the skin
and lungs*
Ihen using external heat it would appear to be a desperate
effort to maintain adequate blood volume levels*
The heart is laboring
with poorly filled arteries for much of the blood is attracted to the
dilated capillaries and veins on the surface of the body by the normal
process of cooling by perspiration and evaporation*
The decreased
blood volume leads to decreased venous return flow and causes the heart
to beat faster in order to keep the minute volume sufficient to carry
On the circulation*
kith reduced circulating blood volume and concentra
tion of the blood, diastolic filling is profoundly disturbed*
- 23 The increase in capillary permeability due to the effeot of heat
i per se, and anoxemia might cause a still further reduction in blood
volume, thus a vicious circle is produced*
Conclusions a
1*
The patient lost more weight when fever was
produced by the external application of heat than by the internal
production of heat, and the difference was statistically significant*
2*
Regardless of this fact, the fluid intake of those patients
treated with external heat exceeded by 157 per cent the fluid intake
of the patients heated by diathermy.
3*
The urinary output for the external heat group was 13 per
cent in excess of the diathermy group*
4* Other investigators have reported that a marked drop in total
j
■1blood and plasma volume occurs when external heat is used for raising
;body temperature.
The extreme demand for fluids found in our patients
|similarly treated would seem to substantiate this work.
’j
j'C •
The Effect of Skin Temperature on Heart Rate.
It is well known that a change in body temperature will increase
ilthe pulse rate.
Hill and Flack (60) with patients lying in a hot water
bath 105° to 110° F observed a mean increase of forty-four beats per
, minute for a rise in rectal temperature of 2.4°C.
Bazett (7) in 1924,
working under similar conditions, reported an increase of thirty-seven
beats per minute for a temperature rise of 2.0° C.
In the same year
Adolph and Fulton (2) exposed subjects in a room with a temperature
of 39*5° to 40*7° C*
cent*
The relative humidity of the room was 100 per
The air was not in motion*
They concluded that the changes in
pulse rate were more closely related to surface than to deep temperature*
- 24 -
j! Grollman (53) in 1930 subjected individuals to room temperatures vary­
ing from 0° C to 45° C, but with relative low humidity for periods of
I an hour.
He found that increasing temperature exerts a progressively
' greater effect on the pulse rate at elevated temperatures.
Benson (12)
I in 1934 showed that the heart rate varies directly with the temperatures
applied to the skin, that by cooling the skin surface, even with a
rising rectal temperature, the pulse rate would drop markedly.
Schmidt,
iHolmquest and Marshall (132) in 1936 published a composite rectal temper;j ature and pulse rate curve taken from a series of eight patients treated
!by means of an air-conditioned cabinet combined with an Inductotherm*
: The environmental temperature of the patients ranged from 100° to 110° F.
with a high relative humidity*
1values.
They plotted both median and maximum
The maximum rectal temperature curve ranged from 106° to 106.6°
F for six hours, while the median rectal temperature was between 104°
i
to 105° F for a similar number of hours.
The maximum pulse rate reached
but once during the entire curve was only 132 beats per minute, while
the
median pulse rate was approximately 100 beats per minute throughout
the treatment.
A comparative study of high and low surface temperature effects
! on the pulse rate during artificial fever was first made in cooperation
with Heymann during 1936 (107).
Dr. Walter Simpson of the Miami Valley
Hospital placed the data of his artificial fever treatments at our
disposal.
We selected on the basis of body temperature response, data
> from fifteen patients, all of whom had been treated with the Kettering
' Hypertherm using high external surface temperatures - 12QP to 160° F,
and a relative humidity of approximately 30 to 40 per cent*
We selected
from our records a similar group of patients who had been treated by
- 25 I',
jbeans of high frequency current which permitted a low surface temperature
with a relative high humidity.
A composite curve of the data showing
jfche mean pulse rate and mean rectal temperature was plotted. The temperal;
ture curves were almost identical after the fever plateau had been
reached, but the pulse rate curve for low surface heating was decidedly
lower than the other.
This was not due to the particular apparatus,
for Cook (3) in 1939,
using a Kettering Hypertherm, but modified to
secure low temperature, found that pulse rates remain moderate even
during fever induction.
Phillips (115) in 1938 was able to demonstrate
on the same subject by an ingenious method that high skin temperature
produces high pulse rates regardless of the rectal temperature.
Bazett
(9) states that there is rarely any exact parallelism between rectal
temperature and pulse rate.
The following study was made entirely from our own data.
We
wished to learn whether by substituting our own external heating data
i
f
ifor that of the Simpson data a composite curve similar in trend would
be secured.
Methodt
The charts of thirty patients were secured from our
fecords accumulated from 1930 to 1936, during which time we experimented
with both external and internal heating methods.
parable with that used in our former study.
Thus the data is com­
Fifteen patients treated
by means of either the electric blanket or Hyperpyrexator were selected
for the external heating data.
A similar number was selected for
internal heating, using high frequency current.
The majority of the
patients were being treated for the early stages of general paresis,
but a few cases of multiple sclerosis were included.
The charts were
selected on the basis of the similarity of the fever curve during the
- 26 -
Iperiod of induction and the fever plateau.
The recovery period was
:not included because it added nothing to the study.
Such a basis of
,selection rendered it difficult to secure more cases*
An attempt was
imade to select fever curves at a slightly lower range for the external
1heating method and this tendency is shown in Figure 3.
The rectal
temperature was recorded by means of a Brown recording potentiometer,
:a Leeds and Uorthrup recording thermometer, or a Cenco Themelometer.
- Pulse rates were recorded on the patient’s chart by the attending
; nurse.
Both temperature and pulse rate was recorded every fifteen
minutes.
From this entire data the mean average was oomputed and
1plotted as shown in Figure 3.
Results?
Table VI gives the complete data for the curve.
The
patients treated by the high frequency method - low surface temperature
-showed a much lower pulse rate than the other group of eight of the
;ten treatment hours charted.
The curves made from this data are
quite similar to those for the Neymann-Simpson data.
Until a tempera­
ture of 102.1° F is exceeded there is no significant difference in
the two pulse rates.
With a rectal temperature of 102.9° F for
,external heating and 103.3° F for high frequency heating the pulse
rate is 19 beats per minute higher for the method of high surface
temperature even though the rectal temperature is lower.
The pulse
rate differences were checked by statistical methods at 102*1° F,
102.9° F, 103.5° F, and 104.4° F; at all points* with the exception
of the first, the differences were significant.
the remainder of the curve to be significant.
data is found in Table VII.
Inspection also shows
A summary of this
The average pulse rate during the
fever plateau was approximately 20 beats per minute greater with
external than with internal heating#
ij
,,
The individual temperature and pulse rate curves show a greater
tendency to fluctuate when high surface temperature or external
ij
heating methods are used#
I
:s
1
Discussions
Adolph and Fulton (2) believe that it is possible
: that vasomotor sensory impulses are set up in the peripheral vessels
| which reflexly stimulate the accelerator mechanism of the heart.
They
| state that there is a direct correlation between superficial body
■; temperature and heart rate and that the three primary responses to
high temperature, namely, gradual peripheral vasodilatation, accompanied
' by loss of C0£ and acapmia, are initiated by temperature conditions
in the skin, and not by those in the central organs.
Benson (12) attributed the pulse rate acceleration to reflex
f- action probably initiated through the stimulation of the nerve endings temperature spots - in the skin with a subsequent chain of reflexes
which terminate in the cardiac accelerator or depressor mechanism*
It
( is also interesting to note that he states that artificial fevers may
be produced - theoretically at least - without increasing the heart
rate to any great extent.
The pulse curve published by Schmidt,
Holmquest and Marshall (132) would seem to verify this prediction.
However, as already pointed out in the section on water balance,
the increased pulse rate may be due to the heart working faster in an
endeavor to keep the circulation at an adequate level in view of an
actual decrease in blood volume and of a relative dimunition in venous
return due to the marked dilation of the vessels of the skin in the
I' presence of high external temperature.
It is evident, regardless of
the mechanism involved, that a low environmental temperature involves
jj less risk for the patient than high surface temperatures, insofar
| as circulatory embarrassment is concerned*
Conelusionsi
The mean average pulse rate and rectal temperature
>: of two groups of patients was plotted*
One group of 15 patients was
I• subjected to artificial fever induced by high external surface tempera! tures*
A second group of 15 patients subjected to artificial fever
|i were treated with high frequency currents permitting low external
5]
temperatures*
jj
II
jj
A significant pulse rate difference between the two
groups was found for a rectal temperature above 102*9° F*
At this
,1
j! temperature the pulse rate was 19 beats per minute higher for the
i
method using a high external surface temperature*
This relationship
P was maintained for the remainder of the high temperature plateau.
.! In giving artificial fever, the method using the lowest environmental
temperature should prove to be the safest method for the patient*
l! has been suggested that the acceleration of pulse rate due to high
'I
i skin temperature might be due to either a reflex nervous mechanism
!i
■( or to an actual and a relative decrease in blood volume, although
!
■
the exact mechanism is not known*
It
- 29
COMPARATIVE PULSE AND TEMPERATURE CURVES
COMPLETE DATA
TABLE VI
Internal Heat
Time
Minutes
Average
Pulse Rate
0
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
60
15
30
45
79
84
90
95
101
108
109
116
109
113
111
113
113
114
115
117
117
118
117
116
116
116
116
115
115
115
114
116
116
115
115
114
114
114
114
112
110
111
108
106
107
105
102
100
Average
Rectal Temp.
98*7
99*1
99*7
100.2
100.8
101.0
102.1
102.7
103.3
103.8
104.2
104.4
104.7
104.9
105.1
105.2
105.3
105.4
105.5
105.5
105.5
105.5
106.5
105.5
105.5
105.5
105.5
105.5
105.5
105.5
105.5
105.6
105.5
105.5
105.5
105.5
105.5
105.5
105.3
104.8
104.5
104.2
104.0
103.8
External Heat
Average
Average
Rectal Temp.
Pulse Rate
98.4
98.7
98.9
99.4
100.2
100.8
101.6
102.3
102.9
103.5
103.8
104.3
104.6
104.8
105.0
105.2
105.2
105.2
105.3
105.2
105.2
105.3
105.3
105.2
105.0
105.0
105.0
104.9
104.9
105.0
105.1
105.0
104.8
104.6
104.4
104.3
104.3
104.6
104.6
104.5
104.5
104.3
103.9
103.5
81
86
90
98
104
115
115
123
128
130
134
139
140
139
141
141
141
140
139
139
141
140
140
139
135
134
133
136
135
136
137
137
136
134
134
135
133
133
131
131
131
128
125
120
Difference in
Pulse Rate
2
2
0
3
3
7
6
7
19
17
23
26
27
25
26
24
24
22
22
23
25
24
24
24
20
19
19
20
19
21
22
23
22
20
20
23
23
22
23
25
24
23
23
20
- 30
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31
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FIGURE 3.
sS
S;
wlerrnl heal
Graph /
g
5k
97
^
5
6
7
8
9
hours
s—
VhQ
130
120
cu
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Graph I
Graph II
Composite Rectal Temperature Curve.
Pulse Rate*
Effects of external and internal heat on the pulse
rate at similar rectal temperatures9
Graph 2.
- 32 I!
General Discussion of the Effects of the Two Methods of Producing
Artificial Fever*
^
The differences observed when the two methods of producing
jartificial fever are used will be summarized and briefly discussed.
h
r
jj
A high skin temperature as is produced by high environmental
t
jtemperatures does not directly paralyze the sweat glands* An indirect
<-
jjparalysis
jj
jj
may possibly occur due to a central failure of the sweat
centers or to a peripheral effect of a change in the composition of
j;
;the blood or some substance carried by the blood*
This indirect failure
of the sweat glands apparently occurs in collapse or heat stroke*
!j
■j
I
Fever produced by high external temperatures causes a reversal
jof the normal heat gradients of the body during the induction period
sof fever* After the fever plateau has been reached the “normal” temperaj;
i!ture gradients return. It is probable that the greater discomfort
i,
reported by the patient when fever is induced by high external tempera■;tures is due to the high skin temperature and the reversal of normal
j!
r heat gradients. After the fever plateau has been reached this factor
I should no longer be responsible for discomfort.
This view is in
iagreement with Cook (31) who believes that the patient’s discomfort is
in ratio to his or her skin temperature and there is less need for
sedatives when low environmental temperatures are used*
This matter
j
'
i
1 should be settled when all our results on subjecting the same patient
I to the two methods are at hand*
The patient treated with externally applied heat looses more
weight regardless of a greater intake of water*
be limited, otherwise it is vomited*
The water intake must
This is also true when 4 gm. of
NaCl is given per liter of water, although no evidence has been presented
- 33 -
or collected to establish the point*
In the experiments reported,
the object was to ascertain if a difference in weight loss and water
intake occurred when the two methods were employed to produoe fever*
If, regardless of intake, the weight loss was greater with one method
than with the other, then in the one in which the weight loss was
greater the tendency to hemoconcentration and “shook” would be greater.
This observation has not been correlated with the hematocrit, specific
gravity and acid-base balance, because adequate work of that type has
been done*
The results (Gibson and Kopp, Pijoan) show that fever
produced by high environmental temperature is associated with greater
hemoconcentration than when diathermy is used, and that when the latter
method is used, the hematocrit change is minimal and the alkalosis is
mild*
The greater dehydration, hemoconcentration, and acapnia associated
with fever induced by high environmental temperature, correlates well
with the greater increase in pulse rate that occurs when higher
environmental temperatures are used*
However, as pointed out previously,
the increased pulse rate associated with external heating is not
entirely due to a decrease in blood volume*
It should be pointed out
in this connection that data now being collected on the response of
the same patient to the two different methods of produoing fever will
have the merit of avoiding the element of coincidence, a criticism
that may be leveled at the method of comparing the data provided above
in this thesis*
However, the observations made by the author and those reported
in the literature constitute strong presumptive evidence indicating
that the use of high environmental temperature to produce fever is
- 34 -
potentially more hazardous than the use of internal heating or
Inductothermy.
It should be made clear that when proper precautions
are taken in the selection and treatment of the patient there is no
serious objection to the method of external heating.
In fact, proper
precautions must be taken when the internal heating method is
employed.
Neither is fool-proof.
The author now combines the two
methods to the extent of protecting the patient from rapid heat loss.
In the following sections of this thesis the author will
present the observations made on the effect internal heating, or
Inductothermy, has on the temperature of various tissues and on
various physiological processes*
Ill*
Temperature Measurements of Various Organs and Tissues During
Hyperpyrexia
Literature:
For many years a temperature of 98.6° F, or there­
abouts, as registered by reotal or oral thermometers, was assumed to
be the average temperature of the body tissues*
no longer held*
Today this view is
A subject, lightly clothed, in a room at a temperature
of 77° F will have an average skin surface temperature approximately
7° F lower*
While the temperature of the feet may be as low as 70° F,
the abdominal surface may be as high as 95° F*
Benedict and Stack (ll)
;in 1910 found a constant temperature in the vagina and rectum was not
attained until a depth of five to seven centimeters was reached*
They
also showed that a rise or fall of the rectal temperature was accompanied
by a corresponding change in other parts of the body such as the axilla
and groin*
In 1927 Bazett and McGlone (9) reported that a constant
temperature in the forearm and thigh was not reached until a depth
of 2*5 cms* was penetrated*
Burton (21) states that the temperature
of the interior of the body is not reached until at a depth of several
centimeters, and that this temperature is 4° to 5° higher than the
surface temperature*
He calculated that about fifty per cent of the
body was within an inch of the surface.
He concluded that for scientific
purposes the measurement of the surface temperature was equally, if
not more, important than the rectal temperature in the calculation of
the average body temperature.
The literature shows few temperature measurements other than
oral, rectal, and axillary temperatures during hyperpyrexia*
Bierman
(15) shows a single temperature curve in which he plots both the rectal
and vaginal temperature.
However, the recorded vaginal temperature was
- 36 -
mad© during a localized application of diathermy to the vagina during
a hyperpyrexia treatment*
Neymann and Osborne (ill) in 1934 made
several temperature graphs which included the reotum, axilla, subcutan­
eous tissues of the abdomen, forearm, lower leg, thigh, Hunter's canal,
liver, oisterna magnum, and lumbar spine temperatures, taken during
artificial fever treatment*
Kendall, Webb, and Simpson (76) in 1936
in addition to plotting the rectal temperature, recorded temperatures
by means of thermocouples of the knee joint, as well as the posterior
and anterior urethra during a single hyperpyrexia treatment*
During
1936 Culler and Simpson (33) using the external heating method, pub­
lished a temperature curve of a single treatment, during which the tem­
perature of the orbit of the eye, of the blood in the median antibrachial
vein, as well as the rectal temperature was recorded*
They reported
that their values for deep temperatures obtained by external heating
were essentially similar to those found during fever induced by high
frequency currents*
They also stated they made temperature measurements
in Hunter's canal, the rectosigmoid junction, the cervi uteri, the
urinary bladder and the stomach, but unfortunately no data or curves
were presented*
They found that the temperature of the blood rose
slightly faster than that of the other tissues during the induction
of the fever, but all temperatures reached practically the same level
as that of the rectum at the end of the first hour and remained at
approximately the same level during the five hours or more of fever
maintenance •
Inspired by the researches of Besseman and his several collabor­
ators, we (ill) became interested in the possibilities of applying
artificial fever to the treatment of syphilis as early as 1930*
These
- 37 -
investigators, working with rabbits as well as man, came to the
conclusion that a temperature of 42° C maintained for one hour, or a
temperature of 40° C maintained for two hours was capable of destroy­
ing the treponema pallidum in vivo#
Boak, Carpenter, and Warren (19)
presented similar evidence in 1932#
Recognizing, then, that to be
successful in the treatment of syphilis in the human, it would be
.necessary to have all the tissues of the body at this thermal death
temperature for a given period of time, we decided to make measurements
in as many parts of the body as opportunity would permit#
Therefore
the following study was undertaken.
Methods
The temperature records were made on general paretics*
jtThe initial temperatures were taken as soon as the patient was prepared
and ready for treatment to begin*
In some instances the patient's
temperature was raised with external heat, in others by high frequency
current, and some by a combination of both methods*
By the combined
methods we sought to overcome the temperature gradient between skin
surface and internal tissues*
It was our endeavor to have all of the
tissues exceed the thermal death temperature of the treponema pallidum
- namely 105*8° F for at least 2 hours or 107*6° F for one hour*
The oral temperature was taken by means of the usual clinical
thermometer*
Rectal and axillary temperatures were recorded by means
of the Brown, or Leeds and Horthrup recording thermometers previously
mentioned*
Temperature readings on other tissues were made by means
of thermocouples*
The thermocouples were made by passing a $26
enamelled, cotton and silk covered copper wire, together with a $26
similarly insulated constantan wire through a number 22 gauge hypo­
dermic needle.
These wires, well insulated to the needle tip, were
carefully soldered at the bevelled edge of the needle.
The reminder
of the wires was threaded through a protecting rubber tube and the
ends fastened and soldered to form a satisfactory constant temperature
jjunction.
j.
The constant temperature junction was placed in a quart
thermos flask which was filled with crushed ice.
Care was taken to
jhave the junction placed in the center of the flask.
An absence
|of air pockets was secured by the introduction of ice cold water into
ilthe flask.
Thermocouples were calibrated in a constant temperature
i,oil bath against a special Fahrenheit thermometer calibrated by the
TJ. 3. Bureau of Standards.
The standard error was 4^0*02 degrees*
|The couples were mounted on a board and controlled by double-pole
■'1
double-throw switches.
The high frequency current was turned off
|while the temperatures were taken*
The couples were placed in the
tissues in such a way as to avoid current heating.
'recorded every fifteen minutes.
Temperatures were
Liver temperatures were taken by
plunging the hypo-dermic thermocouple through the intercostal tissues
into the liver.
Anterior urethral temperatures were taken by passing
a thermocouple made from a urethral catheter into the urethra.
A
thermocouple was inserted in the region of the Hunter's canal to
secure temperatures in the depths of the thigh.
The superficial
temperatures of the cheek, neck, skin, thigh, forearm, forehead and
groin were made by inserting
the couple into the subcutaneous layers
of these areas.
Resuitst
Table VIII gives a summary of the average temperature
of the various regions studied.
Taking the rectal temperature as a
base, the changes are recorded for approximately each degree change
in rectal temperature•
Each temperature recorded in the table was
the average of the number of observations made*
The more difficult
and dangerous regions to study naturally were measured less frequently
than the more accessible regions*
Table IX gives the differences found in the subcutaneous tissues
when external and internal heating methods were used.
Table X gives temperature measurements taken on a single indivi­
dual*
It will be noted that a rectal temperature of 108*5° F was
reached and this was maintained for half an hour*
Table XI and Figure
4 give the complete temperature readings of this patient, which show
a rectal temperature of 108° F, or above, purposefully maintained for
a period of four hours*
It is of further interest that this patient
subsequently made a complete social adjustment as a result of continued
treatment*
Discussions
Table VIII shows how varied is the temperature of
various parts of the body under resting conditions*
Moreover, in
spite of the application of heat sufficient to raise body temperature
several degrees, the abolition of tissue temperature gradients is
not realized, although the tissue temperature gradients is not so
great*
Once a rectal temperature of 103*3° F was reached the liver
temperature led all other parts of the body, although the deep muscles
of the thigh followed very closely*
For a while the temperature of
the cisterna magnum lagged somewhat behind that of the lumbar spine,
but finally reached equilibrium with it*
The oral temperature was
lower than rectal temperature, but in this form of therapy oral
temperatures are unreliable once a high temperature is reached, due
to the restlessness and discomfort of the patient*
The subcutaneous
temperatures are lowest and are undoubtedly so due to evaporation of
- 40 -
i sweat*
The anterior -urethral temperature exhibited a rather interesting
; cycle although our record doesn*t show it*
The temperature would
■!gradually rise to a peak temperature and then quickly return to a
ij
jj lower level*
jjnature*
This was repeated often and appeared to be of a 11sinusoidal11
Initially the anterior urethral temperature was next to the
k
;lowest of those measured*
ii
|jthe
i
The temperature of the forearm lagged behind
majority of the tissue measurements*
The influence of external
Iheat on the skin temperature is shown in Table IX*
I!
:
The curves of Figure 5 are plotted from the data of Tables II
sand IX and Figure 2*
•i
The skin and axillary temperatures are plotted
against the values of the rectal temperature, which is used as a
Preference temperature*
In this way the relationships between the
Ij various body temperatures are far more easily recognized than in
!
J the usual graphs representing the temperatures as a function of the
time of treatment*
Bhen applying internal heating (high frequency)
ithere is a manifest tendency to maintain the original temperature
differences between the various body regions throughout the entire
;;course of the treatment*
The difference between axillary temperature
:and skin temperature is constant for all values of the rectal tempera­
ture (Figure 5).
The temperature rise is uniform and only slightly
higher than the rise in rectal temperature*
For every temperature
i;rise of 1° F in the rectum, the skin and the axillary temperature
f respond with a rise of 1*1° F*
The rectal temperature is always
higher than the skin and axillary temperature*
This relationship
iholds true in the entire range of the measured temperatures between
98° and 107° F rectal temperatures*
If the body temperature is raised by external heating, the axillary
temperature as a function of the rectal temperature shows the typical
exponential behavior of a temperature curve which is always obtained
if two tissues with various thermal capacity and thermal conductivity
'jar© heated by thermal conduction.
In the beginning of the treatment
"the skin temperature rises suddenly and reaches far higher values than
i!
the rectal temperature. The axillary temperature rises considerably
ii
[higher than the rectal temperature when the rectal temperature is
[between 98.2° and 104° F (Figure 5).
