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I

The  Cartwright  Lectures.
ON THE
GENERAL PATHOLOGY OF FEVER. 
 
       THE  CARTWRIGHTLECTURES.




                      ON THE



GENERAL  PATHOLOGY  OF  FEVER.




                          BY       ^/

           WILLIAM  H.  WfLCH, M.D.,
    PROFESSOR OF PATHOLOGY, JOHNS HOPKINS UNIVERSITY, BALTIMORE.
          Delivered before the Association of the

Alumni of the College of Physicians and Surgeons, New York,

            March 2g, April j and 12,1888.
 LECTURE I.—The Nature of Fever.
 LECTURE II.—The Effects of Increased Temperature of the Body.
LECTURE III.—The Etiology of Fever.


                    -----               IV


                   PHILADELPHIA:
           WM. J. DOR NAN,  PRINTER.
                         1888. 
wc
W4-4\e- 
LECTURE   I.
THE NATURE OF FEVER.
  There is no subject in medicine of more  general and
varied interest than  fever.  The practitioner in every
department of medicine, the pathologist and the physiol-
ogist  are  equally interested in the investigation of the
nature and effects of fever.  Even the  physicist  and the
chemist,  who are  not directly concerned with medical
science, have lent their aid to the study of  animal  heat
and its disorders.  The history  of opinion  regarding
fever  is in great part the history of medicine itself, for no
feature of the great systems of medicine from Hippoc-  „
rates and  Galen to the present century so characterizes
these  systems as the views held concerning the nature of
fever.  In consequence of the importance of the subject
and of the number and ability of those engaged in its
investigation, it might be supposed  that no chapter in
medical science would be better understood  than  that
pertaining  to fever.   That such is not the case is due to
the fact which is becoming more  and more evident  that
the reaction of  the animal system which we  call  fever is
dependent upon the most fundamental and essential pro-
perties of  protoplasm  and of nerve energy.  In  propor-
tion as our knowledge of these properties increases and-
becomes more accurate, we gain a clearer insight  into the 
4
WELCH,
complicated  processes  involved in  the  production of
fever.
  I should hardly have selected for this course of lec-
tures a subject where so many problems remain unsolved
and which must necessarily be presented in so  fragmen-
tary a form, were it not that in all ages the opinions held
concerning the nature of fever have controlled  measures
employed in  its treatment.   In  proof of this, one  need
not go back to the time when fever was regarded as an
almost conscious struggle  of an anima with a noxious
principle, in which struggle the physician was to interfere
as little as possible, or  to the  time when fever  was sup-
posed to  result from morbid humors which the physician
should aim to eliminate by the  production of  a  critical
discharge, or  to  the  period when the  treatment  hinged
upon  the belief  either in  the  sthenic or the asthenic
nature of fever.   In our own  time the treatment of fever
is intimately connected with the  answers variously given
to such questions as whether fever aids in the  elimination
or destruction of infectious agents concerned in its pro-
duction ;  whether increased waste of tissue is a constant
condition and a  source of danger in fever; what part is
played by infection  and what part by elevation of tem-
perature in causing the grave symptoms of fever; what
in addition to lowering of temperature are the  effects of
so-called antipyretic measures of treatment ?
  I  need hardly  say that the subject of these lectures
relates to fever as a condition common to  all  febrile dis-
eases.  Some writers understand by the term fever used
in this sense merely abnormal elevation of temperature,
others  elevation of  temperature and the  symptoms
directly caused by Jhis, and still  others  a  complex of
symptoms of which  increased temperature is  the most
prominent but not necessarily the cause of  the  others.
In considering the general pathology of fever  it  is con-
venient  to adopt the last meaning, although  it would 
        THE  CARTWRIGHT  LECTURES.      5

