William Ferdinand Petersen.

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bacterial destruction that follows the injection or the amount of necrotic tissue
involvement of the patient.

Just how much of the nonspecific reaction is essential, whether
the discomfort of the intravenous bacteriotherapy can be modified by
using the protein split products without sacrificing any of the remark-
able therapeutic effects that are at times achieved, is not to be de-
termined at present but must be the subject of further clinical investi-
gation. For purposes of orientation we have in the following pages
described the reaction that follows the intravenous injection of typhoid
bacilli in moderate dosage 25 to 50 million organisms; not because
it may be the ideal form of therapy of this type but because it is
the reaction which is most familiar clinically and, because of the
availability of the vaccine, the most easily obtained agent for ex-
perimentation.

It is practically impossible to ascertain beforehand, because of
the varying individual factors, the degree of the reaction that will
be produced. When, however, experience has been gained with a
definite preparation and with a certain class of clinical material
it is usually possible to gauge the results that are to be expected
with some measure of exactitude. Needless to state it is an elemental
precaution to begin with a small dose when undertaking a study of
the effect on patients.

The Chill. Usually the first symptom that comes to the attention
of the patient following the injection is a chill or rigor. This may set in
as early as fifteen minutes after the intravenous injection of typhoid
bacilli or a proteose solution, usually within 30 minutes, but may
be delayed for several hours. When colon bacilli and some other
organisms are used the chill may not be observed for several hours,
in one of our cases not until 8 hours after the injection. With intramus-
cular milk injections the rigor commences in from two to three hours.

The degree of the reaction varies there may be merely twitch-
ing of the leg or arm muscles, or the chill or rigor may be quite
general and severe and last from 20 minutes to an hour. Commonly
this phase of the reaction begins to wear off in from one-half to
three-quarters of an hour after its inception.

During this time the patient may complain of actual sensation of
chilling and demand extra covering and hot water bottles; in other
cases there is merely the muscular twitching and trembling with-
out sensory disturbance. In .the acute arthritides this phase of
the reaction may be of considerable discomfort to the patient be-
cause of the added motion and its resulting pain in the involved joints.



48 PROTEIN THERAPY

The analgesic effect that follows shortly in the wake of the chill
as a rule compensates for this short period of increased pain.

The Temperature Curve. The temperature reaction of the patient
varies greatly with the vaccine or protein used, and even when one ad-
heres to a single agent such as typhoid vaccine, differences in the age of
the vaccine, the dosage, the strain of bacilli and the method of killing
the bacteria when the vaccine is prepared, all have a definite effect on
the reaction; and this apart from the individual variation that we meet
on the part of the patient variations that depend, as already men-
tioned, on the disease, its duration, the previous temperature, previous
injections, etc.

With the subsidence of the chill or during its later stages the
temperature of the patient has as a rule commenced to rise. In
typical arthritic cases running a febrile course of from 100 F. to
101 F. the injection of typhoid vaccine will raise the temperature
to about 103 F. or 104 F., the maximum increase being recorded
in from three to four hours after the injection. With intramuscular
milk injections the temperature maximum may not be reached until
six or eight hours after the injection. As a rule the defervescence
is more rapid with the intravenous injections, but even in the case
of the milk injections the former level is reached within 24 hours.
Subcutaneous nuclein injections are followed by a febrile reaction
that begins later and recedes more slowly than observed with the
other methods.

Schmidt has classified the reactions following milk injections into
5 groups, according to the degree of febrile reaction of the patient
following a uniform amount of milk intramuscularly injected. In
the first group are the cases that react with 37 C. or under; in the
second that react with 37 C. to 38 C. (98.6-100 F.) ; in the third
that react with 38 C. to 39 C. (100-102 F.) ; in the fourth that
react with 39 C. to 40 C. (102-104 F.) ; in the fifth that react with
40 C. to 41 C. (104-106 F.).