After a rectal temperature of
i:
h
o
:jl04 F is obtained, the rectal temperature rises more rapidly than
jthe axillary temperature (dotted line, Figure 5).
jj
jj
The skin temperature differences are even more marked than the
i
i
ij
[axillary. It is interesting to note that both axillary and skin
j!
[jtemperature achieve identical values when both reach the rectal temperaJjture at 104.2° F.
fi
j)
The complete temperature data given in Table XI shows that in
[spite of the existing temperature gradients during the high temperature
Ji
plateau, all temperatures of the tissues measured show that the thermal
i*
death time of the treponema pallidum was reached or exceeded
•j
Conclusionsa
I;
jj
2. At no time during treatment lasting from ten to twelve
hours were all parts of the body at the same temperature, although
there was some lowering of the various gradients.
ji
1. Temperature measurements in various parts of the
body were made during hyperpyrexia treatments.
I
}i
3. Temperatures were reached in all parts of the body
measured at the plateau of the temperature curve equivalent to
the thermal death time of the treponema pallidum.
ii
jj
■■
4. The temperature of the liver was found to be the tissue
temperature highest throughout most of the treatment period.
5. The subcutaneous temperature of the skin was found to
be at a higher level when external heat was used.
42 *
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[P
43 -
INTERNAL AND EXTERNAL HEATING
SUBCUTANEOUS TEMPERATURE COMPARISON
TABLE IX
Method
Temperature
°F
Mean of
Internal Heat
External Heat
Reotal
Skin
Skin
94.6
96.3
98.3
99.7
100.8
101.7
102.7
103.7
104.3
92.2
95.3
98.0
100.4
101.7
103.1
105.4
105.2
105.5
106.2
105.6
6
6
93*6
99.5
100.4
101.4
102.2
103.5
104.4
105.4
106.1
26
Reotal
98.5
99.3
100.3
101.4
102.4
103.3
104.3
105.2
106.3
107.3
108.3
26
- 44 -
1-3
jr
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©
Axilla
Lumbar Spin©
Cisterm Magnum
ct*
•
Subout*
g
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c
Thigh
J2j
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- 45
TEMPERATURE OP VARIOUS BODY REGIONS ON SAME INDIVIDUAL DURING
HYPERPYREXIA TREATMENT
TABLE XI
Rectal °P
Axilla °F
Cisterna
Magnum
Luntoar
Spine
Subcut.
Posterior
Thigh
Time
Min.
Time
Hr s.
1
98.2
99.2
99.1
99.1
99.8
97.6
98.0
98.2
98.2
98.8
98.4
98.0
98.0
98.1
98.2
100.2
100.4
101.0
97.2
98.0
97.7
0
15
30
45
60
100.1
101.0
102.0
102.6
99.7
100.5
101.4
102.0
99.0
100.0
100.9
103.8
102.6
103.6
104.4
105.4
98.2
99.0
99.8
100.2
15
30
45
60
103.6
103.8
104.8
104.9
102.8
103.3
104.0
103.7
102.6
102.9
103.5
103.4
106.0
105.9
106.1
104.7
100.7
101.1
102.4
103.5
15
30
45
60
104.9
105.9
10613
106.5
103.9
105.2
104.7
105.1
104.1
104.8
104.6
105.1
104.6
106.5
105.5
105.6
103.8
103.6
103.3
15
30
45
60
107.1
107.4
107.6
107.8
106.3
106.6
106.8
107.0
106.5
106.8
107.0
107.2
106.3
106.8
107.0
107.2
104.5
104.6
103.8
103.9
15
30
45
60
108.0
108.3
108.5
108.6
107.2
107.4
107.6
107.6
107.5
107.6
107.7
107.7
107.5
107.6
107.7
107.8
103.2
102.6
102.5
102.6
15
30
45
60
108.5
108.3
108.2
108.1
107.6
107.5
107.6
107.3
107.6
107.5
107.5
107.4
107.8
107.5
107.5
107.6
103.7
104.2
104.5
104.8
15
30
45
60
108.1
108.3
108.8
108.3
107.4
107.6
107.6
107.4
107.5
107.6
107.7
107.4
107.5
107.6
107.7
107.8
105.3
105.3
105.5
105.5
15
30
45
60
108.1
108.0
108.0
108.0
107.3
107.3
107.3
107.3
107.4
107*4
107*4
107.5
107.6
107«5
107.6
107.6
105.5
105.2
105.2
104.8
16
30
45
60
»
100.2
-
<
96.3
-
(cont. on next page)
2
3
4
5
6
7
8
9
- 46
TABLE XI
Reotal °F
Axilla °F
-
(Cont. )
Cisterna
Magnum
Lumbar
Spine
Subout.
Posterior
Thigh
Time
Min.
Time
Hrs.
1
108*0
107.9
107.6
107.1
107.3
107.0
106.8
106.2
107.3
106.9
106.6
106.6
107.6
107.4
106.9
106.7
104.8
102.4
103.2
103.1
15
30
45
60
106.7
106.2
105.8
105.5
105.9
105.5
105.2
104.9
105.7
105.5
105.0
104.9
106.5
106.1
105.7
105.4
102.6
102.1
102.0
101.7
15
30
45
60
105.2
104.9
104.6
104.3
104.7
104.5
104.2
103.9
104.5
104.4
104.1
103.7
105.0
104.8
104.6
104.3
100.5
100.2
100.2
99.4
15
30
45
60
104.0
103.6
103.1
102.8
103.5
103.2
102.7
102.4
|
103.3
103.1
102.7
102.2
104.0
103.3
103.1
102.7
96.6
•
-
15
30
45
60
102.4
101.8
101.4
101.4
101.3
101.3
102.0
101.8
101.4
101.2
101.0
101.0
1
101.9
101.3
101.1
100.9
100.9
100.9
102.1
101.9
101.6
101.1
100.9
100.9
.
______
________________________ _______________________
15
30
45
60
15
30
—
___________
—
-------
—
-----
Reotal Ten^erature of 108*5° F maintained for 30 minutes*
»
«
w 108*0° 11
w
M
4 hours*
10
11
12
13
14
____
1/2
- 47 -
Figaro 4*
IZ
106
13 hours rectal'
cisterna - axillaruS
maqna
ICS
p—
101
Individual Temperature Curve plotted from Table XI
Reotal Temperature 108*5° F for 30 minutes, and
108°
F
w
4 hours*
Figure 5*
UK
105
102
external heat
1100
Axillary and Skin Temperature as a Function of the
Rectal Temperature in Fever Therapy*
Left Curve m Internal heat*
Right Curve s= External heat*
Dotted Line represents rectal temperature*
- 49
TV*
-
The Effect of Hyperpyrexia on Basal Metabolism
A review of the literature discloses but three reports on the
effect of hyperpyrexia on basal metabolism of human subjects (21, 82,
and 111)*
Kasset, Bishop and Warren (105) and Nasset (104) made a oompre—
hensive study of basal metabolism on dogs using high frequenoy current
to raise the body temperature.
The following study on basal metabolism was made on patients
before, during and after hyperpyrexia while undergoing treatment for
general paresis*
Method t
The patients were placed in bed prior to treatment, having
fasted since the previous evening meal*
Only cooperative patients were
used, and after an hour of rest to secure a basal condition, they were
connected to a Jones metabolism unit and the test commenced*
checks were made*
Duplicate
When the rectal temperature became stabilized at
105° F, a second test was made*
A third and final test was made at the
conclusion of the treatment when the temperature had returned to the
original level*
Rectal temperatures were taken by means of the record­
ing thermometer previously mentioned*
Body temperature was raised by
means of conventional diathermy, using the ,lNeyman,, electrodes applied
anteriorly and posteriorly to the trunk*
The Du Bois standards as modified by Bootby and Sandiford were
used in the calculation of the results*
and after the treatment*
Patients were weighed before
Three of the patients were given duplicate
tests, the remaining eight were given but one*
Results!
The following table gives the results of all experiments*
- 50
TABLE XII
Experiment
No.
Basal
Metab*
105° F
Basal
Metab*
Start
1
2
3
4
5
6
7
8
9
10
11
+
+
+
+
+
+
+
+
10
13
10
4
8
3
18
12
25
28
30
+
+
+
+
+
+
+
+
+
+
+
Mean
=
60
75
40
50
40
35
75
42
50
65
90
Basal
Metab •
Final
+
+
+
+
+
+
+
+
8
12
12
10
10
1
12
20
20
20
50
Subject
No.
Percent
Increase
1
1
2
2
3
3
4
5
6
7
8
45
54
55
58
43
30
48
27
20
21
46
41*0 % increase.
The average rise of rectal temperature was 6*0
o
F and hence gave
practically a 7 per cent increase of basal metabolism for each degree
of temperature rise*
Discussion:
Our data shows that in each of the eleven determina­
tions made there was an appreciable increase in the metabolic rate from
basal when a rectal temperature of 105° F was reached*
When the
patient*s temperature returned to the initial temperature at the
beginning of the experiment, the basal rate had returned to its basal
level within experimental errors in the majority of the tests*
The
basal rate of subject 4, 6, 7 and 8 exceeded the usual + deviation of
10 to 15 per cent*
Repeated determinations made on several days might
have shown these readings to be within the variability of these subjects*
Kopp found that the initial metabolic rates obtained on each patient
before the start of fever therapy, on each treatment day, fluctuated
from 15 to 35 per cent*
He also reported that four of the seven patients
showed greater variations than the usually accepted 10 per cent*
He
- 51
attributed this to the restricted early morning meal which his
patients received*
Our patients received no food and the question
arises in spite of oare, whether the patients were in a basal condi­
tion, or whether the basal metabolic rate of the general paretic might
not follow that of the normal individual*
Kopp found an increase of basal metabolism in his patients of
7 to 14 per cent for each degree Fahrenheit rise of body temperature*
Our patients showed an average of 7 per cent per degree Fahrenheit rise
of body temperature*
Du Bois (39) found a similar increase for his
patients with an infectious fever*
Du Bois (39) called attention to
the fact that the increase of metabolism with increased temperatures
follows Vant Hoff*s law*
He states that for ordinary temperatures
this law can be expressed as follows*
"With a rise of temperature of
10° C, the velocity of chemical reactions increases between 2 and 3
times*
In other words, the coefficient is between 2 and 3M*
He
further states that practically all of the fever experiments are
within these limits, and the average line shows a temperature coeffi­
cient of 2*3*
According to Basett (9), the factor by which the velocity
at any given temperature must be multiplied to give the velocity at a
temperature 10° higher is commonly written as Q^q *
It nay be calculated
by the following formula derived from that of Arrhenius*
log Kj
Log Q *
--
- log Kg
■----- -- x 10
ti
- t2
Where K^ is the velocity at the higher, Kg at the lower temperature,
and t^ “ ^2
indicates the difference in temperature.
- 52 -
Nasset (104), producing artificial fever in dogs, was unable
to obtain the Du Bois temperature coefficient (Q^q ) of 2,3 when he
substituted in the formula the data obtained from his experiments.
He used a Q-^q sc 2,54 in attempting to account for a portion of the
heat production of their animals.
Similar values can be obtained from
the data of others who used hot air or hot water to elevate the body
temperature.
The results of McConnell, Yogloglou and Fulton (94)
show that on exposure to hot, humid air, the oxygen consumption was in
many cases excessively high, giving some
us high as 49,2.
Plaut and Willbrand (119) report an experiment on a human subject from
which a Q^q * 13,4 may be calculated,
Nasset concluded that increased
pulmonary ventilation was probably the factor largely responsible for
the high heat production in his experiments,
Kopp (82) expressed a
similar view.
Burton states that the rectal temperature at no time represents
the true average temperature of the body.
He is of the opinion that
many of the contradictory results in this field are due to the inadequacy
of the rectal temperature to represent the true average temperature of
the active tissues.
Burton uses the following formula in plotting the
average body temperature!
Average temperature » rectal temperature x
0,65 + 0,36 x average surface temperature.
This, he states, renders the
average error reduced from 7,5 per cent, using rectal temperature alone,
to 5,6 when using his formula.
Conclusions!
’—
1,
Mstabolio rates were determined on eight patients
with general paresis in whom artificial fever
was induced by means of the diathermy (conven­
tional) current,
2, For each degree Fahrenheit rise of the rectal temperature,
there was an average increase of the metabolic rate of approximately
7 per cent.
53 -
V,
The Effect of Hyperpyrexia on the Electrocardiogram
The effect of hyperpyrexia on the electrocardiogram has received
very little attention.
Some animal experimentation has been done (151),
Neymann and Osborne (110) in 1931 reported a summary of an electrocardio­
graph study they made while treating patients with dementia paralytica,
but details of the study were not provided.
Bishop, Horton, end Warren
(18) in 1932 state that the electrocardiograms show some changes, but
that their interpretation is not clear.
The first and, at present, the
only complete study devoted to this important phase of hyperpyrexia
appeared in 1936 by Vessell and Bierman (146),
In 1936 Neymann, Blatt
and Osborne (108) published an electrocardiographic tracing of a
patient before and after treatment for chorea with rheumatic carditis,
which showed improvement after the treatments,
Osborne, Blatt and
Neymann (112) in 1938 reported that artificial fever does not adversely
affect the normal heart on the cardiovascular system,
Huddleston, Baldes
and Krusen (68) reported a study of seven normal subjects and four
patients on whom they recorded electrocardiograms and optical polygrams
simultaneously at various intervals during hyperpyrexia treatments.
In 1933 and 1934 Maher (92) in conjunction with the author made
a study of the electrocardiographic changes occurring during and follow­
ing hyperpyrexia in an attempt to evaluate the effects and possible
hazards of the treatment upon the heart.
The results of this investiga­
tion which were not reported are given below.
In addition, the unpub­
lished data of Neymann and Osborne (110) will be presented also.
Method;
Twenty-five hyperpyrexia treatments were given to twelve
patients suffering
from various disorders.
54 Prior to treatment the patient was subjected to a routine physical
examination, including a cardiovascular survey to determine as accurately
as possible the cardiac condition before the treatment#
This included
a routine history, a two-meter heart film, and an electrocardiogram.
An enema was given the evening preceding the treatment and the patients
received no breakfast.
Adequate fluids were given during the treatment,
consisting of 0.4 per cent of sodium chloride.
During the hyperpyrexia the rectal temperature ranged from 104° to
106° F, and was maintained for an eight hour period at this level.
Electrocardiograms were taken by means of a General Electric Portable
Cardiograph every fifteen or thirty minutes during the period of fever
induction.
"When the temperature reached 104° F, electrocardiograms
were taken every hour, unless prior to that period the temperature
rose a full degree higher.
In addition, electrocardiograms were taken
two hours after the patient*s temperature had returned to normal.
Another two-meter heart radiograph and electrocardiogram was made the
next morning after the treatment.
Results:
All twelve patients showed a normal sinus mechanism
before treatment and this mechanism remained unchanged in all oases.
Ro arrhythmia was produced as a result of the high temperature.
Clini­
cally, extrasystoles were not detected, nor were they recorded electrocardiographically.
In one case, paroxysmal auricular fibrillation
occurred previous to treatment.
The paroxysm was noted clinically, and
determined after the electrocardiographic records were studied the
following day*
The first few records taken during the initial tempera­
ture rise showed the arrhythmia, but all records subsequent to a temperature
of 102° F were all those of a normal sinus mechanism.
Chart I gives the
55 complete oardiographio findings of this patient.
Chart 2 is also
presented because of the interesting change in axis deviation.
The oonduotion time from auricles to ventricles were normal in
all oases, namely, 0.16 to 0.20 seconds, and remained so during the
period of therapy#
The QRS complexes showed no changes in the time interval in any
case#
The measurements were all within 0*10 seconds.
At first the
height of the QRS complexes were all lessened during the period of therapy#
This was a progressive change#
proportion to the perspiration.
The decrease seemed to be in direct
This resulted, we thought, in producing
a current path along the skin from one arm lead to the other.
used surgical needles to replace the usual arm leads.
Me therefore
The needles were
inserted just beneath the skin of the chest about four inches apart.
This solved our problem for all subsequent electrocardiograms failed to
show the customary drop in QRS complexes.
The changes in pulse rate were
simply those of tachycardia#
Table XIII gives the eleotrooardiographio findings of the seven
patients studied by Neymann and Osborne (110) in 1929#
Discussion*
In their conclusions Vesell and Bierman (146) state,
wThe alterations of electrocardiographic waves were not
uniform. P and T waves were almost as frequently increased in
size as decreased. The R wave, however, most often became smaller
and the P-R and Q-R-S intervals in most instances shortened#
The RT level was usually depressed, never elevated. Of special
significance was the transformation of several normal amplitudes
or Intervals to abnormal ones as well as the reverse# This involved
particularly the R and T amplitudes. Worthy of mention is the
development of a prominent Qg in one instance.11
They concluded, **that fever produced no harmful effects
upon the heart#*1
Bishop, Horton and Warren (18) state that electrocardiograms show the
- 56 -
decrease in voltage of the action currents of the heart consistent with
a low blood pressure*
Huddelston, Baldes and Krusen (68) reported that
the electrocardiograms showed a disappearance of sinus arrhythmia
a reduction of the conduction time or P-R interval*
Our findings are
in accord with these investigations for we observed no changes in the
intrinsic physiology of the heart*
Conclusions a
1 * A study of the cardiovascular changes of twelve
patients receiving twenty-five treatments of
electropyrexia was made*
2* No changes were observed in the intrinsic physiology
of the heart as shown by electrocardiographic methods*
3*
Pulse rate increased as temperature increased*
CHART
Record of Patient F*
I
Age 64 years*
Diagnosis8
1* Chronic infectious arthritis*
2. Cardiac
Functional Class IIA*
Anatomic Generalized Arteriosclerosis*
Cardiac hypertrophy*
Aortic sclerosis.
Physiologic
Sinus mechanism*
Auricular fibrillation.
Electrocardiographic Findings of Patient F*
Disappearance of Auricular showing Fibrillation at a Rectal
Temperature of 101*8° F*
Electrocardiogram No* I
therapy*
was taken just prior to starting the heat
It shows an auricular fibrillation with a rate of 160*
complexes are slightly slurred in all leads.
The QRS
The T waves are upright in
- 57 I^ad I and apparently diphasic in Leads II and III.
The axis deviation
is normal*
Electrocardiogram No. II > was taken one hour after the heat
therapy started with a temperature
of 100*3.
auricular fibrillation with a rate
of 170.
complexes is approximately the same.
axis deviation in this curve.
The
The patient still hasan
The slurring of the QRS
There is a slight tendency to right
T waves are of the same contour. There
are four beats in Lead I which show a greater amount of slurring and
notching than in the other beats*
Electrocardiogram No* III
was taken one hour and thirty minutes
after the onset of the treatment with a temperature of 101*
tion is still present at a rate of 170.
50 per cent of the original.
The fibrilla­
The voltage is approximately
The slurring is the same and the contour
of the T waves is unchanged.
Electrocardiogram No. IV
was taken two hours after the beginning
of treatment with a temperature of 101.8.
The auricular fibrillation
has disappeared and has been replaced by a normal sinus mechanism with
a rate of 110.
The T waves are upright in Lead I, blunted in Lead II
and flat in Lead III.
is ©bout the same.
The P-R interval is 0.20 seconds.
The slurring
The voltage is still about 50 per cent of the
normal.
Electrocardiogram No. V
was taken two hours and thirty minutes
after the beginning of the treatment with a temperature of 103.
sinus mechanism is still present with a rate of 90.
The
The curve is the
same as Number IV.
Electrocardiogram No. VI
was taken at about two hours and forty
minutes after the onset of treatment with a temperature of 104.
practically the same as No. V with a rate of 100.
It is
- 58 -
Electrocardiogram No* VII
“was taken three hours and fifteen min­
utes after the onset of the treatment*
mild right axis deviation*
There is a
The T waves are changed in contour in Lead
I with a slightly convex RT segment*
diphasic in Lead III*
The rate is 90*
They are upright in Lead II and
The slurring of the
QRS complexes is approximately
the same*
Electrocardiogram No* VIII
was taken four hours after the begin­
ning of treatment and one hour after treatment has been discontinued*
There is a definite right axis deviation with lower voltage in Lead I*
The T waves are almost isolectric in Lead I, blunted in Lead II and
blunted in Lead III*
The slurring of the QRS complexes is the same*
Electrocardiogram Mo* IX
was taken five hours after the begin­
ning of the treatment and two hours after discontinuance*
It is prac­
tically the same as curve No* VIII.
Electrocardiogram No* X
was taken about two hours and a half
after treatment was discontinued*
It shows a normal axis deviation.
A P-R interval of 0*20 seconds*
The T waves are upright in Leads I
and II and blunted in Lead III*
The voltage is approximately normal
and the slur rings of the QRS complexes are about the same*
Electrocardiogram Nol XI
uance of treatment*
is 0*20 seconds.
all leads*
was taken seven hours after the discontin­
It shows a normal axis deviation*
The P-R interval
There is a slight slurring in the QRS complexes in
Kie T waves are upright in all leads.
Summaryt
It would appear that this patient developed an auriculrr
fibrillation before the treatment was started and an emotional upset is
the only factor to account for this*
The fibrillation disappeared during
treatment when the temperature was 102 and remained regular from then on*
- 59 There is a definite change in axis deviation*
in the T waves*
Ihere are many changes
The voltage change was not as marked as it was in
some of the patients*
CHART II
Record of Patient D*
Diagnosis%
Etiologic - syphilis*
Anatomic - Aortitis*
Physiologic - Sinus mechanism*
Functional - Class 11A*
Showing Change in Axis deviation
Electrocardiogram No* I
(Control).
Rate - 100
Rhythm - Sinus mechanism
P-R Interval - 0*19 seconds
Q R S -
Slurred near the base line in Lead II and slurred in
the down stroke in Lead III*
T Waves - Upright in leads I, II and III with a slight elevation
of the RT segment in Lead II*
Blood Pressure 98/64 - Temp* 99*4.
Electrocardiogram No* II.
Shows no change whatsoever.
Blood Pressure 104/70*
Temp* 100.9*
Electrocardiogram No* III*
This curve shows about a 15 per cent decrease in the voltage*
wise no change*
Temp* 101*5 - Blood Pressure 110/88 .
Electrocardiogram No* IV*
Other­
60
This curve shows the greatest decrease in voltage in lead III.
Otherwise the curve remains practically the same#
Temp* 102*6 - Blood Pressure 130/88,
Electrocardiogram No* V*
This is practically the same as curve No* IV*
Temp* 103*7 -
Blood Pressure 126/30*
Electrocardiogram No* VI*
The same as No* V*
Temp* 104*5 - Blood Pressure 108/74*
Electrocardiogram No* VII*
This curve shows a slight blunting of the T waves in heads I
and II.
There is a suggestive change in Lead III of a Q. wave.
Temp* 104.4 - Blood Pressure 108/78*
Electrocardiogram-No. VIII*
The voltage is decreased about 25 per cent*
very small Q wave in Lead III*
There is still a
The voltage is quite low*
Temp* 104*5 - Blood Pressure 108/74*
Electrocardiogram No. IX.
Same as No* VIII*
Temp* 104*5 - Blood Pressure 104.74.
Electrocardiogram No* X*
Hie same as No* VIII and No* IX*
Temp* 104*5 - Blood Pressure 104/74,
Electrocardiogram No. XI*
The voltage is about 30 per cent decreased* most marked in lead
III and the T waves show some blunting*
Temp* 104*5 - Blood
Pressure 108/74*
Electrocardiogram No, XII*
There is almost a 50 per cent decrease in the voltage.