doubtless be less confusing if the word fever were applied
only to abnormal elevation of temperature.
   Increased temperature being the dominant and  essen-
tial symptom of fever, all discussions as to the nature of
fever centre around the  question,  How is the  febrile rise
 of temperature produced ?  It is to  the consideration of
this question that I first invite  your  attention.   As there
are other aspects of fever which I  wish  to discuss, it will
be necessary to present the  matter  belonging to  this
division of the subject in as  succinct a form  as is com-
patible with clearness.  Twelve years  ago Burdon-San-
derson1 brought together in an admirable critical review
the results of investigations upon  this subject  up to that
period.  Since that time  important  additions  have been
made to our knowledge of the mode of production of fever.
   In  the wonderful  preservation of a nearly  constant
temperature which  characterizes  in health  the warm-
blooded animals three factors are  concerned,  viz.,  the
production of heat within the body,  the loss of heat from
the body, and the  regulating  mechanism by which the
varying heat production  and heat loss  are so balanced
that the  internal temperature  remains practically con-
stant.   It is theoretically possible  that  the rise of tem-
perature in fever may be  due to the disturbance of any
one  or more of these factors. It  becomes  necessary,
therefore, to consider the behavior of heat production, of
heat loss, and of the regulating mechanism in fever.
   We  will begin with the consideration of the production
of heat in fever.  The amount of  heat  produced by the
body is estimated by two methods, one  known as direct
calorimetry,  the  other as indirect calorimetry.  In  the
method of direct calorimetry the animal  is placed in a
closed ventilated box surrounded on all sides  by a com-
partment  containing water  or air, and the amount of
heat discharged  from the body is  determined by  the
1  Burdon-Sanderson : The Practitioner, 1876. 
6
WELCH,
quantity of heat imparted to the surrounding  water or
air.   If the temperature  of the  animal  remain  un-
changed during the period  of observation, the heat pro-
duction is equal to the heat loss ;  if the temperature rise
or fall, the amount of heat  corresponding to this change
of temperature—an amount determined by multiplying
the weight of the animal by its specific  heat and by the
number of degrees of altered temperature—is added to
or subtracted from the quantity of heat imparted to the
calorimeter.  Time will  not permit me to enter into ex-
perimental details  in this connection;  it must suffice to
say that the method of direct calorimetry necessitates the
introduction of a number of corrections which cannot be
determined with absolute accuracy, so that the  results
obtained are of relative  rather than  of absolute value.
  Hitherto the estimation of heat production in fever by
determining the entire amount of heat liberated from the
body has been made only upon animals in which fever
has  been  artificially produced.  The most  elaborate
researches of this  nature are those of Senator1 and of
Wood.2  The experiments  of Wood are of the greater
value because he extended his  observations over longer
periods of time.
  In  four  of the  seven calorimetrical experiments of
Wood on  different  fevered dogs  comparison  can be
made of the  amount of heat produced hourly in fever
with that  produced by  the same animal when fed  and
when in a state of hunger.  During the period of fever
the animal was also in  a condition of hunger.  I have
computed from Wood's tables that the average  hourly
heat production during  seven days described as first and
second  fever days, is a little over  23  per  cent, greater
  1 Senator: Untersuchungen liber d. Fieberhaften Process, Ber-
lin, 1873.
  2 Wood :  Fever, A Study in Morbid and Normal Physiology,
Philadelphia, 1880. 
        THE CARTWRIGHT  LECTURES.      7