Schmidt and Kaznelson worked chiefly with milk injections, using
10 c.c. injected intragluteally. The temperature rise occurred usually in
from 6 to 8 hours and was at times accompanied by a chill (rather rare),
more often by sweating, and some headache. The blood pressure was not
altered. Herpes were seldom noted. The temperature increase at times
persisted for from 24 to 48 hours. Among the five groups into which
Schmidt and Kaznelson have classified their patients it will be of interest to
observe some of the cases in the first three groups. They are as follows :

Temperature under 37 C., Group I Carcinoma, 4

(98.6 F.) (Normal) Secondary Anemia, 1

Myotonia (Thomsen's Disease), 1
Diabetes, 2
Influenza, 1



THE NONSPECIFIC REACTION 49

3Y 0. to 38 C., Group II Hysteria, 1

(98.6-100 F.) Achylia, 1

Icterus, 1
Acromegaly, 1
Chlorosis, 1

Posthemorrhagic Anemia, 2
Gonitis, 1
Polyarthritis, 3
Chronic Arthritis, 2
Carcinoma, 8
Diabetes, 3
Cholecystitis, 1

38 C. to 39 C., Group III Tuberculosis, 4

(100 to 102 F.) Gumma, Liver, 1

Hemophilia, 1

It is of peculiar interest to observe the relative resistance of the carci-
noma cases of this series to temperature response following the injections
(most of these were stomach and esophageal cases). The reactivity of the
neoplasms varies greatly some observers report rather violent reactions;
others, such as Schmidt, believe that they are examples of decided resist-
ance. It seems most probable that the reaction depends largely on the
amount of necrosis present in the tumor, its vascularity and its ana-
tomical position. Schmidt correlated this relative resistance to the milk
injections with his previous observations concerning the relatively low
"Infection Index" of carcinoma patients and their resistance to vaccines.
Wetzel believes that the absence of a febrile reaction to parenteral injection
of milk is not constant enough to aid in diagnosis, although it is occasionally
conspicuous in diabetes and cancer.

Schmidt noticed that the reaction was independent of the dosage
to a considerable degree, although after one or more doses had been
given, the reaction became less marked. It depended to a large degree
on the individual, and the type of the disease. Thus in a normal
person one can inject as much as 1 c.c. of a 10% solution of al-
bumose without appreciable temperature reaction or constitutional
effect of any nature. In an arthritic patient the same injection
may raise the temperature two or three degrees; in a typhoid or
tuberculous patient by as much as five degrees (F.). On the other
hand, when the same dose is injected in a pneumonic patient who
already has a high temperature (let us say 103 F.) the tempera-
ture may not be increased, or may actually show a decline without
any preliminary increase after the injection.

Habetin, using 0.5 gm. of sodium nucleate subcutaneously in a
series of some 60-odd patients ill with a variety of diseases, classified
his reactions according to the system of Schmidt.

It will be observed that the most marked pyrogenic effect is manifest
in diseases involving hematopoietic organs and those in which definite



50



PROTEIN THERAPY



foci of pathological tissue exist such as sarcoma, tuberculosis, etc.
The degree of febrile reaction is independent to a considerable de-
gree of the agent or the dosage; it depends on the infection and the
state of the patient, i.e., on an individual factor.





I


II


III


IV


V




2


5


4


4







o


2


4


1


1







2


3


6







o


1


1








Multiple Sclerosis


o


3


3


1





Diabetes





1













o


1





o







o





1
















1








Typhoid








1


3





Pernicious Anemia





o


1


2





Chlorosis





o


1













o





1





Pyemia





o








1


Endocarditis ,





o


o


o


1















Gow, who early employed heterovaccines, came finally to the use
of the colon vaccine as being most dependable, other vaccines such
as streptococcus, etc., being followed by little temperature effect. He
noted the fact that the reaction varies greatly in different individuals,
just as had Schmidt. A dose of 50 million might in one instance
cause a severe reaction but little in another. For therapeutic result
Gow concluded that a moderate reaction was essential.

That the injection of bacteria would cause fever and that the reaction
depended to some degree on the digestion of the bacteria was noted many
years ago. (Gamaleia.) Roux and Lepine had observed the pyrogenic ef-
fect of the other protein substances before this, while Charrin and Ruffer
determined that the pyrogenic effect of the bacteria was thermostable, that
is, they heated the bacterial emulsions to 110 C. and were still able to
get the original pyrogenic effect on injection.