101*5 - Blood Pressure 104/74.
Electrocardiogram No. XIII*
Temp*
61 -
This curve shows a marked change in voltage*
Right axis devia­
tion appears with a diphasic complex in Lead I, small upright
complex in Lead II and an upright complex in Lead III which is
higher than that of Lead II*
The T waves are upright but blunted*
There is a very small Q wave in Lead III and the voltage is
higher*
Temp* 101*1 - Blood Pressure 104/74*
Electrocardiogram No* XIV.
The right axis deviation is still present - otherwise no change*
Temp* 98*6 - Blood Pressure 108/80 - taken 2 hours after return
of normal temp*
Electrocardiogram No. XV.
This curve shows a normal axis deviation again and the ourve is
practically the same as that of the control.
Taken 4 hours
after return of normal temp.
Electrocardiogram No* XVI*
This is essentially the same as the control except the voltage is
somewhat less in Lead III*
Taken 8 j30 A.M., following morning*
Summary i
The outstanding change in this case was the change in the axis
deviation*
There was a moderate change in voltage*
were slightly blunted.
The T waves
There was a suggestive Q wave in Lead III.
- 62
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63 VI*
A.
The Effect of Hyperpyrexia on the Blood and Circulation
Blood pH*
Several reports have appeared on the effect of an elevation of
body temperature on the pH of the blood*
Haggard (54) in 1920,
experimenting on himself found a distinct lowering of the CO2 tension
after twenty minutes in a very hot bath#
As no corresponding fall in
the COg-combining power of the blood was found, he suggested that a
change in the reaction of the blood had taken place*
This suggestion
was verified by the direct measurements of Koehler (80) in 1923*
He
showed that the acid-b&3e equilibrium shifted toward the alkaline side
not only during acute clinical fevers, but also during a Mpure thermic
fever" as he designated it*
He secured his "thermic fever" by immersing
four subjects in a hot bath for a maximum period of thirty-seven minutes*
The oral temperature ranged from 103*2° to 105*3° F and the change in
blood pH was from a minimum of 7*365 to a maximum of 7*605*
In the
same year Cajori, Crouter and Pemberton (23) studied the effect of heat
on acid-base balance*
These workers exposed fifteen subjects to the
heat of an electric light cabinet, from which only the head protruded.
They were exposed to this heat for a period of forty to fifty minutes,
but neither oral nor rectal temperature was recorded*
Hiey state that
the temperature of the skin reached 120° to 130° F after twenty minutes*
The pH values of the height of the temperature was from 7*24 to 7o55,
a change of -0*03 to +0*26 point.
Several other groups of investigators
have reported rises in pH of the blood associated with artificial fever,
the elevation of pH ranging from 7*43 to 7.7 (16, 17, 34, 64, 89).
The observations just referred to were for the most part carried
out chiefly on normal individuals*
In the majority of the cases the
- 64
fever attained was not held for any appreciable period of time*
It
was, therefore, thought advisable to study pH changes of the blood of
patients while undergoing fever therapy*
Methodi
Determinations of the blood pH were made on ten patients
undergoing fever therapy for the treatment of infectious arthritis.
The patient's temperature was raised by a combination of the inductotherm and an insulated metal cabinet.
Rectal temperature was elevated
to 104-105° F and maintained at that level for four hours, and then
permitted to return to normal.
Fluids were given by mouth as needed
and consisted of an 0.4 per cent salt solution.
Blood samples were drawn with the usual precautions from the median
basilic vein of the arm.
With the hypo-dermic needle in place the syringe
was removed and replaced with the Dole glass electrode*
The inflowing
blood displaced a small amount of sterile distilled water from the glass
electrode, and by this means prevented the blood from making contact
with the air*
potentiometer*
The pH determinations were read directly by a Coleman
The instrument was calibrated against a known standard
at the beginning and end of each, experiment*
Determinations were not
accepted that could not be duplicated with an error of less than pH 0*01*
Determinations were made prior to starting the treatment, when the
rectal temperature reached 104° F, and again, at the end of the four-hour
temperature maintenance period, and finally when the patient's rectal
temperature returned to normal.
Results!
Thirty-three experiments were performed.
The complete data is recorded in Table XIV.
gives a complete summary of the data*
Table XV
Table XVI gives a summary of the
work completed by other investigators as well as our own.
The pH of the blood for the control period at the beginning of the
- 65
experiments ranged from 7*30 to 7*52, the average value of all the
determinations being 7*415
0*01*
When the reotal temperature
reached 104° F, the pH was elevated, showing a range of 7*35 to 7.72
with an average value of 7*55 and a standard error of + 0.016*
After
four hours of temperature maintenance, the pH range was from 7.30 to
7*83, the average for the period being 7*52 with a standard error
of
0.0197*
When the temperature returned to normal the pH values
decreased to approximately their control levels, « the range being
7*32 to 7*51 with an average value of 7*418 + 0.0095.
Disoussion*
It is apparent from the data obtained that an artifi­
cial fever causes a significant elevation of the blood pH.
Cajori,
Crouter, and Pemberton (23) believe that the increase in alkali reserve
is caused by a migration of base from the tissues into the blood.
The
loss of COg by the body through the lungs and sweat during the fever is
undoubtedly of prime importance in increasing the alkalinity of the
blood.
The skin is a path of COg loss of some importance•
Ihese
investigators state that three to four per cent of the total COg lost
during a period of raised body temperature and active sweating is
eliminated by the skin.
Koehler (80) seems to think there is a direct
correlation between cyanosis and certain types of alkalosis.
We find
that cyanosis is not an uncommon occurrence in patients undergoing
fever therapy.
It probably indicates cardiac embarrassment*
Koehler
(80) believes that the fever alkalosis is due to the increased lung
ventilation and the rapid elimination of COg from the blood, thus causing
a COg deficit, which in turn results in the passage of Na ion into the
tissue fluids and partially into the urine.
On the other hand, Landis,
Long, Dunn, Jackson, and Meyers (89) do not believe that hyperventilation
- 66
-
is the sole cause of the change in pH but is probably dependent on
several factors, such as the kidneys, the degree of sweating, and
lactic acid formation*
The latter faotor, they seem to believe, may
be of some importance in some cases.
In one
of their tables they show
that the greatest change in pH occurred with the least hyperpnea, and
the smallest change in pH with the greatest ventilation.
They state
that there is a much closer relationship between blood pH and the
alveolar COg.
These investigators used hot water baths as a means of
raising the body temperature and encountered tetany in most of their
subjects*
In the period of tetany, there occurred on two occasions,
when two blood samples were taken during the stage of severe symptoms,
a fall of pH with a simultaneous fall in COg content*
This, they
point out could only be due to an organic acid such as lactic acid
formed by the tissues and poured into the blood stream.
Bisohoff and
co-workers (16) found that the greatest changes in pH occurred with the
greatest degree of hyperpnea.
Bischoff, Ullmann, Hill and Long (17) as well as Cajori (23)
do not agree with Koehler that an anoxemia exists in the presenoe of
a fever alkalosis*
of the
They found that there is always an increase in pH
blood* As a result of the lowered COg tension in the blood, and
increased pH, the stability of the oxyhemoglobin incree.ses.
If the
circulation and the metabolism did not increase at the same time, the
question would be quite simple*
With an increase in circulation, how­
ever, the tissues are exposed to more blood per unit of time, so that
the effect of the stability of the hemoglobin might be offset if the
demand for more oxygen due to increased metabolism were not too great.
Conclusionss1*
T
Thirty-five experiments were made to ascertain
thechanges occurring in the blood pH of ten
- 67
patients while undergoing artificial fever therapy for the
treatment of chronic, infectious arthritis*
2*
A rectal temperature of 104°-1Q5°F was secured and maintained
for four hours during each experiment and then permitted to
return to normal*
3*
Artificial fever produced by physical means elevated the blood
pH in the absence of tetany and oardiac embamassment*
4*
The average pH value of 7*55 found at a temperature of 104° F
would seem to indicate a state of uncompensated alkalosis*
5*
With a return to normal temperature there was a return of the
blood pH to its former level*
-
68 -
TABLE XXV
THE EFFECT OF ARTIFICIAL FEVER ON BLOOD pH
Complete Data
An#
it
AJk:.
M
U
It
It
Ko.
»
it
i
t
M.
11
it
t
t
it
0.
M
tt
A*
tt
B.
it
tt
tt
Uk.
tt
G.
«
t
t
tt
it
K*
tt
Averages
cr +
Before
Ht.
7.43
7.46
7.39
7.48
7.46
7.43
7.39
7.52
7.52
7.46
7.48
7.50
7.41
7.30
7.40
7.30
7.41
7.39
7.46
7.40
7.35
7.32
7.42
7.35
7.36
7.34
7.39
7.48
7.41
7.40
7.41
7.39
7.50
4 Hr s.
After
7.56
7.35
7.72
7.53
7.35
7.61
7.61
7.58
7.66
7.51
7.62
7.60
7.61
7.70
7.51
7.56
7.57
7.49
7.44
7.50
7.50
7.48
7.50
7.49
7.62
7.65
7.66
7.45
7.62
7.54
7.62
7.41
7.63
7.30
7.52
7.53
7.48
7.30
7.52
7.46
7.42
7.49
7.57
7.56
7.62
7.63
7.40
7.83
7.51
7.53
7.60
7.40
7.49
7.49
7.44
7.42
7.49
7.59
7.71
7.70
7.61
7.49
7.59
7.41
7.47
7.37
7.48
7.48
7.44
7.37
7.40
7.50
7.51
7.41
7.50
7.40
7.42
7.46
7.39
7.44
7.42
7.33
7.37
7.32
7.42
7.35
7.34
7.35
7.40
7.47
7.44
7.39
7.43
7.50
7.416
7.55
7.52
7.418
0.01
0.016
0.0197
0.0095
- 69 -
TABLE XV
SUMMARY OP BLOOD pH DATA
PH
Minimum
and
Maximum
Average
of
33 De terminator a
cr +
Increase
over
Control Period
Control
Period
7.30 7.52
7.41
0.01
Temperature at
7.35 7.72
7.55
0.016
0.14
End of 4 hours of
Temp, at 104° 7.30 7.83
7.52
0.0197
0.11
Normal Temp.
Return
7.418
0.0095
0.003
104° P
7.32 7.51
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- 71
B*
The Specific Gravity of Blood
Introduotion>
In an earlier communication (110) we made red
cell counts as an index of blood concentration*
The following study
was undertaken to determine the validity of those observations.
Literature >
Several investigations (4, 6, 20, 91, 110) have
been made, chiefly on animals, a few on human subjects, but none under
comparable conditions, on the effect of fever on hemoconcentration.
Several workers (110, 28, 47, 116) have explained the blood count
changes as due to a concentration phenomena*
Decreases in plasma volume
have been observed after artificially induced fever in animals (95)*
Gibson and Kopp (50) have made observations on blood plasma volume, as
well as on the total blood volume changes, following fever induction by
foreign proteins, Conventional Diathermy” (cuff technique), the Kettering
hypertherm, and radiant heat cabinets#
Methodst
Thirty blood density determinations were made on eleven
patients by means of the Barbour and Hamilton (5) falling drop method*
A standard solution of potassium sulphate of known density is the
basis for the determination*
The proper xylene-bromobenzene solution
is held in a tube of standard bore.
Just below the surface of the
xylene-bromobenzene solution a drop containing exactly 10 mm* of standard
solution (l*056l) is released from the pipette*
The falling time over
a distance of 30 cm# is determined by a stop watch#
density is tested similarly*
Die fluid of unknown
Hie computation is made then by means of
a nomograph*
All of the patients were suffering from arthritis#
Their reotal
temperature was elevated to 104° F in approximately one to two hours,
and maintained at this level for four hours, when their temperature was
- 72
permitted to return to its prefebrile level*
-
The experiment required
from seven to eight hours for completion*
A 0*4 per cent of KaCl solution was given by mouth and the amount,
and rate, regulated solely on the basis of the physician*s judgement
as to the patient*s requirements*
Blood was drawn from the median basilic vein of the arm with the
usual care and tested immediately*
Determinations were made just prior
to treatment, when the patient’s temperature reached 104° F, four hours
later, and finally after the patient's temperature had returned to normal,
usually three hours after the four hour febrile period*
Forty determinations on the percentage change of blood solids were
made on ten patients —
gravity determinations*
only one of whom was included in the specific
The follo\ving method was used*
paper was out into strips twenty-six millimeters wide*
A special filter
These were
immersed in acetic acid, then in distilled water at 50 - 60° C, and dried
at room temperature*
These strips were then cut into pieces 16 x 26 mm*
and placed in a weighing phial glass stoppered*
oven for one hour at 100° C and then weighed*
This was placed in an
Blood was then placed in
sufficient amount to be completely blotted up by the filter paper, and
weighed again*
Finally, sifter drying in an oven at 100° C for an hour,
it was weighed again*
The percentage difference of the weight before
and after drying was recorded during the various phases of the treatment
as described before*
Re suitsi
Table XVII gives the complete data*
Table XVIII gives
a summary of the average values and the results of a statistical analysis*
The greatest ehange occurred during induction of the fever, but inasmuch
as the only significant figure was in the fourth decimal place, we have
- 73 considered the change as insignificant*
At no time during the experiment
did we find any significant change in the specific gravity of the blood*
Table XVIIa and XVTIIa give the complete data and summary of the
percentage change in blood solids*
There is apparently a real signifi-
cant difference after the temperature of 104° F had been maintained
i(
for four hours, and a somewhat less, but still significant, change when
ij
the temperature reaohed 104° F*
Disoussiont
According to Howell (8 ) the specific gravity of
human blood may vary from 1*041 to 1*067, the average being 1.055*
All of our determinations came within this range*
Gibson and Kopp (50) state that one of the major physiological
effects of artificial fever induced by physical means is a diminution
in circulating blood volume.
This is the result, they state, of an
uncompensated loss of large quantities of water from the blood stream,
resulting in a reduction in the plasma portion of the blood and hemoconoentration*
This effect, they claim, is slightly augmented by
small increases in the number of circulating red cells*
They further
state that the degree of reduction in plasma volume is determined by
the difference in rate of outflow by skin, lungs, and kidneys, and of
effective absorption of fluids administered*
If insufficient fluids
are given, the tissue fluids of the body are drawn upon for the main­
tenance of plasma volume with resultant dehydration*
Undoubtedly the blood density will be dependent upon the balance
of fluid loss and fluid gain, and one might readily criticize our work
in that we did not control these variables*
As previously stated, we
gave fluids both in regard to quantity and rate, according to our judge­
ment of the patient's need*
However, as can be seen from our data, the
- 74 -
total amount of fluid ingested by each patient did not vary a great
deal in most instances, and we were primarily interested in ascertain­
ing ehanges in hemoconoentration under the conditions of our therapeutic
regime, it being well demonstrated that hemoconcentration occurs with
fever when no fluids are given.
The rate and degree of fluid absorp­
tion undoubtedly is not the same in eaoh patient, and this factor alone
would be difficult to dispose of with ease.
Another extremely variable
factor is the amount of perspiration,which will vary not only from patient
to patient, but with the same patient from treatment to treatment (ill).
Gibson and Kopp (50) state that water may pass out of the blood stream
more rapidly than it can be absorbed from the intestinal tract, and this
fact has an important bearing on the determination of the optimal rate
of fluid administration.
It is also interesting to note that these
workers found that there was a direct relationship between the gross
water loss and the environmental temperature of the patient.
The water
loss was greatest in those cases in which the differential temperature
between the patient's body and his environment was highest, and least
in those cases in which it was lowest.
own (Table V, page 19).
This observation confirms our
The environmental temperature of our patients,
once the temperature plateau was reached, was usually below that of
the rectum, or at the same level.
This temperature was lower, somewhat,
than the lowest recorded by Gibson and Kopp, and may in part account
for the insignificant changes which we found in the specific gravity
of the blood.
Conclusions?
—
—
1. A temperature of 104° F, maintained for four
hourg wag induced in ten patients by means of the
induototherm, and heat-insulating cabinet. Fluid
containing NaCl was given in amounts and at a rate
determined to be proper by experience*
- 75
2,
Qnoe the temperature plateau m s reached, the patient*s
environmental temperature was usually maintained below,
or at, the level of the rectum. This we believe to be
of considerable importance,
3,
Thirty determinations of the specific gravity of the blood
were made before, at the temperature plateau, four hours
later, and finally when the rectal temperature had returned
to normal, No significant changes in the specific gravity
of the blood were found,
4,
Apparently hemoconcentration is not the mechanism involved
to account for the changes occurring in the blood cell
count, when fluids axe administered during the course of
treatment,
5,
The percentage change of the blood solids as a result of
fever showed significant differences during the entire
febrile period.
- 76 -
TABLE XVII
DATA OF BLOOD SPECIFIC GRAVITY
i Patient
;
1.
Initial
Ht. of
Fever
4 Hr s.
Fever
Final
Total
Fluid Intake
1*0546
1.0519
1.0546
1.0544
1.0568
1.0557
1.0571
1.0572
1.0574
1.0564
1.0558
1.0525
1.0571
1.0557
1.0558
1.0533
1,370 cc »
2,750 it
3,500 tt
3,300 tt
1.0507
1.0494
1.0494
1.0502
1.0452
1.0518
1.0513
1.0489
1.0497
1.0474
1.0497
1.0479
1.0494
1.0471
1.0486
1.0459
1.0469
1.0491
1.0444
2,500
2,800
2,575
3,300
2,625
1.0534
1.0548
1.0560
1.0522
1.0526
1.0574
1.0546
1.0551
1.0552
-
1.0564
1.0581
1.0571
1.0542
1.0530
275
820
1,565
2,440
2,385
1.0567
1.0560
1.0586
1.0591
1.0679
1.0558
1.0595
1.0620
1.0615
1.0614
1.0596
1.0727
1.0604
1.0596
1.0615
1.0617
1.0587
1.0609
1.0615
1.0619
1.0623
1.0585
2,000
2,000
800
2,000
3,460
1,100
it
1.0561
1.0556
1.0559
1.0553
1.0590
1.0555
1.0578
1.0573
1.0563
1.0559
1.0565
1.0595
1.0586
1.0557
1.0555
1.0589
2,500
2,600
1,600
-
tt
1.0539
1.0526
1.0485
1.0537
1.0538
1.0528
1.0539
1.0489
1.0507
2,200
2,075
1.900
—
tt
1.0522
1.0547
1.0531
1.0526
1.0513
1.0523
7#
1.0521
1.0550
1.0505
1.0492
3,500
tt
8.
1.0520
1.0521
1.0557
1.0582
1,845
tt
2*
3.
4.
5.
6*
mm
mm
1.0557
1.0574
1.0555
1.0573
mm
tt
tt
tt
tt
»
n
it
tt
it
it
tt
it
tt
tt
tt
tt
tt
tt
tt
TABLE XVII A
DATA OF PERCENTAGE CHANGE IN BLOOD SOLIDS
;ient
aber
■*'-'~T
Back to
Normal Temp.
Total Fluid
Intake
During Treatment
Initial
Temperature
Reached
104° F
4 Hours
Temp.
104 F
1.
21*13
19*23
19*29
18*51
19*68
19.18
20*72
20.12
22.57
22.44
20.97
20.18
21.07
21.27
21.16
20.08
20.40
19.97
20.52
20.14
20.65
20.78
20.14
19.76
19.84
19.06
20.72
19.62
2,100 cc.
1,800 ti
2,000 tt
2,600 ti
2,400 tt
2,500 i»
2,000 ti
2.
18*51
19*02
18.06
17.72
18.80
19.34
16.59
18.29
20.42
19.90
17.32
18.54
18.68
19.31
15.93
16.26
2,050
2,500
2,800
2,575
17.28
19.58
19.65
17.92
18.65
20.14
20.50
17.65
17.77
20.76
20.05
20. 33
22.89
19.55
22.79
17.74
22.51
2,000
3,000
-
-
25.15
24.30
3,200
3,200
17.84
19.14
16.52
17.71
20.72
15.73
19.43
18.99
19.30
16.59
17.62
18.65
17.50
17.16
17.57
2,300
2,800
3,880
2,200
2,500
2,500
2,500
II
16.70
19.34
17.91
18.16
17.31
21.68
18.44
20.62
20.13
18.87
18.76
17.85
17.28
19.58
19.65
17.92
18.65
20.14
20.50
17.65
17.77
20.76
20.05
20.33
22.89
19.55
22.79
17.74
22.51
tt
25.15
24.30
2,000
3,000
3,000
3,200
3,200
20.72
18.38
21.12
21.23
21.50
20.42
18.78
20.25
19.27
19.86
21.34
19.22
2,000
3.000
2.000
tt
It
18.79
18.62
16.92
19.11
17.98
18.61
17.35
18.66
17.01
16.96
17.53
18.43
18.05
20.56
14.60
18.94
2,900
2,000
2,200
3,000
3.
4.
5.
6*
7.
-
(Continued )
w
tt
It
tt
tt
It
tt
tt
tt
tt
tt
tt
tt
It
tt
tt
tt
tt
tt
tt
tt
n
tt
78 -
TABLE XVII A
I
Patient
Number
(Cont.)
Perceirt Solids - Blood Concentration
Temperature 4 ftours
Back to
Temp.
Initial
Beached
Normal Temp.
104° P
104° P
8.
loxai riuia
Intake
During Treatment
20*19
13*52
19*92
19*89
19*85
18.82
19.04
16.54
18.99
21.57
19.08
18.50
19.59
20.35
18.22
17.69
2,105
*
9.
19.74
20.76
23 .04
21.93
2,000
*
10*
18*79
18.12
19.92
19.56
665
41
41
39
18*85
19.52
19.70
19.58
0.17
0.24
0.27
0*39
Humber of
Observations
Average
<r +
40
570 cc.
570 w
—
79 -
TABLE XVIII
SUMMARY OP BLOOD DENSITY
Elapsed
Time
in
Hours
Average
of 30
Determin­
ations
cr +
Control
0
1.0536
.0005
-
Temperature
Reached 104° F
2
1.0555
.0007
.0018
.0019
4 Hours Temp*
104-104.6° F
6
1.0552
.0007
.0018
.0016
Temp* Returned
to Normal
8
1.0544
.0009
.002
.0008
2 5“
Diff, +
Change +
from
Control
-
- 80 -
TABLE XVIII A
SUMMARY OP PERCENTAGE CHANGE IN BLOOD SOLIDS
Elapsed
Time
in
Hours
Average
of 40
Determin­
ations
Control
0
18.85
0.17
Temperature
Reached 104° P
2
19.52
0.24
0.60
0.67
4 Hours Temp9
104 - 104.6® F
6
19.70
0.27
0.64
0.85
Temp# Returned
to Normal
8
19.58
0.39
0.84
0.74
0“ +
2 CT
Diff. +
Change Over
Control
+
-
- 81
C.
Blood Count
The following study was made on fifteen patients suffering from
either general paresis, arthritis or asthma.
Method*
The patients were subjected to a rectal temperature of 104°
to 105° P for a total of eight hours.
The finger of the patient was punc­
tured with a sharp stylet and the first few drops of blood discarded before
and after treatment.
During treatment blood samples were collected from
the ear lobe because of convenience.
Blood samples were collected before
treatment, at the height of the fever, at the termination, and twentyfour hours after treatment.
In some instances determinations were made
during one single treatment, but in others successive observations were
made during successive treatments on the same individual.
Thus, as many
as four determinations on separate occasions were taken on the same patient.