than that of the healthy animal during a state of hunger,
the minimum excess being i per cent, and the maximum
55.5 per cent.1   If a comparison be made of different
periods during the existence of fever there are found to
be even greater fluctuations in the amount of heat pro-
duction than these figures would indicate, this amount
being sometimes more than double that in  hunger and
sometimes considerably less than the average production
in hunger.  Moreover, these experiments show no defi-
nite relation between the height of  the temperature and
the amount of heat produced, nor is it possible to deduce
from them any relation between heat production and the
different stages of  fever, such as the more recent  calori-
metrical experiments  of  Wood,  Reichert, and   Hare2
appear to show and which will be  described later.  An
important  outcome of these  as  well as of all similar
calorimetrical experiments is that, although the heat pro-
duction of an animal in fever is greater than that  under
like conditions of  nourishment, it is, as a rule,  less than
that of the same animal upon a full diet.
   There are many reasons which make  it important to
control the experimental results obtained from animals
in fever by corresponding observations of human beings.
The agents  used  in producing experimental fever have
been generally  putrid  fluids or  pus,  the  injection of
which causes sometimes diminution instead of elevation
of temperature.    When  fever is  thus  produced,  it is
usually of short duration and of only moderate  intensity,
the rise of temperature being  rarely  more  than four
degrees, and sometimes not more than one degree Fahren-
heit.  Moreover, a large part of the important role played
  1 In making this computation I have corrected some numerical
errors in Wood's tables ; these errors are not serious and do not
affect his conclusions.
  2 Wood, Reichert, and Hare: Therapeutic Gazette, 1886. 
8
WELCH,
by the skin in the regulation of the bodily temperature in
man is assumed by the lungs in these animals.
  Complete calorimetrical observations of human beings
in fever encounter difficulties which have not yet been over-
come.  The imperfect or incomplete methods employed by
Liebermeister1 and  by Leyden2 in determining  the heat
production of human beings in fever justify the inference
that this production is  increased, and, apparently, as a
rule, to a greater extent than in animals, but they do  not
warrant positive conclusions  as to  the quantity of heat
produced.
  We turn now to the results regarding febrile produc-
tion of heat obtained by what has sometimes been called
indirect calorimetry.  Inasmuch as the heat energy of
the body is the result of chemical changes of its  proteids,
fats, and carbohydrates,  it is evident that if we know  the
kind and the amount and the heat value of the substances
consumed in a given time within the body, we can com-
pute their heat production.3 These chemical changes, so
far  as their final products are concerned, are processes of
oxidation.   The heat values of the substances consumed
in the body were determined first by Frankland and more
recently with accuracy by von Rechenberg, Danilewsky,
and Rubner.   The investigations of Pettenkofer and
Voit have shown that in hunger almost exclusively fats
and proteids are oxidized, and that  in  this condition  by
determining  the amount  of  oxygen  absorbed and of
nitrogen and of carbon excreted, we  can estimate  the
  1 Liebermeister:  Handb. d.  Path.  u.  Therap.  d.  Fiebers.
Leipzig, 1875.
  2 Leyden : Deutsches Arch. f. klin. Med., Bd. 5.
  8 The energy resulting from these  chemical changes appears
partly in the form of heat and partly  in mechanical work.  As
practically all of the internal mechanical work is transformed within
the body into heat energy, it is only the external mechanical work
which is to be considered in estimating the actual heat production.
The influence of this factor in fever will be spoken of later. 
        THE  CARTWRIGHT  LECTURES.      9