The later studies of Buchner, Schittenhelm and Weichardt, of Fried-
berger, Vaughan, etc., are of course well known.

The Pulse. Coincident with the temperature reaction the pulse is
almost invariably increased to some extent, usually about 15 to 30
beats per minute. With the onset of the sweating the peripheral dilata-
tion brings this down to almost the preinjection level. As a rule the
quality of the pulse is not altered, and arrhythmia, if present before-
hand, is not increased. Cyanosis is uncommon ; I have observed it only
once following an injection of proteoses in a case of typhoid fever. In
this case the cyanosis was a transient phenomenon and the patient



THE NONSPECIFIC REACTION 51

went on to a complete recovery from his typhoid in two days.
Cyanosis is but infrequently noted in the literature. Gow has re-
cently studied the pulse rate in patients receiving peptone injec-
tions intravenously. He finds that the higher the leukocytosis, the
greater the rise in pulse frequency after injections. The increase in
pulse rate in his cases varied from 5 to 20 beats per quarter minute.
The pulse frequency returned to normal in from 3 to 5 minutes after
the injections. With vaccines these effects are of course greatly delayed.

The character of the pulse and its rate is of decided importance in de-
termining which cases are suitable for injection. In typhoid a rapid pulse
rate (over 100) is a contraindication to nonspecific therapy. Experimen-
tally it has been shown that small doses of proteoses stimulate the heart
muscle, the amplitude and the force of the beat being increased (Weichardt).
In several cases of long-standing heart lesions associated with arthritis
we have watched the size of the heart after nonspecific injections both
during the acute reaction and the defervescence. In these cases the left
border went out about 1 cm. and returned to the preinjection size in from
24 to 48 hours. The patients showed no evidences whatever of any cardiac
decompensation. Naturally only cardiac patients that were in good con-
dition were selected for the injections.

The Blood Pressure. Scully was one of the first to undertake sys-
tematic studies on the blood pressure of patients after typhoid vaccine
injections. It is of course quite difficult to obtain an accurate reading
during the time that the patient has a chill, but enough observations
have been recorded to indicate that there is a slight increase in blood
pressure during this time. When the chill has subsided and the period
of perspiration sets in, the blood pressure shows a progressive decline
of from 10 to 25 mm., reaching a maximum in from 6 to 8 hours,
and returning to the normal pressure within 24 hours. Considerable
variation is noted, however, in individual cases, depending on the
dosage, the agent used and the infection of the patient. .

When injections are given to a typhoid patient in the later stages
of the illness, where evidence of an unstable vasomotor system fol-
lowing the long continued toxemia is apparent, we have observed a
vasomotor paralysis extending over a period of 48 hours and very
refractory to stimulation. In one such case the systolic pressure
sank to 55 mm. and remained very low for 24 hours. This patient
had been running a very high typhoid temperature for 4 weeks with-
out any evidence of improvement. Following the recovery from the
injection his temperature remained normal and the patient made a
complete recovery.

A number of factors enter into the effect on the blood pressure.
It has been noted for instance that the subcutaneous injection of
relatively large doses of typhoid vaccine Besredka or Vincent
during typhoid fever, while it has a much less apparent effect on
ftie patient in ftie form of chill, fever and sweating, seems to be



52 PROTEIN THERAPY

followed by far greater depressing effects on the cardiovascular
system than the intravenous injection of small amounts of typhoid
vaccine. After milk injections Muller has observed a slight primary
decrease, then an increase in the blood pressure.

While the effect on the blood pressure depends on individual fac-
tors the duration of the disease, the agent used, etc., the fall in the
blood pressure which accompanies shock effects depends largely on
a dilatation of the vascular bed in the splanchnic area. The peripheral
dilatation which one can observe with the sweating of the patient does
not produce the extreme drop in the blood pressure that the splanchnic
engorgement does.