Re suits 8
The complete data of the fifteen patients is submitted
in Table XIX and the average values are found in Table XX.
There is a slight increase from 4.7 to 5.3 in the red cell count.
A marked leukocytosis is apparent during the febrile period, but has
disappeared at the end of twenty-four hours.
maximum at the height of the fever.
The leukocytosis is at its
There is an increase of the poly­
morphonuclear neutrophiles and a steady increase until, at the twenty-four
hour period, the increase is at the maximum height.
During treatment
there is a lymphopenia, but twenty-four hours after treatment the lympho­
cytes had returned to their prefebrile level.
There is no significant
change in the remaining cellular elements.
Discussion*
reports.
These results are in agreement with most of the previous
We were unable to verify the increased eosinophilia as reported
by Neymann and Osborne.
In our first report (Neym&nn and Osborne, 110)
- 82
we stated that the slight increase in the erythrocytes could readily
be attributed to blood concentration#
Call let and Simonds (22) subjected mice to dry heat at 60° C at
intervals of ten days and found a marked leukopenia followed by a marked
rise in the number of white cells soon after the heating, and which
reached a maximum from ten to fourteen days later#
Knud son and Schaible (78) working with dogs found a considerable
increase in red cells and hemoglobin#
They stated they found a marked
increase in immature forms of red cells*
They also reported a marked
increase in total white cells, due to an absolute and relative increase
in the polymorphonuclears#
The lymphocytes and eosinophiles were decreased,
but changes in the monocytes were less marked and less constant#
On the other hand, Hinsie and Carpenter (62) found a slight reduction
in red blood cells as well as adecrease in hemoglobin*
An increase of
polymorphonuclears and a relative decrease in lymphocytes was found.
Hinsie
and Blalock (6 ) reported a seventy-five per cent increase in the leukocyte
count, which usually reached its peak at the end of the ninth hour, regain­
ing its normal level at the end of about twenty hours*
The leukocytosis,
they stated, was characterized by an increase in the percentage of poly­
morphonuclears at the expense, chiefly, of the lymphocytes#
found an increase in the non-filamentous forms#
They also
Tenney (144) made similar
observations#
Feinberg, Osborne, and Steinberg (47) reported an average increase
of red blood cells#
Eighteen oases showed an increase of leukocytes,
neutrophilic polymorphonuclears and transitional cells.
strated a decrease in the eosinophile cells.
entirely on asthmatics#
They also demon­
This investigation was made
Perkins (114) made a study on general paretics, giving ten conse­
cutive fever treatments in two weeks.
The patient’s temperature was
made to simulate a malarial fever curve.
These patients therefore were
not submitted to the usual fever curve used by other workers in this
disease.
At the termination of the tenth treatment, he concluded that
the only effect of the treatment on the red cell count was to lessen
the lability of the cells which characterized them prior to treatment.
The leukocytosis persisted for three days.
Bierman (14) found an initial reduction of twenty to thirty per
cent in the leukocyte count during the first two hours of fever induction.
This initial decrease was followed by a leukocytosis which reached a
maximum in about six to nine hours.
The increased white cell count,
he attributed mainly to changes in the total number of neutrophilea, of
which the staff neutrophiles showed greatest increase*
He showed an
increase in polymorphonuclears and a corresponding lymphopenia.
He also
reported an increase in red cells and in many instances a marked increase
of the immature forms.
These changes, he concluded, indicated a stimula­
tion of bone marrow*
Phillips (115) stated that he found an increase of approximately
ten per cent in the red cell count during hyperpyrexia which was only
temporary.
He found an increase in the total white cells.
phonuclears showed a ten to fifteen per cent increase.
The polymor­
Phillips did not
believe the changes found were due entirely to dehydration.
Cohen and Warren (30) studied ten p at lent s during a total of eleven
treatments.
The temperature was elevated to 40*5° - 41.6° C for five and
three quarter hours.
for twenty-one hours.
One patient was maintained at a temperature of 41*6°
After the control, observations were made every
- 84 -
hour once the temperature reached the desired temperature level.
Determinations were made for several hours following termination of
the treatment, and during which the patient's temperature was normal*
Blood studies were then continued at intervals until the patient left
the hospital*
A leukocytosis was found in every case; the maximum change,
the onset, duration, and the extent of the change in the fever period
varied from patient to patient*
A relative and absolute increase of
|
;
!polymorphonuclear leukocytes was observed during or immediately follow­
ing the febrile period*
There was a substantial relative and absolute
increase in immature polymorphs in six of the eleven cases*
The red
blood cell count showed a slight rise, and so did the hemoglobin, during
or immediately following the period of fever.
immature red cells were found.
In one single instance
These investigators stated that these
observations suggested a mobilization into the circulation of available
and nearly mature cells of the myeloid and erythrocytic series as a
result of fever, while the cells of the lymphoid series decreased
during this period*
lymphocytes*
They could offer no explanation for the fall in
They stated it was not clear whether these cells are
stored somewhere in the body or take some specific part in attacking
the pathological process present, or are destroyed by the febrile reaction.
Simon (138) studied ten patients during seventy-one treatments.
He found a leukocytosis and increased hemoglobin.
due in part to blood concentration.
This he thought was
He reported an increase of thirty
per cent of the non-filamentous cells.
It is evident, he stated, that
the bone marrow responds more quickly than the lymphatic system, as
shown by the relative decrease of lymphocytes.
Stimulation of the
lymphatic system occurs, he stated, but more slowly than the white
cell forming organs*
85
Krusen (86,87) reported one hundred patients whose temperature
ranged from 104° F to 106.8° F for three to seven hours.
He found a
marked leukocytosis and a slight increase of the red cells which he
believed due to blood concentration.
globin.
No change was found in the hemo­
Like other investigators, he observed an increase in the neutro­
phils and a decrease in the lymphocytes, which he stated could not be
due to blood concentration.
He noted a slight shift (2.7 per oent)
to the left, although not comparable to the marked shift produced by
malarial inoculations*
In discussing the work of Krusen, Hargraves
stated,
wthe work did not take into consideration the succession of
changes that occur for the next twenty hours following the
onset of fever, and hence might be misleading and mask the
true post-febrile picture. If this period is studied with
multiple serial counts, say at intervals of half an hour,
a rather constant response will be found. The response is
so constant that we feel that the term febrile hemogram is
justified. It is characterized by a post-febrile leukocy­
tosis, the duration and extent of which is an individual affair,
and bears a relationship to the duration and height of the
fever. The peak of leukocytosis is dependent on a poly­
morphonuclear increase and often goes as high or higher them
40,000 leukocytes per ou. mm. total white cell blood count.
It is here that the younger cells, as shown by a changing
filament - non-filament ratio, are increased; this is evi­
dence of bone marrow delivery and not a redistribution phe­
nomenon. As the polymorphonuclear peak declines, the total
count is usually sustained, or partially sustained, by an
influx of monocytes. The last cell to reappear in numbers
is the lymphocyte, which usually assumes lymphopenic pro­
portions during the the episode of fever*M
Doane (36) states that the majority of the cells making up the
post-febrile leukocytosis are polymorphonuclear neutrophiles newly
delivered by the bone marrow as shown by their youth.
This reaction
he believed to be by no means the most important from the standpoint of
the fundamental body defenses.
He demonstrated by lymphnode studies
during hyperpyrexia that there was a destruction of lymphocytes, and
86 ! by the return to the circulation of very young cells*
He believed
there was probably in human patients some destruction or redistribu­
tion of monocytes as shown by a delayed monocytosis made up primarily
of younger forms*
He stated that the hemograms following malaria and
I B typhosis are quite different from those observed during fever induced
by physical means*
■j
The shift to the left in the neutrophilic granulo-
cytes in malaria is outstanding and the appearance of olasmatocytes in
the peripheral blood has been observed in no other type of fever study*
Palitz (113) induced artificial fever in four unanesthetized dogs,
raising their temperature from two to four degrees Fahrenheit maintained
for one or two hours*
He reported an absolute and relative increase in
the formed elements of the blood*
These changes, he found, did not
occur in the spleneotomized animal.
The increased red cell count, he
thought, could be explained by contraction of the spleen*
He stated
that contraction of the spleen might be due to a nervous mechanism (a
view held by Baroroft and Elliott), or a shift of blood from the viscera
to the periphery, or an oxygen want*
Experiments which consisted of
adding concentrated red cells from the spleen to the circulation were
performed causing a displacement of fluid from the serum possibly in
order to maintain a constant blood volume*
Doan (36) in an endeavor to determine whether the increase in
circulating cells was due to splenic contraction subjected a patient
to an adrenaline test during hyperpyrexia, following which the blood
picture showed little change other than a moderate increase in lympho­
cytes*
He also subjected a spleneotomized patient to four hours of
fever of 106 to 107° F*
A leukocytosis of 50,000 was reached, he
stated, by the same tide-like variations as in normal individuals*
87 Cyanosis has been recognized as a stimulus to the spleen and bone
marrow*
Doan had the opportunity to observe a patient who became
excited, cyanosized and finally passed into an epileptic seizure.
He
reported that such an episode had no significant effect on the curve
of leukocytosis*
Sloan and Doan (139) 1940 have recently shown that artificially
induced fever decreased prothrombin and fibrinogen.
They reported their
results on four young adult individuals, normal except for some type of
gonorrheal infection*
Fever with a temperature of 104° to 107° F was
induced with the Kettering Hypertherm and maintained from nine to ten
hours, with a resultant relative and absolute throiribooytopenia*
They
found megakaryocytes in the bone marrow with definite cytoplasmic and
nuclear damage*
The degree of thrombocytopenia, they stated, depended
upon the extent of the megakaryocytic damage*
They pointed out that the
pathogenesis of hemorrhage in artificially induced fever may be followed
in orderly sequence; the elevation of body temperature results in anoxia
and a depletion of liver glycogen; these factors may result in hepatic
and megakaryocytic damage, following which there is a decrease in pro­
thrombin and circulating platelets*
be decreased*
Fibrinogen, they stated, may also
They pointed out that the regeneration of the damaged
parenchymatous tissues apparently takes place quite promptly and com­
pletely, the ohange being reversible*
Their patient’s normal equili­
brium was reestablished between five and seven days*
The most marked
decrease of prothrombin occurred during the twenty-four hour period
following treatment*
Conclusions; 1* Differential blood counts were made of fifteen
~ patients before, during, and following hyperpyrexia
treatments*
- 88 -
2.
Blood samples were studied before, at the height of
temperature, at the termination, and twenty-four
hours after treatment.
3.
There was a slight increase in the red cell count.
A leukocytosis was present in all cases.
4.
There was an absolute and relative increase of the
polymorphonuclear neutrophils and a decrease of
lymphocytes. Other cellular elements showed no significant
change.
39
TABLE XIX
EFFECT OF HYPERPYREXIA ON BLOOD COUNT
Complete Data
Patient No#
Red Cell
Count in
Millions
White
Cell
Count
Polys*
lymph. Mono.
Trans.
Basoph. Eos in.
1# Before
After
4.2
5.6
6,000
12,300
61
81
33
14
4
3
2
2
2# Before
After
4,0
4.4
7,000
9,200
65
70]
23
21
10
8
2
1
3# Before
After
4.2
6*2
16,000
18,000
73
81
21
15
4
2
2
2
4# Before
After
4#8
5.2
4,400
10,500
65
70
25
25
8
5
2
0
5# Before
After
4#3
4.7
7,500
8,400
68
71
22
24
9
5
1
0
6# Before
After
5*2
4.8
8,000
9,200
65
69
25
25
8
6
2
0
7# Before
After
5.2
4.9
10,000
11,500
70
69
23
25
5
3
0
1
8# Before
After
4.8
4.3
14,550
8,500
65
60
30
28
5
8
9# Before
After
3.8
3.7
8,800
9,200
61
74
33
23
2
2
-
5,800
9,700
9,300
54
79
78
44
18
18
0
0
1
3.5
4.5
4.3
5,200
14,000
7.400
63
72
60
35
26
38
4.0
4.7
5.1
5,400
17,100
5,700
56
78
62
4.3
5.9
6.4
8,700
12,800
9,300
73
71
60
10# First Treatment
Before
H. of Fever
24 Hrs. After
Fourth Treatment
Before
H# of Fever
24 Hrs. After
Eighth Treatment
Before
H. of Fever
24 Hrs. After
11. Fourth Treatment
Before
H# of Fever
24 Hrs. After
1
0
3
1
1
1
2
0
0
0
1
2
1
0
1
0
0
0
0
1
1
0
1
0
2
42
20
37
0
0
0
1
2
0
0
0
0
1
0
1
25
28
36
1
0
0
1
1
2
0
0
0
0
0
2
(Continued)
- 90 -
TABLE XIX
Patient No.
11. Sixth Treatment
Before
H. of Fever
24 Hrs. After
Eighth Treatment
Before
H. of Fever
24 Hrs* After
12. First Treatment
Before
H. of Fever
24 Hrs. After
ted Cell
<Jount in
Millions
(Continued)
White
Cell
Count
Polys.
4.3
4,9
5.0
8,900
12,200
7,400
55
71
65
27
28
33
2
1
1
1
0
0
0
0
0
5
0
1
5.1
5.7
9,400
12,000
9,200
60
65
47
38
32
48
0
0
0
0
2
2
0
0
0
2
1
3
4.3
4.8
4.6
8,000
8,100
6,800
42
73
43
56
25
54
0
0
0
2
2
1
0
0
0
0
0
1
5.7
5.6
6.3
8,800
15,900
14,000
51
67
63
47
32
36
0
0
0
1
0
0
0
0
0
1
1
1
6.4
5.5
4.9
8,800
12,900
8,000
54
83
63
42
16
35
1
0
0
3
1
1
0
0
0
0
0
1
5.3
7,500
1
0
0
-
41
26
1
-
-
-
-
-
0
4
0
0
lymph. Mono,
Trans,
Ehsoph. Eosin.
13. First Treatment
Before
H. of Fever
24 Hrs. After
Fourth Treatment
Before
H. of Fever
24 Hrs. After
Sixth Treatment
Before
H* of Fever
24 Hrs. After
Eighth Treatment
Before
H. of Fever
24 Hrs. After
-
11,190
57
70
5.6
5.4
5.3
8,500
11,600
7,000
55
69
60
45
26
40
0
0
0
0
0
0
0
0
0
0
3
0
14. First Treatment
Before
H. of Fever
24 Hrs. After
5.3
5.9
6.3
6,800
15,400
7,100
62
79
67
35
21
40
0
0
0
3
0
2
0
0
0
0
0
1
4.9
4.3
9,200
6,300
6,900
49
74
48
50
26
47
0
0
1
0
0
3
0
0
0
1
0
1
4.8
-
5,600
9,900
-
47
60
44
37
4
1
-
-
3
1
-
-
0
1
-
2
0
-
4.7
8,900
31
65
0
1
0
3
15. First Treatment
Before
H. of Fever
24 Hrs. After
Second Treatment
Before
H. of Fever
24 Hrs. After
Sixth Treatment
Before
(Continued)
91 -
TABIE XIX
Patient No*
15• Sixth Treatment
Before
E* of Fever
24 Hrs* After
Eighth Treatmen
Before
H* of Fever
24 Hrs* After
(Continued)
Red Cell
Count in
Millions
"White
Cell
Count
Polys.
5.1
-
13,000
8,100
53
33
45
62
4.3
4.5
4.6
7, 700
9,700
7,400
4*9
60
59
46
37
42
Trans*
Basoph
Eosin*
0
0
0
1
0
0
2
3
0
0
0
4
2
1
0
0
0
1
1
3
Lymph* Mono*
- 92
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- 93 D*
The Carbon Dioxide Combining Power of the Blood
"While studying the physiological effects of hot water baths on
human subjects, Hill and Flack (60) in 1909 found a rise of body temper­
ature was accompanied by a reduction of the alveolar carbon dioxide tension.
,A decrease in the COg-combining power of the blood has been observed
by a number of investigators who used external heating methods.
The first blood chemistry studies to appear, in which the method
of internal heating was employed were those of Bischoff, Ulmann, Hill
and Long (17) in 1930, and by Bischoff, Long and Hill (16) in 1931.
They found a fall in the total COg content of the blood of from four
to twelve volumes per cent.
Mortimer (102) in 1931, working with dogs
found a decrease in the plasma CO2 combining power in dogs and man
amounting to as much as twenty per cent.
In the same year, Neymann and
Osborne (110) report ten observations made on a single individual
showing a decrease in the plasma COg combining power of the blood.
Feinberg, Osborne and Steinberg (47) while studying the effects of
artificial fever in the treatment of intractable asthma reported that
the CO2 combining power of the plasma decreased.
They made seventy
determinations and the average decrease was found to be eight volumes
per cent.
They also state that in three instances there was an increase
of the CO2 combining power of the blood with high fever greater than
ten volumes per cent.
In fourteen instances the change was less than
five volumes per cent either way.
Hopkins (64) in 1934 made chemical
blood studies of twelve patients using the hot water bath to induce
hyperpyrexia and reported a deorease of the total CO2 combining power
amounting to five volumes per cent.
Krusen (86) using the Kettering
Hypertherm for the production of artificial fever reported in 1935 that
the average decrease of the CC>2 content of the blood for the average
of one hundred fevers at a temperature of 104° to 106.8° F was ten
'.volumes per cent.
Philips and Shikany (116) in 1935 reported on the
ji
ijblood chemistry of nine patients undergoing fever therapy for the
treatment of asthma.
Four of their patients showed a decreased COg
content of alveolar air, one an increase, and four no change at all.
The following study was undertaken while treating general paretics
with artificial fever.
Methods
Twenty-six determinations were made on six patients while
undergoing artificial fever therapy for the treatment of dementia paraly­
tica.
The body temperature was raised by means of high frequency current
from 104° to 106° F.
A temperature plateau of at least 104° F was main­
tained for eight hours.
Blood samples were drawn just prior to the
^beginning of the treatment and then immediately after treatment.
The
carbon dioxide capacity of the plasma was determined by the Van Slyke
and Cullen method.
The blood samples were collected under a neutral
mineral oil and a twenty-one gauge needle was used to insure a quick
flow of blood from the median basilic vein of the arm.
Results:
Table XXI.
The data of the twenty-six observations are shown in
The average carbon dioxide combining power before treatment
was 51*4 volumes per cent.
The standard error being ± 1.4.
After
treatment the average dropped to 45.8 volumes per cent with a standard
error of Hh 1.2.
The average decrease of the carbon dioxide combining
power of the plasma, therefore, was 5.6 volumes per cent.
Twice the
standard error difference was HH 3*6 so that the decrease is quite sig­
nificant.
In five instances the C0g combining power of the blood plasma showed
- 95
no change after treatment, but the remaining twenty-five determinations
showed a decrease.
Discussion;
The interpretation of the pH and acid-base changes
in the blood is not easy.
This is due principally to the fact that
simultaneous determinations of pH, acid-base balance, and alveolar
carbon dioxide tension have not been made.
The interpretations are varied.
Bazett and Haldane (8) believed that the respiratory center becomes more
sensitive to carbon dioxide with a rise in body temperature and in this
manner produces a hyperpnea.
Koehler (80) thinks it is altogether pro­
bable that there is a definite oxygen want in the tissues resulting in
an anoxemic stimulation of the respiration.
He states that in spite
of a blood alkalosis the early view of the hydrogen ion stimulation of
respiration during anoxemia is a possible one.
Cajori, Crouter, and
Pemberton (23), on the other hand, do not agree with Koehler that there
is always an increase in the oxygen saturation of the venous blood
following the increase of the blood pH.
Bischoff, Long, and Hill state
that the ohange in the total carbon dioxide content of the blood is
readily accounted for by the shift of base to the blood proteins due
to the increased pH of the blood.
They found no evidence to believe
that the body attempts to compensate for the lowered COg tension by
lowering the alkali reserve.
In fact, both Cajori and Bischoff found
evidence of a slight increase in the alkali reserve.
It would appear
that the
ratio is changed with either no change, or a slight
HCOjj
rise in the BHCOg and a decrease in the HCOg. Bazett and Haldane (8)
reported that the symptoms of faintness, mental confusion and tingling
of the extremities was experienced by some of their subjects exposed to
the hot water bath.
One of the subjects had marked hyperpnea.
These
96 -
workers felt that while hyperventilation played an important role in
the production of these symptoms, a too rapid rise of the body temper­
ature might well be a contributing factor.
Landis, Long, Dunn, Jackson
and Meyer believed that the factors which seemed to influence the fall
in alveolar COg were chiefly the rate of ventilation, the type of
breathing, and the length of the experimental period.
They found, as
might be expected, that the total COg content of the blood was reduced
in general according to the degree of hyperpnea.
Bazett and Haldane found that the distressing symptoms, mentioned
in the preceding paragraph, were instantly relieved by breathing 8.5
per cent COg or by re-breathing expired air in a rubber bag.
This
indicates that acapnia or a depressed respiratory center was present
in their subject.
It would seem then, that instead of supplying the
very distressed patient with oxygen, as has been the tendency during
the last three years, that it might be far more effective to give 8.5
per cent of COg, or have the patient re-breathe air from a rubber bag.
In the presence of cyanosis, 5 per cent COg and 95 per cent oxygen would
be preferable.
The period of greatest hyperventilation is during the
fever induction and is particularly evident when the external heating
methods are used*
As a general rule, once the desired temperature has
been reached, the respiratory changes quieten down considerably, so that
the use of COg to increase the depth of respiration during the stages of
fever induction might be of considerable value in some instances.
Conclusion*
""
2.
1. Twenty-six determinations of the carbon dioxide
combining power of plasma were made on six patients
suffering from general paresis.
Bach patient was subjected to a fever of 104° to 106° F for a
period of eight hours. The fever was induced by means of
conventional diathermy.
Blood samples drawn under a neutral mineral oil were taken
before and after treatment» and the determinations made
by the Van Slyke and Cullen method.
Twenty-one determinations showed a decrease averaging 5.6
volumes per cent.
In five determinations there was no change.
The use of CO2 as a therapeutic measure during the induction
of fever has been discussed.
- 98 -
TABLE XXI
CARBON DIOXIDE COMBINING FOT3R OF BLOOD PLASMA DURING HYPERPYREXIA
Patient
Before
After
€2.0 oo*
57.0
55.4
55.4
53.8
54.65
57.0
55.4
55.4
49.7
54.6 co.
55*0
50.5
52.3
51.3
50.5
49.7
51.3
49.7
44.0
F. M.
58.0
33.5
E. w.
52.0
42.0
45.0
48.3
41.6
37.0
39.6
48.3
F. S.
52.0
52.0
60.0
36.5
41.6
54.0
48.0
41.0
51.0
47.0
36.5
37.9
49.0
48.0
R. T.
43.4
43.4
R. TST.
47.0
49.0
52.0
37.0
49.0
50.0
E. B.
I
!
Average
51,4 0“= + 1.4
45.8
Change • • • • • • • • • • • •
5 *6
................................. +__3.6
2
CT= + 1.2 Vol.%
— 99 "
Oni
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Non-Protein Nitrogen and Urea Nitrogen of the Blood.
Neymann and Osborne (llO) in 1931 noted an increase in the non-protein
nitrogen and uric acid in the blood of their paretic patients while
undergoing fever treatment.
In the same year Bischoff, Long, and Hill
(16) stated that they found a slight increase in the blood non-protein
nitrogen and urea nitrogen.
At about the same time Nasset, Bishop, and
Warren (105), working with anesthetized dogs, reported a marked increase
in non-protein nitrogen values.
Again in 1931 Knudson and Schaible (78)
reported that both the non-protein nitrogen and urea nitrogen of the
blood was increased to the extent that it was related to the temperature
of the dog and the duration of the experiment.