quantity of fat and of proteid substances oxidized during
the period of observation.
   Physicians of past centuries regarded increased con-
sumption  of the  material of the  body in fever as so
evident that it needed  no especial demonstration, and
after Lavoisier made apparent the sources  of  animal
heat, it was accepted  almost unquestioningly until the
last quarter of a century  that fever is essentially a process
of increased combustion or  oxidation.  The immense
historical importance  of the promulgation  in   1863 of
Traube's  theory, which  denied the dependence of fever
upon increased production of heat, is that this theory has
led to a careful inquiry into the grounds of beliefs hitherto
generally accepted,  and to the demonstration of the un-
satisfactory nature of the evidence  hitherto thought to be
conclusive.
   The striking loss of weight of most fever patients is, as
is well known, a fact of great clinical importance.  Weber
and Finkler have  demonstrated that animals in fever lose
weight  more rapidly  than  healthy animals in hunger,
and although observations on human  beings  with refer-
ence to this point  are  not  concordant in their results,
there can be little doubt that the  tendency of fever is to
cause a greater  loss of weight than  can  be explained
simply  by insufficient nutriment.  This tendency, how-
ever, may be  masked by the retention of water within
the body as the investigations of Leyden and others have
shown.   While,  therefore, the  studies of the  loss of
weight in fever leave no  doubt that there is increased de-
struction  of tissue in this condition, we cannot consider
this loss as an accurate measure of the  increased destruc-
tion, nor,  without further knowledge, as an indication of
increased oxidation, still  less as proof of excessive pro-
duction of heat.
  It was for a long time  believed that  the excessive ex-
cretion of urea in  fever afforded satisfactory evidence of
increased oxidation and of greater production of heat.  We 
IO
WELCH,
now know, especially from the researches of A. Frankel,1
that this is so far from being true that we could explain
the excessive elimination of urea better upon the assump-
tion of diminished than of increased oxidation of tissue-
In  certain pathological conditions, notably phosphorus
poisoning, the amount of urea excreted may be increased
more than threefold, nothwithstanding,  or, as Frankel
believes, in consequence of diminished absorption of
oxygen and elimination of carbonic acid.  It can, more-
over, be computed that even without any diminution of
the respiratory gases the discharge of urea may be in-
creased without  greater production  of heat.  While,
therefore,  the  enormous  increase in  the  discharge of
urea in fever sheds valuable light upon  a most  obscure
subject, the nature of febrile metabolism, it does not, re-
garded by itself, afford us any information as  to the pro-
duction of heat.
   Failing to find satisfactory proof of increased oxidation
in the loss of weight of the  body, or the excessive  ex-
cretion of urea in fever, attention was then directed to
the elimination of carbonic acid, an excretory  product
which bears a much closer relation to the  production of
heat  than does urea.   Immense  importance has been
justly  attached to the  determination of  the  amount of
carbonic acid excreted by an  individual in fever.  No
point in the whole battle-ground of fever pathology has
been more hotly contested than whether increased pro-
duction of carbonic acid is an essential part of the febrile
process.   The first investigators of this question, Leyden,
Liebermeister,  Senator,  contented themselves with the
determination of the amount of carbonic acid eliminated
by an individual in fever and in apyrexia.  There are
several considerations  which greatly diminish the value
to be attached to the mere estimation of carbonic acid
excreted  without  simultaneous determination   of  the
1 Frankel: Virchow's Archiv, Bd. 67. 
        THE  CARTWRIGHT  LECTURES.     II

amount of oxygen absorbed.   As has been urged by
Senator, and with especial clearness by Pfliiger, increased
discharge of carbonic  acid does  not necessarily imply
increased production of the  same.  The  discharge of
carbonic acid  varies,  independently  of its  production,
with the rhythm and  depth of respiration, and with the
temperature and the alkalinity  of the blood, all factors
which are altered in fever in such  a manner  as  to favor
increased liberation of carbonic acid.   It is true that the
influence of these factors would cause increased discharge
of carbonic acid out of proportion to its production only
for a limited period, and that the  prolonged  increase in
the amount of carbonic acid discharged in fever, which
has been found by several observers, can  hardly be in-
terpreted otherwise than in favor of increased  production.
There is another point which detracts  still further from
the value of exclusive determinations of the  quantity of
carbonic acid discharged, and this is that it makes a great
difference, so far as the production of heat is concerned,
whether the  carbonic  acid  is the result of oxidation of
carbohydrates, of fats, or of proteids, a difference amount-
ing,  according to Rubner,1 to 29.5 per cent.;  or, if only
the proteids and fats be considered, to over 20 per cent.
In investigations of nutrition it  is now known to be of
the utmost importance to determine the so-called respira-
tory quotient—that is,  the ratio  between the amount of
carbonic acid discharged and that of oxygen absorbed.
This quotient varies in a definite  way  with the  kind of
material oxidized in the body, and an accurate knowledge
of it would enable us to draw conclusions as  to  the sub-
stances consumed in fever.
  The investigations which have been  published within
the last few years upon the absorption of oxygen, as well
as the discharge of carbonic  acid in  fever, are to  be
ranked as most valuable contributions  to our knowledge
' Rubner: Zeitschrift f. Biologie, Bd. xxi. 
12
WELCH,
of the subject.  The  first determination by trustworthy
methods of the amount of oxygen absorbed and of car-
bonic acid excreted in fever was made in Pfliiger's labo-
ratory by Colasanti upon a guinea-pig, and was published
in 1877.  Since  that  time  two  careful and elaborate
researches upon this  subject have been made, the one
by Finkler, and the other by Lilienfeld.1
  These experimenters found  that in  fever  there  is
increase of the amount, both of oxygen absorbed and of
carbonic acid excreted. Making comparison with healthy
animals under the same conditions of nutrition, Colasanti
found that  the increase in the  absorption  of  oxygen
amounted to 18 per cent, and in the excretion of carbonic
acid to  24  per cent.; Finkler, whose experiments were
made also  upon guinea-pigs, found, under varying con-
ditions of external  temperature, the average febrile in-
crease of oxygen to be 13.8 per  cent., and  of carbonic
acid 15.3 per cent., and Lilienfeld, who experimented on
rabbits, found the average increase of oxygen to be 13.9
per  cent.  The statement  of these averages gives an
incomplete conception of the oxidation  in fever, as they
are derived from all stages of fever, and varying eleva-
tions of temperature.  No constant proportion was found
to exist between the height of the temperature and the
amount of oxidation.  On the other hand, a relation was
observed between the oxidation and the stages of fever,
viz., the  initial stage with rising  temperature, the  acme
with constant  high  temperature, and  the defervescence
with falling temperature.   During the  period of rising
temperature oxidation was  increased, and in this  stage
Finkler  found the  highest  percentages, amounting  to
36.6 per cent,  in the increase  of oxygen, and  37.6  of
carbonic acid.  There were, however, marked fluctuations
in this stage, both in the temperature and the amount of