Different animals respond to the injection of protein split products,
peptone, histamin, etc., with different effects on the blood pressure, de-
pending on which part of the vascular bed is subject to constriction, on
stimulation of the vasomotor nerves, etc. The liver of carnivora responds
with a spasm of the capillaries with a resulting diminution of the blood sup-
ply to the right heart and a lowering of the blood pressure. The primary ef-
fect is followed by a dilatation. The liver of the herbivora is quite in-
different, indicating a difference in innervation. The spasm of the arteri-
oles of the portal area results in a passive filling of these vessels while in
the lungs we have also a contraction of the arterial system with a re-
sulting dilatation of the right heart, accompanied by a fall in pressure in
the left heart and the general circulation. In discussing this mechanism
Mantner and Pick call attention to the fact that the difference in the
effect of the shock poisons in herbivora and carnivora is easily explained by
the differences in the behavior of the various capillary systems. Simonds
has recently noted this same difference in the behavior of the musculature
of the hepatic vein and has drawn conclusions similar to those of Mantner
and Pick. Dale's conception of the mechanism does not quite follow that
here presented.

It becomes apparent from a consideration of the possible mechanism in
the dog and the human after such shock effects why stimulants such as
adrenalin are relatively ineffective while vasodilating agents such as caffein
are said to be followed by more effect in the acute stage of shock depend-
ing on such vasoconstriction of the hepatic vein and its branches.

The possibility that other factors enter into the change in the blood
pressure is by no means excluded, v. Behring laid great stress on the
finding of thrombi in the capillaries of the lungs in acute anaphylactic
shock and Hanzlik and Karsner have recently called attention to the fact
that the intravenous injection of a number of colloids and typical non-
specific agents may be followed by such changes in the finer capillaries.

Sweating. Shortly after the subsidence of the chill the patient
may sweat profusely; in arthritic patients one finds this most fre-
quently; typhoid and pneumonic patients are less apt to sweat after
the injections, but may do so if the injection is followed by an in-
crease in temperature and a critical fall.



THE NONSPECIFIC REACTION 53

A number of observers have claimed that the mere production of
a profuse perspiration will relieve arthritic symptoms and a variety
of therapeutic procedures have been elaborated which have as their
object the production of a sweat, either by applying external heat
or the administration of a variety of drugs. There seems little doubt
that many patients are relieved to some extent by such measures
but there is almost invariably a recurrence of the symptoms after
the sweating has stopped for 24 hours. The possible mechanism
that is involved in any therapeutic stimulation of the skin such as
occurs when the patient is sweated is discussed in the chapter on
the relation of the skin to internal diseases.

Nausea and Vomiting. This is occasionally observed after rela-
tively large doses of vaccines or after particularly toxic strains of
bacteria. It is usually an indication that the dosage has been too
large or that the patient is particularly sensitive. The entire gastro-
intestinal tract will frequently show increased peristalsis.

Palpable Spleen. Gow has observed that the spleen may become
palpable immediately after the reaction.

Effect on Menstruation. Lux has observed that the menstrual
flow is augmented after nonspecific injections.

Nervous Irritability. Kling showed some years ago that during
the period sensitization following on the injection of some protein
parenterally the nervous irritability of the animal was considerably
increased.

Following nonspecific injections it has been found that a similar
alteration tales place but the effect on the threshold of the nerve
reaction is a diphasic one. There is for a short period following
the injection a lowering of the threshold for nerve stimuli, clinically
demonstrable by the increase in the pain, and the general hyperex-
citability. This is followed by a period of lessened susceptibility to
pain, somnolence, and the clinical manifestations of the marked euphoria
which has been commented on by almost every one who has had
experience with nonspecific therapy. Dollken, working with neuritides
has observed a similar reaction in the local effect on nerve tissues.
He found that after heterovaccine injections there would be a re-
sponse on the part of the lesion either in a negative sense increased
pain, etc., or as a positive phase analgesia and complete restitution
to normal in some instances.

Herpes and Urticaria. Herpes has been observed to follow a num-
ber of intravenous injections. We have noted a labial herpes after use
of typhoid and colon vaccines (certain strains seem to be more prone
to produce herpes than others) . Auld has reported an occasional herpes
after intravenous injection of colloidal metals. Gow has observed such
eruptions after heterovaccination and they have also been reported
after milk injections.

Urticarial eruptions are not so common. We have observed one



54 PROTEIN THERAPY

quite generalized rash in an arthritic patient that came on within
three hours after the injection and had disappeared after 24 hours;
other observers also report that skin manifestations are uncommon
in their experience.