Mortimer (102) in 1931,
also working on anesthetized dogs, made a similar observation.
Feinberg,
Osborne, and Steinberg (47), studying the value of hyperpyrexia in the
treatment of asthma, reported in 1931 that they found an increased non­
protein nitrogen and urea nitrogen content of the blood in the majority
of their patients.
On the other hand, Cameron (24) in 1933 stated that
he found no change in the total nitrogen.
Phillips and Shikany (116) in
1936 state that they made a study of fifty consecutive asthmatic patients
while undergoing fever therapy and found very little variation in the
non-protein and urea nitrogen.
The following observations were made on a single individual because
so few repeated determinations on this one patient have been made while
undergoing fever therapy for the treatment of general paresis.
Method*
for
The patient was subjected to a temperature of 104° to 106° F
a period of eight hours for the treatment of general paresis. A
blood sample collected under a neutral mineral oil was taken from the
median basilic vein of the arm.
Estimation of the non-protein nitrogen
- 100
was made by the procedure of Folin-Wu*
made by the direct method of Folin.
Uric acid determinations were
Blood samples were collected
before and at the termination of treatment.
Treatment was given twice
each week at three to four day intervals.
Results*
The complete data is presented in Table XXII.
In
addition to the non-protein nitrogen and uric acid values, other de­
terminations that were made at the same time are also shown.
The
average value of the non-protein nitrogen increased from 22.5 mg. per
100 cc. to 26.4.
It is interesting to note that there was an almost
steady decrease in the n.p.n* from treatment to treatment, so that
while it was 32.4 mg. per 100 cc. at the beginning of the treatment,
it had dropped to a level of 15.0 mg. per 100 cc. by the tenth treat­
ment.
The uric acid Increased from an average value of 3.7 to 4.7 mg.
per 100 cc.
The value at the tenth treatment was higher than the
initial one.
Discussion*
The average increase of 3.9 mg. per 100 cc. of
blood are well within the range of the changes reported by Bischoff,
Long, and Hill (16)* namely, 2.3 mg. per 100 cc.
Feinberg, Osborne,
and Steinberg (47) reported an average increase of 2.8.
As previously
noted, both Phillips (115) and Cameron (24) state they found no change.
Animal experimentation on the other hand shows a far greater increase
in the non-protein nitrogen.
Khudson and Schaible (78) report that at
a maximum temperature of 107° F there was a ten per cent increase, while
at a temperature of 110° F the averaged value showed an increase of 75
per cent.
Nasset, Carr and Peters (106) noted in their dogs instances
of a two hundred per cent increase.
They attributed these high values,
however, to tissue destruction which frequently occurred at the site of
- 101 application.
Mortimer (102) found a change of 3.7 mg. per 100 cc. for
his animals, whose temperature varied from 106° to 109° F.
Nasset,
Carr, and Peters (106) stated that at temperatures beyond 107.6° F
there was a very marked increase.
Knudson and Schaible (78) expressed
the opinion that blood concentration might be the cause of the increased
non-protein nitrogen, although, as they stated, in many of the experiments
the increase was all out of proportion to the blood concentration.
Un­
doubtedly, another contributing cause was the increased basal metabolism,
also with the rise in body temperature an aliguria occurs, and the pro­
duction of metabolites, which continues whether the urine is excreted
or not, results in an accumulation in excess in the body.
Bischoff,
Long, and Hill (16) state that these increases were comparable to the
change in the oxygen capacity.
Nasset, Bishop, and Warren (105) believe
that the smaller increases in non-protein nitrogen are due to blood con­
centration.
According to Gibson and Kopp (50) the question of blood concentration
is far from settled.
They criticize the technique used by previous workers
in arriving at their conclusions, and one is led to believe that they
doubt whether there is any significant blood concentration.
The high
values in animal experimentation are undoubtedly influenced by tissue
damage by the high frequency current.
This tissue damage frequently
is in the subcutaneous layers and hence it is quite possible that many
of the early workers may not have noted these burns below the surface,
and as Nasset, Bishop, and Warren (105) stated, these might readily
account for the high values found in their dogs.
It must not be over­
looked, however, that the body temperature in the human subjects was
not carried to as high a level as that of the dogs, ©.lthough it was
- 102
sustained in most instances over a longer period of time*
In our patient there was no evidence to indicate that repeated
hyperpyrexia causes kidney damage.
What might happen in the presence
of a low margin of safety in the kidney is problematic.
Conclusions*
2.
1. There is a definite increase in the non-protein
nitrogen of the blood which in our observations
averaged seventeen per cent.
The uric acid showed an average increase of 1 mg. per 100 cc.
of blood.
- 103
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- 104
F*
Pulse Volume Changes*
An investigation by Johnson, Osborne, and Scupham (69) was the
only reference found in the literature in regard to the pulse volume
changes that occur during artificial fever.
The object of the problem
was to ascertain the extent of the peripheral vascular change during
hyperpyrexia, and at what temperature the maximum change occurred*
Methods
A study was made of one normal individual and a patient
with rheumatoid arthritis*
In each experiment the blood pressure,
respiration, heart rate and circulatory changes were measured at in­
tervals of fifteen to thirty minutes.
In addition, a continuous record
of the rectal temperature was obtained by means of a Brown Recording
Resistance Thermometer*
The circulatory changes were measured in one
finger by means of the Johnson air conduction plethysmograph.
The
plethysmograph consisted of a large test tube about three inches In
length, the open end of which was covered with dental rubber dam with
a hole sufficiently large to admit any finger snugly.
From the base
of the test tube a small glass tube was fused and connected to a glass
stopcock by means of rubber tubing*
A one cubic centimeter pipette,
graduated to 0*01 cc* was placed in a horizontal position on the photo­
graphic registering apparatus*
A small drop of alcohol was placed in
the center of the horizontally placed pipette*
With the finger in the
test tube, and the stopcock opened, a rubber tube connected the stopcock
leading from the finger to the pipette*
When the stopcock was closed
the drop of alcohol oscillated with each heart beat.
The pipette was a
sufficient distance from the sensitive paper in the camera so that the
graduation markings appeared as horizontal white lines, and the finger
volume changes were registered by the change in position of the white
band*
From the photographic record it was possible to estimate a
0*002 cc* deflection*
In the normal subject the oscillation varies
from 0*01 to about 0*05 cc.
We interpreted these changes as giving
an index of the peripheral circulation*
In each experiment artificial fever to approximately 104*5° was
induced and maintained for eight hours.
The interval between each
fever treatment was dependent upon the patient's clinical condition,
but was usually seven days*
One eight-hour control period was run,
during which the paitent was in bed.
Artificial fever was induced by the following methods*
radiant
heat electric light cabinet, radiant heat - infrared of long wave lengths,
hot water bath, conventional diathermy, short wave diathermy, and
foreign protein.
The fever was maintained during the course of the experiment
by means of a zipper bag which prevented heat loss from the patient.
Results*
XXIII*
A summary of the results obtained are recorded in Table
Figures 6, 7, and 8 give a photographic record illustrating
the magnitude of the changes found.
There was a marked pulse volume
inorease in the finger with all types of artificial fever.
With foreign
protein fever there was at first an initial decrease, which, however,
was followed by an increase.
When foreign proteins were given, the
patient was placed in the zipper heat insulated bag, and carefully
guarded against heat loss.
Under these conditions the pulse volume
changes were comparable to the other methods used.
The maximum increase in pulse volume change occurred before the
maximum temperature was reached.
The maximum increase usually occurred
at a temperature of 103° to 104° F.
- 106
Once -the maximum amplitude, ranging from 0.043 to 0.08 com.,
was reached, the pulse volume change fluctuated from hour to hour.
The changes gradually decreased in volume with falling temperature,
and when the rectal temperature returned to normal, the amplitude was
usually back to the control level or only slightly above.
Figure 6a is the record of an eight-hour control period with the
patient in bed.
to 0.016 com.
In this instance the fluctuations varied from 0.08 com.
Figure 6b shows the tremendous finger volume increase
obtained within five minutes after the body was immersed in a hot water
bath.
An average of the blood pressure records on 24 patients, Table
XXIV, shows a definite fall in both systolic and diastolic blood pressure
during hyperpyrexia.
The averages are before treatment of 129/83 and
at the end of an eight-hour temperature of 104° to 105° F was 108/69.
These differences are statistically significant.
Discussion*
These results show an increased pulse volume change
with all types of fever used, except that foreign protein first gave
a primary decrease of the pulse volume which wa3 associated with the
chill.
W© interpreted these changes as evidence of an increased circu­
lation as the result of the vasodilatation and probably increased
cardiac output.
This interpretation undoubtedly is open to some
question, but we are not unmindful of the fact
that the same factors
which maintain blood pressure and in addition the resistance of the
soft tissues in question, are important factors in determining the
extent of the excursion.
It might be possible to have an increased
circulation without increased pulsation, but not possible to have an
increased pulsation without increased circulation.
A striking feature was that the maximum response occurred at
F
temperatures (103° - 104°) considerably lower than the maximum used.
Furthermore, the amplitude of the excursions measuring the circulatory
response showed marked variations as the temperature was maintained
which we interpreted as due to instability of the vasomotor system.
These results indicate that there may be an optimum temperature at
which a maximum response occurs.
This suggests that where increased
circulation is the main therapeutic object, the patient's temperature
should not exceed 103° to 104° F.
The least desirable of the methods used, when considering the
safety of the patient, was the hot water bath (temp. 110° F).
Five
minutes after immersion the pulse volume change increased from 0.01 ccm.
to 0.046 ccm. and had reached its maximum of 0.06 ccm. within fortythree minutes.
The infra-red cabinet using long wave lengths was not
much safer than the hot water bath, and because of the patient’s reao"
tions we did not feel justified in raising the temperature above 102.4° F.
Yet, inspite of the low temperature level, the pulse volume change was
maximum as is shown in Figure 7b.
Other investigators have measured the velocity of blood flow.
Kissin and Bierman (77) 1933 studied the relation between body tempera­
ture and the circulation time.
They injected small measured doses of
sodium cyanide intravenously into the patient.
The time from the end
of the injection to the first deop breath was measured with a stop
watch.
This interval was taken as the circulation time.
They found
that the circulation time shortened as the body temperature rose, and
conversely, the circulation time lengthened as the temperature fell.
The blood velocity was not always proportional to the temperature, nor
- 108 -
to th© pulse rate, but followed the temperature more closely than it
did the pulse*
Kopp (8) in 1936 measured the arm to tongue velocity time by
the decholin method#.
He induced fever in two patients with dementia
Jit
paralytica# one of whom had a syphiJLic. aortic regurgitation and cardiac
hypertrophy.
During the second half of the fever treatments for the
patient with an apparently normal heart, an increase of the basal velo­
city of flow occurred, and was accompanied by an increase in the pulse
rate.
The basal velocity of blood flow of the patient with syphilitic
heart disease tended also to increase as fever therapy was continued,
but was accompanied by a slowing of the pulse rate.
He suggested that
the changes in the basal velocity of blood flow and pulse rate of
both patients was due to the beneficial effects of therapeutic fever
on themyocardium, the changes in the patient with syphilitic
disease resembling those characteristic of digitalis therapy.
heart
Like
Kissin and Bierraan (77) he found no absolute quantitative relationship
between the percentage increases in the velocity of flow and the degree
of temperature rise.
He also found that the velocity of flow was less
marked during typhoid vaccine fever.
Conclusions^
2.
1. There was a marked increase in the pulse volume
changes of the finger with all types of artificial
fever used, except that foreign protein fever was
preceded by a decreased volume change associated
with the chill*
The maximum increased circulation from artificial fever occurred
in general at temperatures between 103° and 104° F. This was
below the maximum temperature used and this suggests that
there is an optimum temperature at which peripheral circula­
tion reaches a maximum.
- 109 that the maximum circulatory changes occur at the
ture for the maximum circulatory change*
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- 110 TABLE XXIV
EFFECT OF HYPERPYREXIA ON BLOOD PRESSURE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Before
After
115-78
112-88
130-80
150-96
145-85
140-90
110-80
116-73
140-38
130-80
130-84
130-98
150-90
128-80
130-90
110-78
120-70
128-76
118-80
120-80
150-110
124-72
145-75
128-68
115-74
110-70
100-50
108-64
100-80
130-80
100-84
110-84
94-48
110-70
80-50
100—60
120-80
108-64
130-90
90-46
110-76
110-70
110-80
100-70
120-80
120-70
110-60
112-60
129/83
Average B.P.
108/69
Systolic 0" + 2.61
<r + 2.41
Diastolic"
11 + 2.54
+ 1,94
Average Pulse Pressure
Before Treatment
After
"
Difference
46
39
IM.Hg.
129
CT +
2.61
108
2.41
2 CT diff.+
7
21
Diastolic Blood Pressure Summary
cr.+
2 CT diff.+
MM.Hg«
Before Treatment
83
1.94
After
69
2.54
"
Difference
14
6.4
Ill -
TABLE XXIV A
SHOWING THE RELATIONSHIP BETWEEN SYSTOLIC
BLOOD PRESSURE AND PULSE PRESSURE •
Patient
No*
Systolic Blood Pressure
Initial
After Treat*
Pulse Pressure
Average
4
13
21
150 mm hg.
150 * w
150 11 u
108
120
120
42
30
30
51
5
23
145
145
100
110
45
35
AT\
w
6
9
140
140
130
94
10
36
d>o
3
10
11
12
14
15
13
24
130
130
130
130
128
130
128
128
100
110
80
100
108
130
110
112
30
20
50
30
22
0
18
16
22
20
17
19
124
120
120
118
120
100
110
110
4
20
10
8
1
2
8
7
16
115
112
116
110
110
115
110
110
100
90
0
2
6
10
20
23
12
7
- 1X2 -
Figure 6*
Finqer Volume C h a n q e s
Control
BI.R
Tim e Pulse R esp.
8.30
80
18
Finqer Vet Chqs. m Artificial F e v e r
86/ s 8
-r
lim e
820
9.30
88
16
80
i
r-,
80 16
80
16
IM
%
16
1.00
88
18
M/rdfo n tro l
120 20 100.6f
*3 90/ro
103.8
...
130 13
t'lar.fcrrio.
126 13 109.3
ICO.I
">%* 5.15
126 18 im
l
1.30
8H
16
fAc^yntrcursion
Removed from Bath
18
Z.00
m
n e m a r fa
Im m ersion of IlC’F
130 20
12.30
Ho! W a t e r B a l k
-r
n ilse nesp.Temtx ____________ Bl.B
9%z 8JJ
aBawramseg''T'!&b*
10.50
n
100.1
LL
90 16
Finger-volume changes during artificial
fever periods* 2he record on the left is the
control and the record on the right shows the
effects of fever induced with a hot-water bath
and maintained by prevention of heat loss* Note
the minor variations in the control record as com­
pared with the marked changes occurring during
fever* Also note that the maximum excursions
occurred at 103*8° F, while the maximum temperature
used was 104*6° F. We interpret the increased
volume changes of the finger as increased circulation*
- 113 -
Figure 7*
F i n g e r Vol. C h q s . i n A r t i f i c i a l F e v e r
Time
Liqhl Cabi n e t
Pul se R e s p - T e m p .
MJiijflgjEg
8.Z0 70
16
BI.P.
I
R em a rK e
,0%o Control
9 8. 6
C u rren t On
8.15
Time
8.30
F i n g e r Vol. Chqs. in A r tific ia lF e ver
R adi a n t H ea t~ ln frd R ed
Pulse R e s p . T e m p
BI.P.
Rem arKs
78
16
^Vsz C ontrol
99.9
9.10
C u rre n t On
C u rren t Off
9.95
9.15
120
19
'101.6
19.00 los io m /*
11
J9a.x. Excursion
nuenSSanu—
ws\ 129 19
109.9
W rzTffl9
w .
'
^
hax.Temp
“%°C u7r r eTnZt Ofif
995
12.00 190
19
I0 9 J
122
16
102.7
1.9S 82
16
l06A s F la x .E x cu rsio n
1030110 u ] m ? c n £ n
“ r' “-
IZ.I5 100
18
101.6
2.15
16
ICZ.I
' r
6.00
m
100
• m u m
7.15 99 16 991
The effects of artificial fever induced with
external heat and maintained by the prevention of
heat loss on the pulse, respiration, blood pressure
and circulation* In the one case the radiant heat
from the ordinary electric-light cabinet was used
and in the other from the infra-red*
- 114 -
Figure 8*
F m o e r Vol. Ch q s . i n f i r t i J i e i a l F e v e r
T im e
810
P u ls e R e s p .T e m p .
90
zc
n t
Finqer V ol.C hqs in f i r t i l i c i d l Fever
r~r' BI.P.
. -J5&r.
,0 ,/to
splemp-PiSESt
5 %-6 -
C o n tr o l
Bl. P. | Rem arK a
‘°y“ \0nUo1
98.6
Chill
9Vrv S e v e r e C hill
10.26 100
101.3
10.90
108
102.0
12.00
130
1012
100
128
11.00 IOZ
2.15
130
118
/I a x .Excursion
103.
99.8
The results of artificial fever induced with
foreign protein on the pulse, respiration, blood
pressure and circulation. Note the primary vasocon­
striction associated with the chill followed by a
vosadilatation. Oie results of artificial fever on
the peripheral circulation differ in this respect
from those obtained with artificial fever induced
with the application of external heat.
- 115 I
I
G#
Thg Influence of Hyperpyrexia on Ascorbic Acid Concentration in
the Blood »
i Introductions
The object of this investigation was to ascertain the influence
,of hyperpyrexia on plasma ascorbic acid concentration*
was initiated no such study had been reported*
When this work
Inasmuch as we were
;investigating the value of hyperpyrexia in the treatment of arthritis,
’{our interest was intensified, because Rinehart (125, 126) associated
low ascorbic blood plasma levels with the etiology of arthritis*
;i
Literature:
Two similar investigations have since been reported
(156, 35)*
Method:
Eighteen patients suffering from chronic arthritis were
{subjected to hyperpyrexia*
The rectal temperature ranged from 104° to
104*6° F for a period of four hours, following which their temperature
iiwas permitted to return to normal*
A combination of fever cabinet and
Induototherm was used to elevate the patient*s temperature*
Treatments
were given once weekly.
The ascorbic acid concentration of the blood plasma was deter­
mined by the micro method of Farmer and Abt (46).
Approximately 0*3
ml* blood was used from a sample being collected from the median basilic
vein for other blood studies*
contained an anticoagulant*
The phial in which the blood was placed
The blood was deproteinized by means of a
5 per cent metaphosphoric acid solution.
The reduced ascorbic acid in
the deproteinized plasma was titrated with a standardized solution of
sodium 2*6 dichlorobenzenoneindophenol*
Two of the patients, 1 and 13, because of low initial values, were
given 450 mg* of Cebione (Merck) daily, patient 1 after the third treatment,
land patient 13 after the first treatment, for four and six weeks
respectively*
Seventy-seven experiments were made on the eighteen patients*
;Determinations were made just prior to treatment, when the rectal
|temperature reached 104° F, after a temperature of 104° F had been
maintained for four hours, and finally after the patient's temperature
had returned to normal*
I;
Results *
The complete data of the seventy—seven experiments are
;shown in Table XXVI*
Table XXVII gives a summary of the average values
and the result of the statistical analysis*
Obviously there are no
significant changes in the ascorbio acid concentration of the blood plasma
that can be attributed to the influence of the hyperpyrexia*
Piscussion:
Investigators vary markedly in their reports as to
what constitutes the normal blood level of ascorbic acid either in
health or disease*
Abt and Farmer (l) in their studies on children
and young adults report normal values are from 0*7 to 1*5 mg* per hun­
dred cubic centimeters.
0*7 mg* to be suboptimal*
They also consider blood plasma values below
They also state that active scurvy may occur
with values ranging from 0*4 to 0*5 mg*
These values, however, they
believe while true during the period of growth, may not hold for the
adult*
Wolff, Banning
cent is adequate but
and Van Eekelan (154) state 0*4 to 1*2
mg* per
not the optimum*
Daum, Boyd, and Paul (35) state that the normal ascorbic acid
content of the blood ranges between 0*7 to 2*0 mg* per cent*
The assumption has been made that fever increases vitamin C re­
quirement, but direct experimental proof is lacking.Zoak,
and Sharpless
- 117 (156) 1938 fed guinea pigs a scorbutic diet and submitted them to a
hyperpyrexia of 105° to 106° F for two to six hours daily.
pigs were killed after 4, 7* 15 and 25 days.
for vitamin C content.
Groups of
The tissues were analyzed
Their results showed that the vitamin C stores
were depleted faster in the animals submitted to fever, than in the
control group, but they found very little difference when a state of
scurvy was approached (15 days).
They found a highly significant dif­
ference between the vitamin C content of the adrenal glands, but less
in the kidneys, of the controls and the fever treated pigs.
These same
investigators studied the effects of artificial fever on vitamin C excre­
tion in the urine as well as its concentration in the blood on six patients.
Determinations were made before and immediately after treatment.
Because
of difficulties they were able to secure but four reliable results on
the urine studies.
The following table —
made from their data —
shows
ascorbic acid content of the urine to be lower following the fever;
TABLE XXV
Day of
Treatment
After
Treatment
Patient
No.
Before
Treatment
1
17 mg*
10 mg.
8 mg.
Had treatment
previously.
2
17 mg.
10 mg*
15 mg.
Had treatment
previously.
3
23 mg.
10 mg.
16 mg.
4
16 mg.
10 mg.
16 mg.
The authors state it cannot be determined by this type of experiment
whether fever increases the physiological need for vitamin C or induces an
- 118 excessive loss in sweat*
They found no decrease in the blood ascorbic
acid concentration in any of their patients*
The values found were
equal to or greater than the values before treatment •
This they inter­
preted to mean that vitamin C concentrates with the concentration of
the blood*
Our own studies, however, have shown that the blood of our
spatients was not concentrated as a result of artificial fever*
From
,the preceding study these authors concluded that fever increases the
:vitamin requirement in man.
Daum, Boyd, and Paul (35, 1939 state that the plasma blood level
seems to be no indication of the bodyfs need, but that depletion or satur­
ation must always be studied in connection with the intake and the urinary
output*
Abt and Farmer (1), on the other hand, state that they have
' repeatedly observed, on the oral administration of large quantities of
vitamin C, only small amounts excreted in the urine, while a steady
rise in plasma level occurs*
Further, they point out, if the oral ad­
ministration of vitamin C is continued for a sufficient period, a point
of plasma elevation will be attained, following which a rapid urinary
excretion of a large part of the ingested ascorbic acid occurs*
They
believe that the plasma level at which this quantitative urinary excretion occurs shows considerable individual variation*
Howley, Frazer,
Button and Stephens (57) have shown that more vitamin C will be excreted
in the presence of an acid urine than urine with an alkaline reaction*
Wolff, Banning, and Eekelen (154) state that the condition of the
body with regard to vitamin C cannot be determined solely by testing
the urine; on the other hand, the determination of the vitamin C content
of the blood alone furnishes valuable data*
Daum, Boyd, and Paul induced
hyperpyrexia in a group of patients by means of high frequency current,
119 -
and made studies of the effect on ascorbic acid blood levels and
urinary excretion#
The temperature of their patients ranged from
105° to 106° F and was maintained for a period of two to five hours*
While the patients were under observation they were given 500 to 700
rag* of ascorbic acid daily*
They found a decrease of ascorbic acid in
the blood and excretion in the urine*
The decreased urinary excretion,
they believed, was due to the increased temperature and not to the in­
vading organism*
Falke (45) 1939 induced fever in fifteen patients by means of
pyrifer and determined the vitamin C balance before, and as a result of
treatment#
He found that the vitamin C requirement was about 100 mg*
higher on the days of fever.