  1 Colasanti,  Pfliiger's  Archiv, Bd.  xiv.   Finkler, Ibid.,  Bd.
xxix.  Lilienfeld  Ibid., Bd. xxxii. 
        THE CARTWRIGHT LECTURES.     13

oxidation.   In the stage of constant  high temperature
such high percentages were not noticed, and the fluctua-
tions  were less  marked.   The  processes  of  oxidation,
according to Lilienfeld, are increased, on the average, less
in the acme than in the initial stage of fever.1  During
defervescence of fever the increased oxidation falls, and
may sink below the normal.  Taking a broad view of these
stages, we may say, therefore, that the periods of rising,
constant, and falling temperatures in fever, correspond to
periods o-f rising, constant, and falling oxidation, but we
must  bear in mind that the fluctuations in  oxidation are
much greater than, and bear no constant relation to, those
of temperature;  so  that, in  each period, there are times
when oxidation may rise or fall most  decidedly without
corresponding changes  of temperature.
  Inasmuch as  these experiments  have shown that the
increased excretion of carbonic acid in  fever is accompa-
nied by increased absorption of oxygen, and, as will be
explained presently,  that the respiratory quotient, if  it
changes at all, sinks, it  is evident that we  need not dis-
card experiments in which only  the amount of carbonic
acid excreted has been estimated by good methods.  The
most accurate of these  experiments.are those of Leyden
and Frankel  upon fevered dogs.2   They found  that,
without exception,  carbonic acid is excreted in larger
amount in fever than in health under the same nutritive
conditions, the excess amounting sometimes  to 70 per
cent., and in general being larger than in the experi-
ments which have  been  previously  considered.   The
earlier and meritorious experiments of  Senator upon this
point  did not give uniform results, and  he felt justified in
concluding  that there is  no evidence  of increased pro-
duction of carbonic  acid in fever.  Subsequent experi-
  1 In the period of rising temperature there was an increase of
oxygen absorbed of27 percent., in the acme of 14.9 per cent.
  2 Levden and Frankel, Virchow's Archiv, Bd. 76. 
14
WELCH,
ments with far more accurate methods have demonstrated
the incorrectness of Senator's conclusions.   It may be
well to call to mind that Burdon-Sanderson's deductions,
which  have naturally had great influence among phy-
sicians here and abroad, were based, in great part, upon
the data derived from Senator's experiments.
  Hitherto, the methods employed in studying the respi-
ratory  gases  of human beings in fever have  not ap-
proached  in  accuracy  those used in  the  experiments
described.  If the discordant results of Wertheim,  which
were obtained by methods manifestly very inaccurate, be
discarded, all other investigators have observed augmented
discharge  of carbonic  acid in fever of human beings.
Leyden found  an  excess  of 50 per cent, in  the febrile
discharge  of  carbonic  acid; and Liebermeister, whose
observations were made chiefly on cases of intermittent
fever, found an excess of 30 to 40 per cent, in the period
with rising temperature, and of 19 to 31 per cent, in the
acme of the fever.  During the defervescence of the fever
the excess of  carbonic  acid  discharged diminished, and
sometimes wholly  disappeared.   In  one  instance, in
which  the determination was made during the  rigor of
intermittent fever,  the  carbonic acid excreted was two
and a half times the normal  amount;  an excess so enor-
mous that it  was undoubtedly due, in great  part,  to the
muscular movements which  attended the chill.
  Although we cannot  consider these  figures as  abso-
lutely  accurate, they indicate  clearly that  in human
beings, as well  as  in animals, fever is  characterized by
increased  oxidation, and  apparently that, as a rule, in
man the excess of oxidation is greater than in the experi-
mental fever of animals.  This was to be expected, as it
is difficult to produce experimentally in animals anything
approaching in intensity the well-marked fevers of human
beings.
  As the  result of these  laborious  researches we may
consider it established that increased oxidation is  a part 
        THE  CARTWRIGHT  LECTURES.     15