Headache. Headache of the frontal region is a common symptom
following typhoid and colon vaccine injections, but is observed less
frequently after milk and other substances. The headache is not as a
rule of long duration, lasting usually not more than two or three hours
after the chill.

Delirium. In diseases associated with marked intoxication, such
as typhoid, typhus and erysipelas, the intravenous injection of non-
specific agents may at times be followed by intensification of the
disease manifestations and among them delirium may at times be ob-
served. It is usually a very transient phenomenon that disappears as
soon as the febrile reaction diminishes; only rarely does one observe
any disorientation that persists past the reactive period following the
injections. Care must of course be observed in excluding alcohol-
ics from nonspecific injections, for such patients may develop a de-
lirium tremens during the reaction which, once elicited, may lead
to a fatal termination. Several such cases have come to our atten-
tion.

Glandular Activity. Weichardt has carried out a number of ex-
periments in which he has shown that the injection of moderate
amounts of protein split products increase glandular activity. He
demonstrated this in lactating goats as well as for the salivary glands
of a number of animals. Dollken has reported an increased secretion
of bile following milk injections.

The question of the galactagogue effect of parenteral injections of
milk, of interest to the pediatrician, has been the subject of con-
siderable investigation, but has not been conclusively settled.

Slawik, during the course of his work with nonspecific injections
in infants, had occasion to inject several wet-nurses. Dunkan is said
to have observed a galactagogue effect after the injection of milk
parenterally in lactating women, but Slawik in his cases was not able
to confirm this result. Lonne has published observations that indi-
cate an increased secretion of milk after parenteral injections, but
his conclusions have been criticized by Kirstein, although the latter
does not deny the possibility of glandular activation.

Nitrogen Metabolism. The nitrogen balance shows considerable
variation both experimentally and clinically following the parenteral
introduction of the proteins and their split products. It is of course
beyond the scope of this discussion to examine so-called specific
dynamic effect of proteins in their general effect on the normal metab-
olism after ingestion, although certain facts that have been derived
from a study of this field indicate that there are fundamental differ-
ences involved in the cellular reactivity incident to the digestion of



THE NONSPECIFIC REACTION 55

proteins as contrasted to the absorption and metabolism of the car-
bohydrates and fats.

A number of years ago Italian observers noted that in normal
animals the injections of small doses of toxins and of tuberculin
were followed by an augmentation of the nitrogen metabolism (ex-
cretion) followed by a period in which an excess of nitrogen was
stored. Animals treated with small doses of tuberculin would gain in
weight as contrasted to normal animals without injections.

Much work has been done during the course of studies on anaphy-
laxis, and inasmuch as this simulates the picture that we obtain
in nonspecific therapy to a considerable degree, the results are not
without interest in this connection. Schittenhelm and Weichardt
noted the immediate increase in the nitrogen excretion in anaphylactic v
dogs after a shock. Thus one dog from a normal excretion of 1.88
gm. per day excreted 2.8, 3.3, 2.65, 2.41 the days following shock,
amounts far in excess of the amount of protein injected to produce
the shock. Segale noted the same effect and Manoiloff observed an
increased excretion of nitrogen in rabbits despite the fact that the
temperature had diminished.

Hirsch and Leschke have studied the same subject in a very
thorough manner. They found that with fairly large doses of an-
aphylatoxin a negative nitrogen balance obtained, whereas smaller
doses or mild shocks often led to a positive balance. They noticed
that the excretion of nitrogen did not necessarily bear any direct
relation to the temperature of the animal resulting from the vari-
ous pyrogenic agents. Breed's studies are also of interest in this
connection.

In the patient the injection of the nonspecific agents with the re-
sulting reaction is associated with an increase in the nitrogen ex-
cretion just as such shocks are associated with an increased
metabolism in animals. In a number of cases that we have followed
the total nitrogen excretion of the urine increased from 20% to 30%
above that excreted before the injection. After about two days the
nitrogen excretion again reaches the normal and for a variable period
after this time there exists in many patients a diminution in excretion.

The Weight of the Patient. Uddgren has followed the weight of a J



Online LibraryWilliam Ferdinand PetersenProtein therapy and nonspecific resistance → online text (page 7 of 36)