It also required about 300 mg* of ascorbic
acid to prevent the urinary reduction*
In our investigation it was not practical for us to make urinary
determinations, nor did we find any satisfactory method for sweat
ascorbic acid determinations*
While the average ascorbic acid concentration of the blood for
the group was 0*62 mg* before treatment, the range varied from a low
of 0*28 (patient 2) to 0.72 mg* (patient 3).
Many of the values found
in these patients are considered very low normals#
Thirty three of
the seventy-seven determinations before treatment showed a level below
0*5 mg*
This is of interest in the light of the work of Rinehart
(125, 126) who found that subacute or chronic vitamin C deficiencies
in guinea pigs produced an anthropathy with manifold similarities to
rheumatoid arthritis.
He found that superimposed infection accelerated
or aocentuated the pathological processes.
In his study infeotion in
the presence of adequate vitamin C nutrition failed to produce arthritis.
- 120 -
He further points out that the relatively high vitamin C requirements
for ohildren and the possible influence of fatigue in depleting the
organic reserve.
Gonelusions?
1. Seventy-seven experiments were made on 18
patients suffering with chronic arthritis to
determine the effect of hyperpyrexia on the
concentration of blood ascorbic acid.
2.
No significant changes in the ascorbic acid concentration
occurred as a result of the fever treatment.
3.
Our control levels would seem to support the observation
of Rhinehart that arthritic patients show a low level of
ascorbic acid concentration in the blood plasma.
- 121 -
TABLE XXVI
BLOOD P&ASMA ASCORBIC ACID CONCENTRATION MG. PER CENT
Patient
No.
Before
Treat­
ment
Height
of
Fever
4 Hours
of fever
104° F.
Return
to
Normal
1
0.40
0.64
0.36
0.92
0.44
0.36
0.60
0.28
0.92
0.40
0.28
0.56
0.28
1.00
0.36
0.28
0.64
0.28
0.96
0.36
0.48
0.44
0.32
0.36
0 .32
0.28
0.44
0.40
0*28
0 .32
0.28
0.24
0.40
0.36
0.28
0.32
0.24
0.24
0.44
0.32
0.24
0.28
0.24
3
1.32
1.12
1.32
1.72
1.00
1.60
1.28
1.68
1.92
1.36
0.96
1.40
1.68
1.16
1.20
0.96
1.36
1.44
0.84
•
+
—
4
0.48
0.36
0.32
0.52
0.50
0.48
0.44
0.44
0.44
0.60
0.56
0.48
0.44
0.44
0.70
0.64
0.48
0.72
0.60
0.48
+
+
+
+
—
5
0.38
0.44
0.72
0.88
0.50
0.80
0.48
0.72
0.58
0.80
0.96
0.56
0.80
0.48
0.36
0.80
0.96
1.04
0.64
1.12
0.56
0.72
0.56
0.84
0.84
0.48
1.28
0.64
+
+
+
+
+
6
0.36
0.32
0.52
0.80
0.44
0.44
0.44
0.60
0.48
0.44
0.44
0.96
0.48
0.72
0.60
1.20
+
+
+
+
7
0.56
0.80
0.80
0.40
0.40
0.72
0.84
0.72
0.44
0.40
0.48
0.68
0.52
0.52
0.48
0.68
0.56
0.60
0.36
0.36
+
—
2
Change
£
(Continued)
0
+
-
122
TABLE XXVI
(Cont« )
Patient
No o
Before
Treat­
ment
Height
of
Fever
4 Hours
of fever
104° F.
Return
to
Normal
8
0.56
0o44
0.44
0.56
0.80
0.36
0.30
0.52
0.40
0.52
0.36
0.40
0.48
0.56
0.64
0.40
0.40
0.40
0.40
0.52
—
-
9
0.40
0.44
0.48
0.44
0.44
0.52
0.44
0.52
0.48
0.56
0.76
0.44
0.52
0.48
0.44
0.44
0.48
0.44
0.44
0.40
+
+
—
0
-
10
0.72
0.60
0.44
0.52
0.80
0.68
0.88
0.76
0.84
0 .56
1.68
0.64
0.80
0.68
0.72
0.72
0.76
0.92
0.76
0.60
0.72
0.60
0.96
0.72
+
0
+
+
+
+
11
0.92
0.60
0.64
0.36
0.86
0.72
0.56
0.36
0.80
_
0.32
0.98
0.92
0.72
0.36
0.86
12
1.20
0.96
1.08
0.56
1.12
1.00
1.08
0.56
1.08
0.96
1.20
1.48
1.00
1.04
1.08
0.56
+
0
0
13
0.60
0.84
0.88
0.84
1.64
1.12
1*04
1.32
1.68
1.40
1.04
0.76
1.60
1.20
0.80
1.20
0
+
+
14
0.80
0.68
0.92
1.68
0.64
0.92
0.76
0.92
0.60
0.96
0.72
0.72
+
+
—
15
0.60
0.56
0.80
0.40
-
16
0.40
0.44
0.40
0.52
+
0.64
0.48
0.64
0.48
-
=
0.62
0.68
0.66
0.64
s
0.03
0.04
0.03
0 .03
17
—“
Average
<T
I
Change
+
—
+
—
- 125 -
TABLE XXVII
SUMMARY OF BLOOD ASCORBIC ACID DETERMINATION
Elapsed
Time in
Hours
Average of
77 Determ­
inations.
Of-
2 Or
Diff. -
Change
j- from
Control
0
0.62
0.05
Temp, reached
104° F.
2
0.68
0.04
0.104
0.06
Temp, at 104°
F, - 4 hours
6
0.66
0.05
0.106
0.04
Temp, returned
to normal
8
0.64
0.05
0.088
0.02
Control
VII. The Effect of Hyperpyrexia on Immune Bodies
Introducti on >
This investigation was undertaken to determine the effects of
hyperpyrexia on circulating immune bodies and the leucocytes.
Methods:
treatment.
Differential blood counts were made before and after
Blood was drawn into a syringe from the median basilic
vein of the arm under sterile conditions.
One part of the blood was
discharged into a tube containing heparin or sodium citrate solution,
and the rest into a dry sterile tube.
The amount of complement present in the human serum was determined
by first removing the native hemolytic amboceptor for sheep erythro­
cytes.
This was done by incubating the serum with sheep’s washed red
blood cells at 2° C for one hour.
The tube containing the serum and
Icells was then put into a centrifuge tube containing cracked ice and
the mixture centrifuged about two minutes to throw down the red cells.
Since complement does not act at this low temperature, none of it was
used up in the process of removing native hemolysins.
The removal of
the amboceptor, however, was found not to have any significant influence
on the results*
The serum was then diluted one to three, and amounts
varying from 0.01 to 0.04 were put into small tubes by means of a 0.1
cc. pipette graduated in hundreths.
To this were added 0.1 cc. of
anti-sheep amboceptor, diluted 1*250, and 0.1 cc. of a 1 per cent sus­
pension of sheep’s washed red blood cells.
to each tube to make the whole volume 2 cc.
for thirty minutes in a 37° C water bath.
Enough saline was then added
The tubes were incubated
Readings were made at the
end of that time and also after eighteen to twenty-four hours in the
- 125 ice box.
Only the smallest amount of serum showing complete hemol­
ysis is reported in the tables.
Opsonic Index*
The ordinary method for performing the opsonic
test by dividing the percentage of phagocytosis occurring with patient’s
serum by that with normal human serum was used in the asthma cases.
In
the arthritic and general paretic patients, in addition, the opsonins
and phagocytic power of the patient’s leucocytes were evaluated as
follows*
Two cc. of heparinized salt solution (containing 1 mg. of
heparin per cc. of 1.9 per cent HaCo) were put into a test tube and
about 9 cc. of blood added.
In a second dry tube about 1 cc. of blood
was collected and allowed to clot.
The heparinized sample was centri­
fuged and the cells were washed once with salt solution, then divided
into two portions, portion "AH remained untreated, portion ”Bn was
deleucocyted by a modification of the method of Fleming (48).
A U-tube
was prepared of glass tubing with a constriction in one limb into which
absorbent cotton was packed tightly.
The other limb was connected to
the vacuum apparatus, a little salt solution drawn through the cotton,
and finally, the cell suspension B is sucked through three or four
times and was thus rid of most of its leucocytes.
By mixing this
filtered suspension in various proportions with portion nAn, a series
of blood samples were obtained having the same number of erythrocytes,
but different number of leucocytes.
Phagocytic tests were then made.
Two volumes of the blood contain
ing leucocytes were drawn into a bent capillary pipette, followed by one
Volume each of a suspension of a heat-killed culture of streptococcus
and serum from the clotted blood.
These substances were mixed by
drawing back and forth in the pipette, the end of which was then sealed
in a flame and the mixture incubated at 37° C for fifteen minutes.
Smears were then made on slides, stained by Iright’s method, and 50
leucocytes on each edge of the smear counted.
The number of leucocytes
per 100 containing bacteria was noted and constituted the percentage
of phagocytosis.
Agglutination*
Agglutination tests were made by the usual
microscopic dilution method.
Results;
Intractable asthma (patients one to nine), Table XXVIII.
No consistent changes in complement titer or opsonic index were observed.
Ibat slight changes did occur cannot be attributed, therefore, to the
effects of the temperature•
Infectious arthritis (patients ten to sixteen) and general paresis
(patient seventeen), Table XXV.
In thirteen out of fifteen determina­
tions made at the height of temperature there was an increase in the
total number of leucocytes.
In only one instance did the leucocytosis
last twentyrfour hours.
The increase was found to be In the polymor­
phonuclear neutrophils.
The percentage of lymphocytes decreased corres­
pondingly.
In our first communication Neymann and Osborne (110) we
stated that this might be due to concentration of the blood.
Since the
erythrocyte count did not increase in proportion to the count of leu­
cocytes, which was sometimes 100 per cent, and in view of the dispropor­
tionate change in the two types of white cells, this is unlikely.
In
only five out of thirty-five tests was there even a slight increase in
the opsonic index.
In examining the phagocytic property of a patient’s leucocytes
it is not compulsory that their number be constant because variations
can be adjusted, but the serum should be uniform throughout.
This was
possible in only three instances - patient 13, treatment 8 s patient 15,
- 127 treatment 2; and patient 16, treatment 1 - for these were the only
ones tested with normal as well as with their own serum.
Since, how­
ever, diathermy produced little, if any, change in the opsonins and,
further, since the phagocytic power was ascertained in these patients
(13, 14, 15, 16) both before and after treatment, the findings should
be significant*
The results are shown in Figures 9 and 10.
It is
readily seen that diathermy had no effect on the phagocytic property
of the leucocytes.
It is also apparent that when counts above 15,000
are used, the relation of the number of leucocytes to the percentage,
phagocytosis is no longer linear (Figure 10).
The figures for patient 13, treatment 8; patient 15, treatment 2;
and patient 16, treatment 1, in which we were able to study not only
the phagocytic power of the patient’s cells with normal serum, indicate
no noteworthy differences whether normal or patient’s serum was used.
There is a suggestion of a change at the height of temperature in the
phagocytic power of the leucocytes of patient 15, which is apparent
with normal serum but not the serum of the patient.
the number of leucocytes in this patient was slight.
The increase in
Patient 13 and
patient 16 showed no marked differences when theirs’ or normal serum
was used with this patient’s leucocytes.
A large series of patients
treated in this manner might show significant variations.
Since the arthritis patients had received injections of typhoid
vaccine for varying lengths of time preceding their diathermy treatments,
it was thought that there might be some changes in the agglutinins for
Bacillus typhosus and perhaps for organisms in closely related groups.
The sera of patients 10, 11, 13, and 14 were tested with the commercial
vaccine used in their treatment.
In addition, the sera of all four were
- 128 tried with a living laboratory strain of Bacillus typhosus (Table XXIX)
and patient 13 and 14 also with laboratory cultures of Bacillus paratyphosus A, and B, and Bacillus coli (Table XXX).
Only one of the four patients showed any appreciable amount of
agglutinins for the commercial vaccine (Table XXX).
There was a slight
suggestion of an increase in agglutinins in patient 13 (Tables XXIX,
XXX, and XXXI).
This was a gradual augmentation which occurred with
succeeding treatments, but at no time became at all marked.
The greatest
change took place in agglutinins for Bacillus para typhosus B, with
Bacillus coli ranking next.
Discussions
Mendel (96) 1928 found that the usual lethal dose
of streptococci was tolerated by rabbits when these organisms had been
exposed to temperatures varying from 40.5° C for twenty-four hours to
48° C for fifteen minutes.
He stated it required almost one hundred
times the lethal dose before all the injected animals were killed.
The
mouse he observed is far more sensitive to streptococci than the rabbit
because the mouse does not respond with fever to the inoculation, while
the rabbit does.
Further, he proposed the use of heat treatment in
the form of hot air applications on this basis in streptoooccus infec­
tions in man.
Feinberg, Osborne and Steinberg (47) 1932 made quantitative studies
on the skin and on the atopic reagins, before and after fever treatments
for intractable asthma.
We found no decided changes in that direction
and were forced to conclude that the mechanism of relief could not be
explained on this basis.
Hicks and Szymanowski (59) 1932 made similar
observations with guinea pigs.
These workers observed no changes on
the precipitin titer in rabbits when exposed to the high frequency current
- 129 for six hours or more*
Carpenter, Boak and Ifarren (25) 1932 in discussing the results
of their experiments, in which they treated rabbits inoculated with the
treponema pallidum, state,
"It is evident that the increased heat of the fever provides an
unfavorable environment for the spirochetes that either destroys
or injures them so that they lose their infectivity. We do not
know whether in syphilis, the elevated temperature also stimulates,
or activates those factors in the body that are concerned with
its protection against infection* However, in studies on gonorrhea
we have observed increased phagocytosis during artificially
induced fever* This leads us to believe that such factors may
play a prominent part in syphilis."
Neymann, Lawless, and Osborne (109) 1936, treating patients suffar­
ing with early syphilis state that positive, or more intensely positive,
serologic reactions developed after the first fever treatment.
They
believed it safe to conclude that there is a rapid and intense mobili­
zation of antibodies following fever therapy.
They theorized that this
was due to a massive destruction of the spirochetes, but realized that
other factors may play an important role in bringing about this increase
in amboceptor formation.
A further fact of great interest was brought
out by this investigation, namely, the presence of spirochetes in micro­
scopic sections of 5 lymph glands while the chancre or original site of
infection showed no organisms (Figures 11 and 12).
These spirochetes
were somewhat atypical and did not produce syphilomas when transplanted
into rabbit’s testicles.
(See Figures 13 and 14).
From this it was
concluded that not all spirochetes, especially those found in the lymph
glands, are destroyed by heat alone.
The experiments that fix the in
vitro death point of spirochetes at 41° C maintained for two hours, or
42° C maintained for one hour, therefore, do not apply to spirochetes
found in vivo in human beings.
- 130 Ecker and 0 ‘Neal (41), 1932, who induced hyperpyrexia in
rabbits and guinea pigs subjecting them to temperatures of 40° to 43*1°
C* immunized rabbits and guinea pigs to Bacillus typhosus and reported
that they observed a depression of agglutinins during the time of
fever, but the antibody titer soon returned to normal* The guinea pigs
!
all showed a decrease in complement although the complement was not
completely destroyed*
Reimann (123), 1933, showed that an increase in plasma viscosity
depending on an increase in the fibrinogen and globulin fractions of
the blood enhanced specific agglutination and suggested that these
protein changes which occur during infectious diseases played an
important role in immune processes*
In a later study on lobar pneumonia
Moen and Reimann (100) found a prompt increase in the plasma globulin
and fibrinogen fractions together with increased plasma viscosity
within a short while after the chill*
It seems possible that the high
fever associated with the disease, together with the severe toxemia,
may have been an important factor in inducing these blood protein
changes*
Since then Moen, Medes and Chalek (99), 1934, using diathermy
to produce hyperpyrexia in dogs came to the conclusion that fever
alone is not an important factor in evoking the plasma changes usually
observed in infectious diseases.
Carpenter, Boak, Mhcci, end Warren (26), 1933, from their study
of patients infected with gonorrhea, concluded that it was evident in
vivo some injury other than that due to heating occurs to the gonococcus,
making it more susceptible to destruction by normal defense mechanism
of the body*
Clinically, they observed "cures" result5-ng from such
fevers as 41*5° C* maintained for five hours when they were unable to
obtain an in vitro theririal death time for a similar exposure.
Hodjopoulos and Bierman (63), 1934, exposed rabbits to radiothenoy for three to four hours at a temperature of 41° to 42° C* and
reported a temporary diminution of complement-fixing antibody titer
when their animals were immunized against staphylococcus, streptococci,
mircrococci cat&rrhalis and diptheroid bacilli.
They stated they
also found a delayed stimulation phase by observing daily the antibody
titers*
Wulff (155), 1934, demonstrated in 85 per cent of his patients,
a thermostabile bacterial substance in human serum during the febrile
period of infectious fevers*
In 90 per cent of non-febrile patients
this substance could not be demonstrated.
The injection of sulfosin
also appeared to stimulate organisms to produce a thermostabile
bacterial substance*
His experiments showed, further, that this
baotericidal substance possessed enzymic properties*
Tillett (145), 1937, points out that the extracts of leucocytes
(leukin) have been found to be bactericidal and has led some investi­
gators to offer the suggestion that the bactericidin of serum may
be derived from leucocytes*
However, he stated, that among his patients
several of whom had a leucocytosis, when the serum was highly bacter­
icidal for streptococci, there were nevertheless several exceptions
in cases with normal or leucopenic white blood cell count but with
serum markedly effective in streptococcidal activity*
He further
noted a relatively close parallelism between the bactericidal capacity
of the serum and the temperature of the patient when blood was drawn*
He postulated that it should be of great interest to attempt to
determine whether fever itself is of prime importance in influencing
changes in the blood serum, or whether other factors inherent in
active febrile disease cause the appearance and disappearance of
the humoral bactericidal property*
Rich and McKee (124), 1936, have reported that rabbits inoculated
with type XII pneumococous acquire a greatly enhanced resistance to
further infection within twenty-four hours.
They showed this resis­
tance was not due to acquired immunity but to the fever that develops
as a result of the infections*
These encapsulated strains to which the rabbit is resistant,
they found are not phagocytized promptly either in vitro or in vivo,
but after some hours sojourn in the body of the rabbit they gradually
lose their capsule and are then phagocytlzed*
The loss of the
capsule appeared to be dependent upon unfavorable conditions of the
host whether of temperature, or, of surrounding medium*
Extracellu­
lar death of cocci, they stated, a3.so takes place, and the occurrence
of both these processes are accelerated in the zabbit by temperatures
of 104° to 106° P.
Benedict (10), 1936, states that when heat is produced generally,
as in fever, there is in addition to its local action, a physiologic
factor that makes available certain nonspecific antibodies, which
in themselves probably exerts a favorable influence*
According to Doan (36), 1938, the rather constant hemopoietic
response to fever may be non-specific and is by no means necessarily
the most important from the standpoint of the fundamental body defenses
He further states that the hemograms following malaria and B typhosus
innoculation differs from those observed during fever induced by
- 133 physical methods in the marked leucopenia during the chill, in
the temporary disappearance of* the monocytes from the circulation
following typhoid, and its moderate stimulation following typhoid
vaccine*
The shift to the left in the neutrophilic granulocytes
in malaria is outstanding and the appearance of clasmatocytes in the
peripheral blood has been observed in no other type of fever study*
TPfhile artificial fever does not show an increase in clasmatocytes,
he calls attention to the tremendous increase in these phagocytic
cells elsewhere in the tissues, more especially in lymph nodes, spleen
and liver*
He believes to that extent, at least, artificial fever
by physical means not only provides the thermal factor of importance
for the inactivation of the treponema pallidum, and the gonococcus,
but has been demonstrated to exert a profound effect upon the
cellular equilibrium of the body in the direction which at the present
time he believes to be most effective in the mobilization of the
defense forces of the body against these diseases*
Moench (101), 1937, performed a series of in vitro experiments
to ascertain the effect of heat on the growth of meningococcus*
She
was interested to s tudy the effects of the temperatures generally
used in the administration of hyperpyrexia*
Fifteen strains of
meningococci we are submitted to temperatures which ranged from 40° to
42° C* and which were maintained from three to seven hours*
The
growth of all strains, with a few exceptions was either destroyed or
reduced*
Some strains were consistently destroyed at lower temperatures
and with shorter exposures than others which seemed relatively heatresistant*
According to this investigator the experiments indicated
that a temperature of 41*6° C* maintained for at least five hours
- 134 would be desirable for a clinical trial*
Moreover, Moench thought
it might be possible that hyperpyrexia would hasten the absorption
of meningeal exudate and so prevent the development of adhesions
and the resultant block to the circulation of cerebrospinal fluid*
Shaffer, Enders, and Wilson (136), 1938, from previous studies
(43, 44), these investigators believed that the results of their
experiments suggested possible modes of attack upon infections caused
by type III pneumococous meningitis in man.
They accordingly treated
two patients suffering from pneumococcus type III with artificial
fever alone; two patients with rabbit serum of high specific-antibody
titer mixed together with human complement which was injected intrathecally, and in one other patient both measures were used simultan­
eously*
The patients exposed to artificial fever had their tempera­
ture elevated between 105° to 107° F* for five to ten hours*
They
determined at intervals the effect of these various procedures on
the bactericidal population and the fluctuations in content of
soluble specific precipitable antigen, as well as free antibody when
this was injected*
Hyperpyrexia alone produced a marked reduction in the number of
viable pneumococci and the quantity of free soluble type-specific
antigen present*
attained*
But in neither patient was sterility of the fluid
The combined treatment of hyperpyrexia and injection
of rabbit anti serum appeared to produce best results as estimated
by the conditions obtained
in the cerebrospinal fluid*
None of
the five patients treated recovered from the infection*
From the foregoing discussion, it is quite evident from the
- 135 evidence presented that the effect of hyperpyrexia on immunologic
reactions is not completely understood*
Conclusions;
1* A total of 378 determinations, including total leucocyte
counts, erythrocyte counts, complement titer, opsonic index,
phagocytic power of leucocytes, and agglutinins were made on 17
patients*
2* The only significant immunologic change produced by diathermy
was a temporary increase in the leucocyte count immediately after
hyperpyr exi a •
3* In all but one out of fifteen determinations the leucocyte
count was normal in 24 hours*
4* The erythrocyte count showed no notable changes*
5* Alterations in complement content, opsonins, and phagocytic
property of leucocytes were found to be virtually within the limits
of normal variation*
- 136 TABLE 28
Immunologic Effects of Hyperpyrexia
Patient
No*
1*
2,
3•
4,
5,
6*
Opsonic
Index
Com­
plement*
Rectal
Temperature
First treatment
Before
Height of temper attire
1,0
1,2
0,20
0,20
101,8
104*6
First treatment
Before
Height of temperature
5 days after first treatment
3 "
w
second
11
1,0
1,0
1*0
1,0
0,40**
0,40
0.35
0,35
102*0
105*4
1,0
1,0
1*0
0,20
0,20
0,15
99,7
104*8
1*2
1,6
0,20
0.20
104.7
1,0
0,15
99*1
0*8
Sample lost
0,9
0*10
100,2
103.1
102,6
First treatment
Before
24 hrs* after
1.2
1*2
0*25
0,20
100.2
Temp* at height
was 105*1
Second treatment
Before
24 hrs* after
1*1
1.1
0,20
0,20
99,6
Temp* at height
was 102*1
Fi rst treatment
Before
24 hrs, after
1,0
1.0
0.25 (3+)
0*25 (3+)
100*5
Temp* at height
was 103,6
Fir st t reatment
Before
Height of temperature
19 days after
Third treatment
Height of temperature
24 hrs* after
Fourth treatment
Before
Second treatment
Before
Height of temperature
2 hrs* after
Second treatment
Before
1,1
0.20
Not possible to get sample after treatment
100.4
- 137 Table 28 - continued
Patient
No.