of the fever process.  It has been claimed that this aug-
mented oxidation is simply the result of the elevation of
temperature, but  it can be proven that this is not true.
Pfliiger has demonstrated that the processes of oxidation
are more active at high than  at low temperatures of the
body, and he  has also established the increment of oxi-
dation which corresponds  to each degree of rise of tem-
perature.  By means of these  data Finkler has computed
that in guinea-pigs the febrile elevation of temperature of
i° C. could cause  an increase of the absorption of oxygen
of only 3.3 per cent.  Moreover, Lilienfeld found decided
increase in the processes of oxidation before there is any
marked elevation of temperature, and all the experiments
have rendered it quite evident that there is no such rela-
tion in fever between the  height of the temperature and
the energy of oxidation, as would  be expected if the aug-
mented oxidation were merely the result of the increased
temperature.
   There is no  reasonable  doubt that the more energetic
oxidation which we find to be  an essential part  of the
process of fever indicates  increased production of heat.
Exactly what  amount of heat production corresponds to
the increased  oxidation we cannot know until the kind
and the quantity of substances oxidized in  fever have
been determined.   It is to be regretted that no experi-
ments have been made in which the amount  of nitrogen
excreted has been determined at  the same time with the
estimation of  the oxygen absorbed, and of the carbonic
acid discharged.   These  data would enable  us to form
some estimate, although  not an  accurate  one,  of  the
amount of heat production corresponding to  the oxygen
absorbed, unless very different laws from those in health
control the oxidation processes of fever.
   Mention has already been  made of the importance of
determining in fever the respiratory quotient,  or the ratio
between the carbonic  acid discharged  and the oxygen
consumed.  A few words will make this clear. It is well 
i6
WELCH,
known that under ordinary circumstances in health not
all of the oxygen consumed reappears in the carbonic
acid discharged.  This indicates that a part of the oxygen
absorbed is used in other oxidations than those resulting
in the production of carbonic acid.   According  to the
extent of these other oxidations, therefore, the respiratory
quotient must vary.  It is probable that these oxidations,
of which carbonic acid is not a product, result at least in
part, in the formation of water, which is, therefore, one of
the excretory products of the body,  as  has been urged
especially by  Austin Flint.   The influence of various
circumstances upon  the respiratory quotient has been
studied, but what especially concerns  us here is  that
in hunger this quotient sinks, which is to  be expected
from the fact  that in this condition almost exclusively
fats and proteids  are oxidized.  We evidently possess in
the determination of the ratio of carbonic acid discharged
to the oxygen consumed a  means  of  reaching a  con-
clusion as to a cardinal point in the pathology of fever,
viz., whether the processes of oxidation in fever conform
to the laws which govern them in health, and particularly
whether, as  has  been often asserted, unusual  or incom-
plete products of oxidation are formed  to any consider-
able extent in fever.  Colasanti and Lilienfeld found that
the respiratory quotient in their fevered animals did not
vary from that of healthy animals under similar nutritive
conditions.  Finkler observed that the respiratory quotient
fell in fever  somewhat more rapidly than in hunger, and
this he explains by the more active oxidation in  fever.
All three experimenters reached the  conclusion that the
substances oxidized  are the  same in fever as in health,
and that other than the normal products  of combustion
are not formed   in fever  in any considerable amount.
That the metabolism in fever does differ in at least one
important respect from that in hunger, is evident  from
the excessive amount of urea excreted in  fever, but con-
siderable variations in the disintegration  of albuminous 
        THE CARTWRIGHT  LECTURES.     IJ