7.
8.
9*
Opsonic
Index
Com­
plement*
Rectal
Temperature
First treatment
Before
24 hrs* after
1.0
0*8
0.20
0.20
100.2
Temp, at height
was 103.7
First treatment
Before
Height of temperature
0*8
0.8
0.15
0*20
101.4
104.5
Second treatment
Before
Height of temperature
24 hrs* after
1.1
0*8
1.3
0.15
99.9
103.6
First treatment
Before
Height of temperature
24 hrs* after
1.4
0.7
0.9
0.15
0.15
*
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Patient’s serum and leucocytes - Patient 15 treatments
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Leucocytes also tested with
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15
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15
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16
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h w o o h w h h
Effect of Hyperpyrexia on phagocytic property of patient’s blood.
- 145 -
Figure 10#
100
So
60
40
Q_
20
Leucocytes:
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25.000
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146 -
Spiroohetes in a histologic section of a chancre
before treatioent.
147
Figure 12,
Absence of all spirochetes in the histologic
seotion of the site of the chancre after two hyper­
pyrexia treatments* Temperature above 105*8° F for
four and one half hours, and above 107*6° F for on©
hour*
Figure 13*
Fragmented and degenerated spiroohetes
in a histologic section of an inguinal lymph
gland after three sessions of hyperpyrexia at
temperatures above 105.8° F for more than two
hours, and above 107*6° F for approximately
one hour during each session.
149
Figure 14.
Fragmented and degenerated spirochetes
after three sessions of hyperpyrexia. External
skin temperatures and internal (rectal) temper­
atures were maintained above 105*8° F for one
hour and above 107*6° F for an additional hour.
• 150 -
VIII* The Effect of Hyoscine and Pilocarpine on Axillary
Temperature Associated with Hyperpyrexia*
Introduotiout When a sedative was deemed necessary to quieten
& patient while undergoing hyperpyrexia treatment for dementia paraly­
tica* it was our (ill} custom to administer to the patient morphine
sulphate 1/4 gr* in combination with hyoscine 1 /1 0 0 gr* hypodermically*
Not only did this frequently fail to alleviate the restlessness but in
addition apparently caused the temperature to rise in an uncontrollable
manner*
We (ill)* therefore* decided to study the separate aotion of the
two drugs*
A survey of the literature failed to disclose a similar
study*
Methodi
The study was made on six patients who were undergoing
hyperpyrexia treatment for dementia paralytioa*
The patients were
prepared and treated in the usual manner except that during one treat­
ment they were
given one-hundredth grain of hyoscine and during the
next treatment
©ne-eighth grain of pilocarpine*
The drugs were given
to the patient when their rectal temperature reached approximately
100° P*
Rectal and axillary temperatures were recorded by a recording
resistance thermometer*
None of the patients exhibited restlessness
prior to receiving the sedative which was administered solely for
the purpose of the experiment*
The axillary bulb of the resistance
thermometer was held in place and protected from the external environ­
ment by means of a light plaster of paris cast*
Results s
The two charts depicted in figures 15 and 16 are quite
typical of the effect produced by hyosoine and pilocarpine on the
axillary and rectal temperatures*
The administration of hyoscine
-
151 -
caused a marked diminution of perspiration which resulted in the
axillary temperature rising above the rectal*
As can he seen from
Figure 15, the course of the temperature was quite erratic, difficult
to control, and a sinusoidal like temperature curve resulted*
More­
over, it apparently was the cause of violent delirium in some of the
patients*
Morphine did not produce these reactions neither did pilocarpine.
When pilocarpine was given the temperature ran an entirely different
course (Fig* 16)*
that of the rectum*
The axillary temperature at no time rose above
Perspiration was profuse and delirium was not en­
countered*
Discussion: It is unfortunate that a serious investigation of
the use of sedatives in therapeutic hyperpyrexia has not been made*
It is the opinion of the writer that too frequently drugs are used
without discrimination and undoubtedly have in some instances caused
or precipitated a major crisis*
Most of the sedatives used are
respiratory depressants and, as Hartman (55) points out in discussing
the pathological f indings of both experimental animals and patients
which he studied at autopsy, it seems justifiable to place anoxemia
as the underlying cause of the lesions and the sedatives used in
conjunction with artificial fever as the initiating or predisposing
causes of the anoxemia*
All investigators agree that cerebral edema
is a constant effect of anoxia in the brain*
This then might account
for the varying degrees of delirium reported by investigators in this
field*
Landis (88) by demonstrating that fluid passes through capillary
walls at four times the normal rate after only three minutes lack of
- 152 oxygen, furnished the probable explanation*
In 1937 Jowett and
Quastel (71) demonstrated that phenobarbital, decreases or abolishes
oxygen utilization by the brain*
Hartman (55) reported that the
administration of oxygen tended to reduce the sedative effect of
sodium amytal (sodium amytal with other sedatives apparently affects
the cells directly), decreasing their utilization of oxygen, and thus
has a selective action on the brain*
Dowdy and Hartman (38) state that cyanosis and anoxemia are not
synonymous terms but are frequently coexisting conditions#
Strong
barbiturates are respiratory depressants and cyanosis in a marked
degree is frequently noted during fever therapy with these drugs*
They also state that depth and duration of sedation are fundamental
problems in hyperpyrexia*
Deep anesthesia establishes factors conducive
to anoxemia with resultant injury to brain tissue*
Dowdy and Hartman
state that they found sedormid to be a weaker drug with a greater
margin of safety than the barbiturates, and hence, recommended its
use *
As a result of our experiments, we no longer make use of hyoscine,
but use morphine alone*
Any drug that inhibits sweat in a marked
manner, we believe, is contraindicated*
Atrophine is such a drug and
certainly any theoretically beneficial action this drug may possess
by increasing the heart action is outweighed by its effects on the
sweat glands*
Other drugs such as adrenalin and compounds related to it,
constrict the peripheral blood vessels, and therefore, are prone to
cause a rise in body temperature of the patient, as well as to increase
- 153 the heart rate•
Strychnine increases the activity of the striated muscles by
rendering the reflex arcs of the spinal cord more excitable*
produce convulsions in susceptible patients.
It may
A convulsion causes
an immediate unpredictable marked rise in temperature*
In cases of emergency such as shook, digitalis is considered to
be contraindicated, chiefly, because, according to Warfield (148), it
decreases blood volume in shock*
That there already exists a decrease
in blood volume during hyperpyrexia has been shown by Gibson and Kopp
(50)•
On the other hand caffein sodiobenzoate can be safely used and
has a tendency to increase blood volume (148).
This corresponds to
the author*s experience with these drugs*
It is the opinion of the author that sedatives should and can
be used much less frequently than is the case at present*
Moreover,
there should be a more judicious choice of the sedative to be used
when one is necessary*
Conclusions:
1* Hyoscine should not be used for purposes of sedation because
of its activity in suppressing perspiration.
2* Hyoscine is apparently a cause of delirium in many hyperpyrexia
patients*
Pilocarpine by increasing sweating renders it more difficult
to raise the body temperature.
3* A discussion on the use of sedatives in general is given.
Figure
15
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The effect of hyoscine administration during
hyperpyrexia.
- 155 -
Figure 16•
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1 1 ;4C A1 .T
IX. The Effect of* Hyperpyrexia on the Secretion and
Flow of Bile.
Introduction>
This investigation was undertaken to determine the
effect of hyperpyrexia on bile concentration and its rate of flow from
the liver#
literature}
Many investigators (32, 49, 51, 84, 120, 128, 142)
have used heat in various forms including localized diathermy over the
region of the liver, in the belief that heat so applied produced a
choleresis#
ETo conclusive evidence, however, has been presented thus
far#
Methodt
(a)
Both acute and chronic experiments have been performed#
Acute experiments#
Thirty-nine healthy dogs weighing from
thirty to forty-five pounds were used#
The animals were placed on a
standard diet and were not fed for eighteen hours prior to the experi­
ment#
They were placed under intravenous sodium pentobarbital anesthesia
using 32 mgs# per kilo body weight#
into the trachea#
An airway cannula was inserted
Carotid blood pressure tracings were registered on
a Isymograph concurrently with the bile flow record#
The common bile
duct was cannulated close to the duodenum, and a tube brought through
the abdominal incision, dropping the bile into a suitable vessel#
The
cystic duct was ligated and the edges of the abdominal incision were
held in opposition#
Bile flow was recorded electrically#
The bile
dropped across two platinum points, forming an electric circuit, which
worked an electromagnet moving a lever in contact with the smoked drum.
Time was recorded in one minute intervals#
Once regularity of bile
flow was established for a period not less than thirty minutes, a
-
control flow was recorded#
157 -
After a suitable control period, heat
applied and maintained until the dog*s rectal temperature rose
to 42° C#
The inductotherm was used as a source of heat#
The induc­
tance cable or electrode, fashioned in the form of an elipse, was
placed on the animal board and covered with burlap material to form
a suitable dielectric spacing between cable and dog#
tied to the board in the usual supine position#
The dog was
The heating period
usually lasted one hour, after which, the dog,s temperature was
permitted to return to normal#
This usually required several hours
even though an electric fan was used to assist in cooling the animal#
In our early experiments several animals were burned due to our
inexperience in estimating current dosage#
We later arrived at certain
empiric control settings on the machine which gave us satisfactory
heating results without apparent injury to the animal#
A control flow of bile was maintained for a period of from twenty
to thirty minutes, following which, the high frequency current was used
to secure the desired temperature•
The average number of bile drops
per minute, oovering a ten minute period was taken as the basalxate#
The average number of drops per minute during the ten minute period
showing the fastest flow, was selected as the maximum rate of bile
flow#
The difference between this maximum and the basal control rate
determined the rate of increase or decrease#
The increase or decrease
of the rate of bile flow, or minute volume output, was based on the
number of cubic centimeters collected per minute#
In this series we
encountered two incidences of acholia •
Quantitative clinical d eterminations for bile salts (Reinhold -
-
158 -
Wilson modification of the Gregory-Pasooe method (122% cholesterol
(modification of the Liebermann-Burchard method (42), bile pigments
(colorimetric comparison with bilerubin standard and fatty acids
(gravimetric deberuinations (70), were made to ascertain whether or
not there, was & change of the biliary constituents#
Biopsy of the liver, in three dogs, was made before and after
application of the heat#
(b) Chronic Experiments#
Nine healthy female dogs weighing between
twenty to thirty pounds were used#
Under ether anesthesia the cystic
duct was cannulated, the gallbladder removed, and the common bile duct
ligated and cut#
The rubber tubing from the cannula was coiled in the
abdomen, led to the outside through a stab wound, and attached to a
rubber collecting bag#
Following recovery from the operation, which
usually required an average of ten days, the dogs were placed on a
standard diet#
hours#
The bile was collected and measured every twenty-four
TJhen the quantity of bile was constant within jh ten to twelve
per cent, the animal was considered ready for heating#
The day prior
to heating, bile samples were collected and measured at 8 A#M#, 1 P#M#,
3 P#M«, and finally at 6 P#M#
Collections were made and measured at
similar time intervals during the experiment#
Quantitative chemical determinations were made on the collected
samples in a manner comparable to that of the aoufce experiments#
The dogs were placed in a cabinet which was heated by means of
electric light bulbs#
An electric fan kept the air in circulation#
Air from the outside was introduced into the hot chamber through a
rubber tube#
The temperature of the box was kept at approximately
- 159
-
®* to 48° 0# until the dog*a rectal temperature reached 105° to
107° F* which was maintained for a period of one to two hours*
This
method of heating was chosen because of the difficulties enoountered
in using the high frequenoy current when heating dogs.
During the
experiment the dog could be observed through a glass window in the lid
of the cabinet*
The dogs were placed on a wooden frame, which was canvas covered*
They were held in position by means of canvas straps, and then placed
in the cabinet*
Rectal temperature was recorded with a Brown resistance
recording thermometer*
Results!
(a)
Acute Experiments*
Table 32 shows how the thirty-nine dogs in the acute experiments
were used*
Table 33 gives the results of 22 experiments as recorded
by the kymographie tracing*
Subsequent to the heating period the
entire record showed an increase in bile flow*
The maximum rate in
most instances occurred just after the maximum temperature had been
obtained (Fig* 14)*
As a rule the rate of bile flow did not show an
increase until the rectal temperature reached 41*5° C*
the dog usually began to pant*
At this stage
All of the twenty-one treated dogs
showed an increased rate of flow over the basal rate*
ranged from twelve to five hundred per cent*
This increase
Dog 15a (Table 33)
showed this maximum inorease of 500 per cent with a temperature
elevation of 3*5° C*
After cooling to normal this same animal was
reheated to 2*5° C*, and this time the bile flow rate increased to
300 per cent of the original control (Table 33, Dog 15b).
All the
dogs that were burned, with one exception, either showed a decrease
-
or else no change from the basal rate*
160
-
These burns were second or
third degree and always occurred in the region of the electrode*
This
destruction was most marked at the surface and decreased proportionately
as the deeper tissues were reached*
The liver of these dogs, while
not burned, showed evidence of marked congestion*
The duration of the experiment, five to ten hours, had a relation­
ship to the average bile flow, consequently, the longer the experiment
continued the lower would be this average#
In forty*bhree per cent of
the dogs, the increased flow persisted sifter the temperature returned
to its control level*
Table 34 shows the average minute volume output
in nine experiments ranged from 13 to 100 per cent, while in two exper** iments there was a deorease rate of thirty to fourteen per cent*
In addition qualitative and quantitative ohemioal analysis of the
bile was made on eleven of these dogs*
included in Table 34*
experiment*
The summary of this data is
Table 35 gives a typical protocol of an individual
Table 36 gives the summary of bile volume flow and chemical
analysis in nine control dogs that were not heated#
They showed a
deorease in the rate of bile flow from 1*7 to 32 per cent in five dogs,
no change in two, and an inoreased rate in the remaining two dogs#
We
discovered that the rectal temperature of the control dogs did not remain
constant under sodium pentobarbitol anesthesia, but oontinued to rise
as time elapsed*
This occurred even though an attempt was made to
maintain basal temperature by the use of an electric fan*
In seven
of these dogs the temperature rose from 1° to 2*2° C* and was always
maximal at termination of the experiment*
The data on the chemical
analysis of the bile for the heated dogs are found in Table 34 and in
-
Table 36 for the control group*
161
-
Eight of the heated dogs shewed a
decreased concentration of colic acid of 10 to 70 per cent while two
showed an increased concentration*
The total bile salt output per
minute was increased in 4 and decreased in fire dogs*
Fire of the
control dogs showed a deorease in concentration of oholio acid ranging
from 10 to 64 per cent and fire showed a similar deorease in minute
output*
Only one of these dogs showed an increase in cholic acid
concentration and this was accompanied by the maximum temperature
rise of the control group#
In four of the control dogs we were
unable to detect the presence of oholio acid in the last few specimens
collected although the analysis was repeated several times*
The
question arises whether this could be due to a cessation of the
formation of cholic acid by the liver or to a masking of the usual
color encountered by large amounts of pigment with small amounts of
cholic acid*
Three of the heated dogs showed a deorease concentration of
cholesterol, two no change, while in two of the animals it increased*
Half of them showed an increase in the total amount of cholesterol
per minute while the remainder exhibited decreases*
The five control
dogs demonstrated diminished concentration and total cholesterol
output*
Determinations for bile pigments of the heated dogs showed a
decrease in concentration for 5 and an increased for 3 dogs while the
total pigment per minute was increased in seven and decreased in one
dog*
The controls showed an increased concentration and total output
in 8 dogs and a deorease in one*
-
Studies of the fatty aoids were made on three heated
control animals as illustrated in Table 38*
162
-
three
Two of the heated dogs
showed an increased total output of fatty aoids, the saponifiable
fraction being inore&sed*
The three control dogs demonstrated
decreases in the amounts of fatty aoids and a lowering of the non—
saponifiable-saponifiable fatty acid ratio*
(b) Chronic Experiments*
The results of twelve experiments on
nine dogs are tabulated in Table 38*
high frequency currento
One dog was burned with the
The twenty-four hour bile volume output was
increased in two experiments (2 dogs), deoreased in five experiments
(5 dogs), with no significant change in the remainder*
The twenty-four h o w oholio acid output showed an increase in
four experiments (4 dogs), a decrease in three experiments (3 dogs),
and no significant change in the remainder*
The twenty-four hour pigment output was increased in two experi­
ments (2 dogs), deoreased in the same number, and the remainder showed
no significant change*
The twenty-four hour cholesterol output was recorded for ten
experiments on seven dogs*
There was an increase in one instance and
a decrease in another, while the rest shewed no change*
Discussion! Sorokin (142) found by using hot mud over the region
of the liver, -the flow of bile into the duodenum was at first decreased
but later increased*
Kosa (84) using local diathermy to the liver found that a twenty
minute treatment, repeated two or three times during the filling of
the gallbladder accelerated the filling time*
Similar results were
-
163
-
reported by Rousard and Aimard (128) and more recently confirmed
by Rafsky (120)*
Frisch and Lasch (49) state that the normal individual showed
an inorease in the secretion and concentration of bile during and
after diathermy*
Goldgruber (51) reported an inorease in bile flow as observed by
means of a duodenal tube under clinical conditions*
Couperus and Moore (32) applied looal diathersy to the liver of
trained chronic biliary fistula dogs, and reported an inorease in
the bile volume output of eight to forty-six per cent in the first
twelve hour period after treatment*
The total twenty-four bile
volume output was increased seven to seventeen per cent, they reported*
Unfortunately, however, these workers recorded only one twenty-four
hour control period before the heating was performed©
They state
that previous work of other investigators convinoed them that the
total twenty-four hour bile volume output varies but little under
standard conditions, and hence they did not consider it necessary to
record a longer control period#
However, long observation on biliary
fistula dogs on a standard regimen has shown in our laboratory (79,
134) considerable daily variation in volume*
This amounts to +
eight per cent when the suction method is used and may be as high as
♦ twenty per cent when the bag technique is employed*
Hence, we feel
that the seven to seventeen per cent increase reported may well have
been within the normal v ariation of the animal*
Another objection
is the fact that these workers left the gallbladder in plaoe, draining
the bile by way of a tube in the fundus*
This introduces an unoon-
- 164 -
trollable factor, namely, variations in concentrating activity of the
gall bladder.
Karapetyan (75) noted that the local application of diatheray
over the liver caused an augmentation of bile flow, and increased the
amount of bile constituents in Pavlov biliary fistula dogs.
He reported an increased bile flow of 54.4 per cent.
However,
the report does not make clear whether his dogs were standardized in
regard to daily output before the heating period.
Schwiegk (135) showed
an increased blood flow in the hepatic artery by means of the Rein
thermostromuhr following the administration of heat applications to
the liver, and the intravenous injection of decholin.
Tanturi and
Ivy (143) have shown that reflexly increasing the intrahepatic vascular
pressure by stimulating the splanchnic nerves* chologenesis is inhibited,
and that sectioning the hepatic nerves diminishes the intrahepatic vas­
cular pressure and accelerates bile flow.
It might be assumed, then,
that providing the blood pressure is not depressed, fever oauses an
increased blood flow through the liver, which may stimulate bile forma­
tion b y augmenting the metabolism of the liver cells.
The results of our acute experiments show a definite oholerectic
effect#
Each experiment continued over a period of many hours.
The
animals were under an anesthetic which depressed the respiratory center
so that the animals did not pant until a temperature of 41.5° C was
attained.
The panting period did not exceed one half hour.
Heminway
(58) has shown that unanesthetized dogs begin to pant when their temper­
ature is elevated only slightly.
Although heat produced a hydrocholeresis in the acute experiments,
the increased volume flow more than offset the diminished concentration
165 -
of the biliary constituents.
In the control group, although the
volume flow did not always diminish, the total gravimetric output of
solids usually did#
The chronic biliary fistula dogs showed no such choleretic effect.
We are somewhat at a loss to explain this discrepancy between the acute
and chronio experiments.
experiments.
The dogs were unanesthetized during the chronic
Even well-trained dogs become excited and restless when
their rectal temperature is rapidly raised to 106° to 107° F.
As a
result there probably occurs a hyperactivity of the sympathetic or
adrenal mechanism with a generalized sympathetic stimulation.
It has
been shown (143) that stimulation of the hepatic sympathetic nerves
causes a decrease in bile secretion.
contradictory results.
This may explain, in part, these
Moreover, several hours elapsed before the
animals recuperated from the generalized depression which resulted from
the treatment.
Gibson and Kopp (50) have shown that with external heating devices
such as we used, the blood volume shows a very mar Iced decrease, but
that if sweating does not take place the blood volume does not ohange.
An analogous condition exists between the two kinds of experiments.
The dogs in the acute experiments panted very little for a few minutes
(analogous to sweating) while the chronic dogs panted and drooled at
the mouth all through the experiment.
The work of Rinehold and Wilson
(121) indicates that hydremic may produce choleresis.
Conversely then,
a deoreased blood volume may result in a decreased bile volume output.
They stated that in anesthetized dogs, application of heat over the
liver promoted bile flow, but provided no evidence in support of their
observation.
166
-
It is not altogether unlikely that blood pressure was deoreased
as a result of the treatment, and as pointed out, this oould be a
factor in decreasing the volume output.
It is also difficult to be positive that we have accurately eval­
uated the changes found, because of the large spontaneous daily varia­
tion in the dogs.
Ordinarily in the experiments on biliary fistula
dogs a control is taken which represents the average of several days
observation.
This is then compared to an average for the treated dogs
taken over a similar number of days.
When average values of this type
are compared spontaneous daily variations tend to be cancelled.
In
our experiments a control was taken in the manner just described, but
it was compared to the value for only one day, namely, the day of
treatment.
The nature of our experiments made it possible to give
daily treatment.
In this type of comparison, the part contributed by
spontaneous variation is far more difficult to evaluate.
But if a
real choleresis had oocurred, it should have become evident.
Conclusions!
1. A choleretic effect was produced in acute
biliary fistula dogs as a result of hyperpyrexia.
2.
In chronic biliary fistula dogs choleresis was not demon­
strated.
3.
The probable causes of these diverse results are discussed.
TABLE XXXII
DISTRIBUTION OF ACUTE EXPERIMENTAL ANIMALS
Drop Minute Method
10
Drop Minute and Volumetric Method
11
Controls
7
Burned and Discarded
9
Acholic
2
Total Number of dogs
39
• 168
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TABLE XXXIV
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- 170
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- 172
-
TABLE XXXVII
HEATED DOGS
FATTY ACID ANALYSIS MO./fe cc.
Dog No*
27
Sample No*
Non-Saponifiab le - Saponifiable
Control
2
3
4
•5
♦5
•4
28
Control
2
3
4
33
Ratio
4.5
6.0
4.5
1-9
1-12
1-11
.675
.770
1.000
0*845
45*35
26.50
25.40
17.25
1-67
1-34
1-25
1-24
Control
2
3
2.150
1.660
1.650
41.50
43*30
7 *0
1-19
1-26
1-42
34
Control
2
3
0.75
1.00
1.30
43.0
10.6
7.1
1-37
1-10.6
1-5.4
36
Control
2
3
1*0
1.0
1*0
30.0
28.0
15.0
1-30
1-28
1-15
39
Control
2
3
4
5
6
7
0*9
0.9
1.0
1.5
1.0
1.95
Not suffic lent
1
42*3
23.0
22.95
15.2
15.2
14.0
bile.