material may occur without much change in the respira-
tory quotient.
  The only determinations of the febrile consumption of
oxygen and discharge ot carbonic acid in man are those
of Wertheim and of Regnard.  Both investigators found
a decided  diminution of the respiratory quotient.  The
method employed by Wertheim was so  defective that no
confidence can be placed in his results.  The experiments
of Regnard1  are presented with great neatness, but his
results on other points differ so much from those obtained
by trustworthy physiologists and by better methods, that
we  cannot accept  his conclusions  as to  the respiratory
quotient in fever without confirmation.   Regnard found
in all fevers which he studied a most marked diminution
of the respiratory quotient.  If this were true it would
follow that in fever a much larger part  than in health of
the oxygen consumed is employed in  other  oxidations
than those yielding  carbonic acid.   This would confirm
the widely accepted belief that water and products of in-
complete  oxidation  are formed in  excessive amount in
fever.
  From the unfortunate discrepancy of  these results it is
evident that the knowledge which we now possess of the
processes of oxidation in fever is not sufficient to enable
us to form from them an accurate estimate of the heat pro-
duction.  In hunger, from one-fourth to one-third of the
absorbed oxygen is available for combination with hydro-
gen to form water, the remainder uniting with carbon to
form carbonic acid (Regnault and Reiset).  If in fever the
same ratio exists,  then  the excess of  heat production
would be proportionate to the excess of oxygen absorbed,
assuming that the substances oxidized are the same in
both conditions; if, however, as  Regnard's experiments
indicate, a larger proportion of  oxygen  is available in
  1 Regnard : Recherches Exp. sur les Variations Pathologiques
des Combustions Respiratoires.  Paris, 1878.
                          2 
i8
WELCH,
 fever for the oxidation of hydrogen, then the increment
 of heat production would be still greater, for the same
 amount of oxygen produces more heat when employed
 in the oxidation of hydrogen than in that of carbon. It is
 also to be considered that the same quantities of hydrogen
 and  of carbon in their oxidation yield varying amounts
 of heat  according to the chemical compounds in which
 they  are contained, and we cannot say positively whether
 the compounds oxidized are the same in fever as in health
 under like  conditions  of nutrition.    Upon the whole
 the weight of evidence is in favor of the view that the ex-
 cess  of heat production in  fever is  approximately pro-
 portionate to the increase in the consumption of oxygen,
 but it would be  rash to assert this positively.  It is evi-
 dent  that in fever ordinarily a much smaller amount than
 in health of the energy resulting, from chemical processes
 is transformed into external mechanical work, so that re-
 latively more remains in the form of heat.
   In  connection with this discussion of the possibility of
 unusual sources of heat in fever may be mentioned an
 hypothesis which has been advanced with  much ingenuity
 by Dr. Ord.1  This hypothesis is based upon the assump-
 tion, which is probable  enough, that there  are in the body
 chemical processes in which' heat energy is transformed
 or rendered latent.  These processes  are thought to be
 chiefly those concerned in the building up of tissue.   It
 is argued that inasmuch as the construction of tissue is
 manifestly in abeyance in fever, the amount of heat  in
 the body may  be increased  not only by disintegrative
 processes, but also by "the  persistence  in the form  of
 heat of energy which should  have taken  another form."
 That  these building up processes influence decidedly the
amount of heat  produced in  the developing ovum has
been demonstrated by d'Arsonval's calorimetrical deter-
mination that the  egg  during incubation absorbs heat
1 Ord: British Medical Journal, 1885, vol. ii. 
        THE  CARTWRIGHT  LECTURES.     19