1-47
1-25
1-23
1-13
1-15
1- 7
mm
- 173 -
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- 175
Figure 17#
Acute Experiment
Effect
A*
B.
C*
D.
E#
of hyperpyrexia on bile flows
Control period*
Temperature 41.5° C#
Temperature 39.0° C, three hours later thanB*
Two hours after C#
Finish of experiment tenhours aftercontrol
period.
-
176
-
X# Summary and Conclusion
1* The theory on which artificial fever is based#
The present-day use of fever therapy is based on the theory
that fever is one of the physiological defense reactions against
disease.
This possibility was not realized until the end of the
nineteenth century*
The effects of non—speoific protein therapy were
confused with the effects of fever*
The author*3 investigations were
undertaken to ascertain the effects of fever per se on various diseases
and physiological processes#
It was believed that a sufficient fever
maintained for an adequate period mighti (a) kill or inactivate certain
organisms such as treponema pallidum; (b) increase the rate of antibody
production; (©) cause a leuoocytosis; (d) increase the blood flow
through a diseased part; (e) increase the metabolism of cells* which
in turn would augment the processes concerned in resistance and repair;
and (f) would not be harmful*
2# A comparison of the general methods for producing hyperpyrexia by
physical means*
Broadly speaking all of the techniques for the production of
artificial fever by physical agents can be classified under two general
heads#
One method uses external heat with which the production of
fever is dependant upon the patient being placed in a heated environ­
ment#
The other method uses the high frequency electric current to
generate heat in the body tissues themselves* independant of any
external heat application.
In both methods* heat loss must be retarded
in order to elevate effectively body temperature.
The former method
will be referred to as "external heating*1' and the other as "internal
- 177 -
heating#"
It was the author* s clinical impression based on the
observation of many patients, that, when external heat was used, the
subject was more restless, delirium was more frequently encountered,
and vascular collapse and heat stroke were more likely to occur*
These
observations stimulated the author to attempt to ascertain the explan­
ation*
Therefore, certain physiological processes were studied while
patients were undergoing hyperpyrexia treatment*
(a) A study was made of the effects of "external and internal
heating" on normal axillary and rectal temperature gradients*
There
were eight and twelve patients respectively in each group* With the
use of "external heat" the normal temperature gradient was reversed
during the period of fever induotion*
When "internal heat" was
employed the normal temperature relationships were maintained through­
out the entire treatment*
(b) The effect of these two methods on water balance was under­
taken*
Hyperpyrexia was produced by means of "external heating" in
31 patients and of "internal heating" in 14 patients*
The average
total fluid loss was found to be significantly greater in the "exter­
nally heated" group than in the "internally heated" group*
Moreover,
the average fluid intake of the former group exceeded the latter
group intake by
167 per
cent*
(o) The effect of these two methods on pulse rate under compar­
able temperature conditions was investigated*
subjected to each of the two methods*
Fifteen patients were
A significant pulse rate differ­
ence between the two groups was found for a rectal temperature above
102*9° F*
At this temperature the pulse rate averaged 19 beats per
- 178
minute higher in the "externally heated" group*
-
This relationship
existed throughout the high temperature plateau*
(d) The possibility that heat stroke might result from a
paralysis of the sweat glands was investigated, because it is possible
that a high external temperature might produoe directly a "heat
paralysis" of the sweat glands*
By experimentation on six human
subjects it was found that a high skin temperature, the highest that
could be tolerated, 76*5° C*, did not directly paralyze sweat glands*
Hence it was concluded that the direct effect of external heat was
not the cause of heat stroke*
Generalization!
These observations
made by the author, and others reported in the literature, constitute
strong presumptive evidence indicating that the use of high environ­
mental temperature to produce fever is potentially more hazardous
than the use of "internal heating" or inductotheway*
For this reason, inductothermy or internal heating was used
in most of the following studies, and its use is implied unless
othe rwise stated *
3* Do the temperature gradients of the various body tissues differ
during hyperpyrexia? And, is a spiroohetioidal temperature obtained?
During hyperpyrexia treatments, temperatures were recorded by
of thermocouples in the following parts of the body!
the spinal
canal, oistema magnum, liver, deep muscles of the thigh, axillary,
rectum, urethra, subcutaneous tissues of the scalp, face, forearm,
abdorosn, and lower leg*
The normal temperature gradients found prior
to hyperpyrexia were not abolished at the height of fever, although
they were reduced® We found that spiroohetioidal temperatures in
these regions of the body could be secured when the rectal temperature
- 179
was held at 107*6° F® for one or more hours*
-
Biopsy and inooulation
experiments proved that spiroohetes were actually inactivated by the
temperatures obtained*
4* Effect of hyperpyrexia on basal metabolism*
Basal metabolism determinations were made on 8 patients*
Tests
were made before treatment, when the rectal temperature reached 105° F*,
and finally at the conclusion of the treatment*
It was found that for
each degree Fahrenheit rise of the rectal temperature there was an
average increase of the metabolic rate of approximately seven per cent*
5* Effect of hyperpyrexia on cardiac rhythm*
An electrocardiographic study of 12 patients was undertaken.
No
observable changes in the intrinsic physiology of the heart was found*
The heart rate, of course, increased*
6* Effect of hyperpyrexia on the blood and circulation*
A series of experiments on blood and circulation were carried
out as follows!
(a)
Blood pH*
Thirty-three determinations of blood pH were made
on ten arthritic patients before treatment, at a temperature of 104° F*,
after a temperature of 104° F* had been maintained for four hours, and
after the temperature had returned to normal*
The average pH value
was raised from 7*41 at the beginning of treatment to 7*65 at the
height of the fever*
This indicates a state of uncompensated alkalosis*
The blood pH returned to its original level with the return of normal
temperature•
- 180 -
(b)
Differential blood oell counts were made before, during,
and after fever therapy on 15 patients*
The patients were submitted
to a temperature of 104° to 105° F* for eight hours.
slight increase in the red blood cell count*
There was a
A marked leuoocytosis
was apparent during the febrile period but disappeared twenty-four
hours later*
of the fever*
The leuoocytosis was at its maximum during the height
A lymphopenia existed during treatment but after
treatment the lymphocytes returned to their prefebrile level* We
noted no significant changes in other cellular elements*
(o) The effect of hyperpyrexia on hemooonoentration was studied*
We used the "falling drop method" for determining specific gravity*
We also determined the percentage of blood solids by weight*
ficant changes indicating hemooonoentration did not occur*
Signi­
Detemin-
ations were made before, during, and after treatment on 20 patients
to whom 0*4 per cent Na Cl solution was given in amounts varying from
200 to 400 o*c* per hour*
The amounts given were based on the require­
ments of the patient as Judged by the clinical experience of the author*
An arbitrarily, or a routinely administered amount could not be used,
because it would cause nausea and vomiting in some patients*
(d)
Twenty-six determinations of the COg combining power of the
blood plasma was made on 6 patients*
The average decrease of the
COg combining power of the plasma was 5*6 volumes per cent as a result
of the treatment*
ficant*
This decrease was found to be statistically signi­
Thus, the blowing off of COg by hyperventilation during
hyperpyrexia must be assumed to be greater than the reduction in plasma
bicarbonate in order to account for the increase in the alira.U nity
of the blood during hyperpyrexia*
- 181 -
(e) Ten determinations of the plasma non-protein-aaitrogen
were made on a single individual*
No significant changes oocurred,
although the final values were lower after the course of treatments
than at the beginning*
At least the kidneys of this patient did not
appear to be damaged deteotably by successive bouts of hyperpyrexia*
The author has observed no clinical evidence of kidney damage in many
patients repeatedly treated, though careful studies on a number of
patients have not been made by the author*
(f) Two complete studies of the finger pulse volume changes were
made on two patients during the induction of artificial fever by various
physical means including typhoid vaccine*
It was found that all
methods used produced a marked volume increase in the finger*
The
maximum pulse volume increase, however, occurred before the maximum
temperature employed (104° to 105° F*) was reached*
A significant drop in blood pressure (129/83 before) (108/69 after)
was found to occur as a result of fever therapy in 24 patients*
(g) Ascorbic acid determinations before, during, and after fever
therapy was undertaken on 18 patients*
No significant changes were
found to occur as a result of treatment*
The great majority of the
patients (arthritic) were found to have low normal ascorbic acid
concentration values*
(h) A total of 378 determinations including total leucocyte
counts, erythrocyte counts, complement titer, opsonic index, phago­
cytic power of leucocytes and agglutinins were made on 17 patients*
The only significant immunologic ohange found to be produced by
hyperpyrexia was a temporary increase in the leuoooyfce count immediately
- 182 -
after hyperpyrexia*
Alterations in complement content, opsonins,
and phagocytic property of leucocytes were found to be within the
limits of normal variation*
Fever undoubtedly increases the work of the heart, which is
somewhat compensated by the decrease in blood pressure*
To what
extent the work of the heart is actually increased has not been
accurately determined*
No disturbances of cardiac rhythm were observed*
Because of the increase in the work of the heart, fever therapy must
be used very cautiously in patients with cardiac defects*
The shift in the abid-fcase balance of the blood toward an uncom­
pensated alkalosis in an unfavorable response, since a greater degree
of alkalosis than that observed produces undesirable symptoms*
The
observed leuoocytosis is a favorable response, -though there seems to
be no increase in circulating antibodies*
The general increase in
rate of blood flow would be favorable if such ooours in an inflamed
or infected tissue*
7* The effect of hyoscine and pilocarpine on axillary temperature
when associated with hyperpyrexia*
This w$s studied in 6 patients*
The administration of hyoscine
caused a marked diminution of perspiration, which resulted in a very
erratic rectal temperature course# We believed it to be the cause
of violent delirium in some of the patients#
pilocarpine produced these effects*
Neither morphine nor
It is believed that anti-sudorific
drugs should not be employed to facilitate the production of fever*
8# The effect of fever on bile formation*
The effect of hyperpyrexia on choleresis was studied*
Acute
183
experiments were made on thirty-nine dogs* We found that hyperpyrexia
increased bile formation in these experiments*
The increase involved
an increase in the total output of water and cholic acid* though the
inerease in water was greater than that of the cholic acid#
Twelve experiments were performed on nine dogs with a permanent
biliary fistula*
Ho oholeresis was observed in these animals when
the bile was oolleoted over a twenty-four hour period*
The probable
explanation of the discrepancy between the results of these two
experiments has been presented*
There is no reason .to believe that
liver function is harmed by the type of fever therapy employed*
To what extent has the theory on which artificial fever therapy is
based* been supported by the foregoing observations?
(l)
A fever can be produced in the human body of sufficient
degree* and for a sufficient period of time to inactivate or destroy
treponema (spirooheta) pallidum in a primary lesion*
To what extent
this is true for other organisms is uncertain* and even in the case
of a generalised infection with treponema* one cannot rely on fever
therapy alone for the cure of the disease*
(2) Although* according
to the reports of some investigators the rate of antibody production is
augmented* it cannot be stated implioitely that fever augments the
mobilization of antibodies from tissues to the blood stream*
(3) The
mobilization of granulocytes into the blood stream should improve
local defense mechanisms at least temporarily by supplying inflamed
tissues with an increased source of these phagocytic cells*
(4)
An
increase in the rate of the circulation of the blood in the body as
a whole occurs in fever*
It is reasonable to assume that this also
- 184
is true of inflamed tissues; this* however* has not been proven*
(5) An increase in metabolism of the body as a whole ocours in fever*
but whether this improves the ability of cells to combat infection
is still problematic*
The general oonoeption that fever facilitates the defensive
mechanism of the body is supported by the clinical results obtained
with therapeutio hyperpyrexia* particularly in early general paresis
and gonorrheal arthritis*
The results in other diseases* such as
rheumatic fever* chronic arthritis* chorea* asthma* multiple sclerosis
are not so striking* with the possible exception of chorea*
Fever
places a strain on the cardiovascular-respiratory system* and the
thermotatio system*
The evidence shows that these systems are subjected
to less strain by employing the method of ttinternal heating,than
by employing the method of wexteraal heating*w
In either case* if
adequate attention is devoted to the prevention of hemooonoentration
Anri of excessive stimulation of the cardio-vaseular-respiratory* and
thermotatio systems* the potential hazards of hyperpyrexia are obviated*
165
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—
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— ------ ----
||
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therapy* Physioth* Rev©* 16 (I936)i93*
Fever
133. Soheresohewsky* J© W.s The physiological effects of currents of
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17 (1938)#133©
------------137© Simpson, W© M©, F© K. Kielig* and E. C. Sittleri Ultrahigh
frequency pyretotherapy of neurosyphilis. Ann. Int. Med.* 7
(1933)# 64©
138. Simon* J. F©# Effects of hyperpyrexia on the human blood oount*
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400©
139© Sloan* J© W©* and C. A. Doan# The pathogenesis of hemorrhage in
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140© Soiland, A©l Thermogenesis by radio frequency currents©
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142# Sorokin* G© E©* Action of locally applied heat on propulsion of
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143© Tanfcuri* A©* and A. C© Ivy# A study of the effects of the vascular
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144© Tem$r* C. F©# Artificial fever produced by short wave radio and
its therapeutic application. Ann. Int© Med©*
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146© Tillett, W© S.i The bactericidal action of human serum on
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147* von Wagner-Jauregg* Die Tuberkulin-Quecksilberbehandlung der
Progressives Paralyse* Therap* Monatshefte, 28 (1914)*1*
148* Warfield, L* M*» The treatment of circulatory failure*
Int* Med*, £ (1934)*981*
Ann*
"
149* Weiohbrot, R*, and F* Jahnelt Einfluss hoher ELorpertemperaturen
auf die Spirochaeten und Krankheitserscheinungen der Syphiliss
im Tierexperiment* Duetsch* Ifed* Woohensohr*, 45 (1919)*483*
150* Wiggers, C* J** Physiology in health and disease*
edition* Lea and Febiger, 1937*
Second
151* Wiggers, C* J*, and 0* Oreas* Circulation changes during hyper*
thenna produced by short radio waves (r&diothernia)* Am* J* Med*
Sci*, 100 (1932)*614*
152* Wilgus, S* D*, and L* Iurie* The fever treatment of paresis by
means of the diathermy current and the electric blanket* 111*
Med* J*, 60 (1931)*341.
153* Wilson, Erasmus* Thermo-the rapeia* The heat cure* The treatment
of disease by immersion of the body in heated air* Reprint
from British Med* J*, 1860, Oct* 13*
154* Wolff, L* K*, C* Banning, and M* Van Eebe lint Nutrition of
various groups of families in the Netherlands* Quart* Bull*
Health Organ* League of Nations, 5_ (1936)*606*
155* Wulff, F*« On thermostabile bactericidal substance remonstrated
in human serum particularly during fever* J* Immun*, 27 (1934)*
451*
156* Zoak, J*, and G. R* Sharpless* Vitamin C nutrition in artificial
fever* Proo* Soc* Biol* and Exp* Med», 39 (1938)*233*
1.
PUBLISHED ARTICLES
Joint authorehip except starred articles
1212
*1. Heart Rate and Blood Pressure in relation to Pubescence
Graduating Thesis - Springfield College
1915
*2. Grading of Gymnasium Classes
Am* Phy, Ed. Review, Vol. 20* 85-69* Feb., 1915
1924
Sacro-Iliac and Lumbo-Sacral Strain
Am. J. Electrotherapeutics and Radiology, July, 1924
1926
*4. Peripheral Nerve Lesions
Am. J* Physical Therapy, Feb., 1926
♦5. Treatment of Foot Strain Following Fracture of the Lower Leg
Am. J. Physical Therapy, July, 1926
1929
6. Artificial Fever Produced by High Frequency Currents
Preliminary Report. 111. Med. J., Sept., 1929
1251
7. The Treatment of Dementia Paralytica with Hyperpyrexia Produced by
Diathermy
J. A.M.A., Jan. 2, 1951
8. A New Msthod of Producing Fever
physiotherapy Review, Maroh-April, 1951
9. A New Method of Nonspecific Treatment of Allergic Disease
J. of Allergy, May, 1951
10. Fever by Diathermy in the Treatment of Allergic Disease
j. of Allergy, Sept., 1951
2.
11* The Treatment of Arthritis by Sustained Fever Therapy
J* of Allergy, Sept*, 195*
12. Elevation Thermique Procoque par la Diathermia dans le Traitment
de 11Asthma Aigue
La Presse Medicals, May 21, 1952
15* Sustained Artificial Fever in the Treatment of Intractable Asthma Physiologic and Therapeutic Considerations
J* A.M*A« Sept* % 1952
14* The Present Status of Electropyrexia
Arch* Phy* Therap* X-Ray and Radium, Dec*, 1952
1222
15« The Treatment of Arthritis by Sustained Fever Therapy
111. Med* J*, Sept., 1955
16* Hyperpyrexia
Physiotherapy Review, Nov*-Dec*, 1955
1954
17* The Physiology of Hyperpyrexia
Am* J* of Syphilis, Jan*, 1954
18# The History of Hyperpyrexia
Arch* of Phy* Ther* X-Ray & Rad*, March, 1954
19* The Treatment of Infectious Arthritis by Electropyrexia
Arch* Phys* Ther* X-Ray and Rad*, March, 1954
20* Electropyrexia - A Resume of Therapeutic Technic and Application
Annal* Int* Med*, May, 1954
21* The Treatment of Some Multiple Scleroses by Electropyrexia
J* Nervous and Mental Diseases, April, 1954
22* The Inductotherm*
A New Method of Heating Tissues
Am* J* Med* Sci*, May 1954
25* Treatment Technique with the Inductotherm
Physiotherapy Review, July-August, 1954
24* Technics Para Tratamientos Con El Equipo Para Inductotermia
Revista De Radiologia and Fisrioter&pia, Nov.-Dec*, 1954
2-
1225
25* Tissue Heating by Short Wave Diathermy - Some Biologic Considerations
J. A.M.A., April 20, 1925
26. Methods of Producing Hyperpyrexia by Various Physical Agents
111. Med. J., Sept., 1955
27* Studies of Peripheral Vascular Phenomena. The Effect of Artificial
Fever on the Pulse Volume Changes of the Finger
Am. J. Med. Sci., Oct., 1925
125£
26. Short Wave Diathermy — A Comparative Study in Pelvic Heating
Arch. Phy. Ther. X-Ray & Rad., March, 1926
29* The Treatment of Early Syphilis with Electropyrexia
J. A.M.A., July 18, 1926
20. The Treatment of Chorea Minor by Means of Electropyrexia
J. A.M.A. Sept., 192* 1926
21* Measurements of the Temperature of the Maxillary Sinus after
Tre atmen t by Various Methods of Heatin g - A Comparative Study
Arch, of Otolaryngology, Sept., 1926
22. Short Wave Diathermy in Heating Human Tissues
Arch. Phys* Therapy X-Ray & Rad., Nov., 1926
22* SI Tratamiento de la Sifilis Temprano con la Electropirexia
Nov.—Dec., 1926
24. Observations on the Use of Acetyl B Methy1cho1ine Chloride in
Chronic Arthritis
A m . Int. Med., Dec. 1926
1927
25* Treatment of Chorea Minor by Means of Electropyrexia
Arch, of Neurol.
Peychiat., Jan., 1927
26. El Tratamiento De La Corea Minor par Medio de la Elect ropirexia
Revista de la Eleetropirexia
Revista de Radiologia y Fisioterapia, Mareh-April, 1927
27* La Diathermia de Indas Coras. Estudio comparative del calentamiente
de ka pelviB
Revista de Radiologia y Fisioterapia, March-April, 1927
4.
58* La Diathermia da Onae Oortae en el Galentamiento de los Teiidoa
del Hombre
J
Rev 1sta de Radiologia y Fisioterapia, May-June, 1957
59* Physiologic and Chemical Effects of Short Wave Diathermy
J* of Medicine, Aug*, 1957
1958
40. Relationship of wavelength in the Heating of Human Tissues by
Short Wave Diathermy
J* A.M.A., Feb* 26, 1958
4l# Electropyrexia in Rheumatic Carditis Chorea and Certain other
Childhood Diseases
Physiotherapy Review, Maroh-April, 1958
42* Thermal Effects of Short Wave Diathermy on Bone and Muscle
Arch* Phy* Therapy, X-Ray and Radium, May, 1958
45* Electropyrexia* Technic of Applications and Therapeutic Indications
Ann* Int. Med., Aug., 1958
44* Effactos Cl ini coa y Fisiologicos de la Diathermia por Qndas Cortae
Radiologia y Fisioterapia, July-August, 1958
45* La Longitud de la Onda en el Calerrtamiento de Los Tejidos del
Hombre por Medic de la Diathermia por Ondas Cortas
Revista de Radiologia y Fisioterapia, Sept *-0ct*, 1958
1222
6* The Physiology of Heat
The Physiotherapy Review, 19*59-62; Maroh-April, 1959
47# Short Wave Medical Diathermy* Clinical Applications
New York State Journal of Medicine, 59*#7; April 1*1959, 699-705
48* Efectos Termicos de la Diathermia por Ondas en el Hueso Y El
Musculo
Revista de Radiologia Y Fisioterapia, vol. 6, #5* 118-122;
May-June, 1959
49# Electropyrexia* Tecnica de su Aplicaoion, e Indicaciones Terapeuticas
Revista de Radiologia y Fisioterapia, July-August, 1959
50. Treatment of Arthritis with Acetyl-Beta-Methylcholine Chloride
Archives Phy* Therapy, July, 1959, 406-410
51* Temperature Changes and Changes in Caliber of Retinal Blood Vessels
after Short Wave Diathermy
Archives of Opthalmology, August, 1959, 22*211-227
The Dangers of Elect r©pyrexia#
Ifed# Record, December 20, 1939,
CHAPTERS IN BOOKS
±12£
1* Medical Diathermy, Chapter 22
Principles and Practice of Physical Therapy*
Prior Co*
1958
2* Short Wave Diathermy* Technique of Application, Chapter 25
Principles and Practice of Physical Therapy* Prior Co*
1959
5* Hyperpyrexia by Physical Agents, Chapter 54, volume 5
Treatment in General Medicine* F* A* Davis Co*
BOOK
4* Fever Therapy Technic
Svalt, Parsons, Warren & Osbornes
Paul Hoeber Co*, July, 1959
7
ARTICLES TO BE PUBLISHED
1* The effect of artificial fever on brain tissues#
study#
A histological
2# The effect of artificial fever in the treatment of arthritis#
3# Inductothermy localized to the prostate in the treatment of
prostatitis#
4# She effect of hyperpyrexia on ascorbic a d d concentration of
plasma#
6# The effect of hyperpyrexia on hemoconcentration#
6# The effect of hyperpyrexia on bile flow#
7# The effect of bile salts on hepatic blood flow#
8# Short wave diathermy#
intensity#
A new method to accurately determine dosage
VITA
Stafford Lennox Osbofne
Bornt
May 16# 1885#
Pub lie Schoolss
Vancouver# B# C## Canada*
Vancouver# B* C*
B# P* E#s
1913# International Young Men,s Christian Association
College# Springfield# Massachusetts#
Sigma Xii
Northwestern Chapter# 1937#
M* S#t
Northwestern University# 1938#
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