notwithstanding the consumption of oxygen  and the ex-
cretion of carbonic  acid.   This fact, which might  have
been predicted, certainly does  not justify us in refusing
to attach any calorimetrical value to the determination of
the  respiratory gases and the urinary nitrogen.  From
the  little  we  know of these constructive  processes in
human beings we should infer that the amount of energy
in the form of heat which  they appropriate bears only a
very small ratio to the total heat energy set free by heat-
producing processes, so that their cessation  would not
bring a large increment to the heat of the body.  More-
over, these  constructive processes are also in abeyance,
although  doubtless  to a less extent, in starvation, with
which experimental fever is usually contrasted as regards
heat production  and heat loss.  It is not  probable that
any extraordinary difference  in  the behavior of the pro-
cesses of tissue-building in fever  and in starvation can
occur without affecting the respiratory quotient.   For the
present, therefore, we cannot attach any great importance,
so far as the increase of heat energy in fever is concerned
to the inactivity of heat-absorbing processes.
   We have gone over now the evidence which, in my
judgment, establishes the fact that there is increased pro-
duction of heat in fever.  The same conclusion is reached
also by the study of the loss of heat from the body in
fever.  That fever is accompanied by increased production
of heat and by more active combustion, has been in all
ages the belief of the majority of physicians.  This belief,
however, has been  rather instinctive than based  upon
actual demonstration.   It has been contested by investi-
gators of great ability, and on  the  ground of scientific
observation.  For these reasons, and on  account of the
importance of the subject,  it has seemed to me desirable
to present to you the exact evidence, although many of
its details,  I fear,  may have wearied you.  We  have
learned, moreover, certain facts concerning febrile thermo-
genesis  which  the mere  observation of  fever  patients 
20
WELCH,
does not render so apparent.  We have found that there
is no definite relation between heat  production and the
height of the temperature, so that we may have excessive
thermogenesis with low as well as with high temperatures.
There  appears to be,  however, a relation between the
stages  of fever and heat production, this being in spite of
remarkable fluctuations greatest in the initial stage, and
least in defervescence.
   Although for reasons which have been mentioned, and
others  might have been adduced, we can attach  hardly
an approximative value to figures which purport to give
the actual heat production in fever, still, unless far more
serious errors than seems possible inhere in the methods of
direct and of indirect calorimetry, we can draw one impor-
tant  conclusion.   This is that while an individual in
fever produces more heat than he would in health under
similar conditions as to food and muscular movements,
he does not produce necessarily in fever more heat than he
would  in health on a full diet.  And it is certain that he
usually produces far less heat in fever than he often  does
under  circumstances which  normally increase heat pro-
duction, such as a cool environment  and muscular exer-
cise.   That  one in health,  with little or  no  change of
temperature, may produce twice or more the  quantity of
heat  which  he produces in fever, makes it  plain  that
it  is  impossible to explain  febrile  rise of temperature
simply on the basis of increased thermogenesis, or what
probably comes to the  same thing,  of increased  oxida-
tion.   That in  health vastly increased heat  production
may  occur with comparatively little  change of tempera-
ture is, of course, due to the fact that the dissipation of
heat is proportionately increased. It  is self-evident,  and,
so far as I know, has never been disputed that in fever
the equilibrium is so disturbed that  heat loss  does  not
correspond to heat production  as it should  in health.
This  disturbance of equilibrium can be brought about in
various ways, and it is  only  by the determination of the 
THE CARTWRIGHT LECTURES.     21
actual heat production and heat loss in fever that we can
say in what direction the balance is disturbed.
  We have found that the production of heat is increased
in fever when the comparison is made with like condi-
tions of nourishment and of environment.  It is obvious
that the total loss of heat cannot equal the total  produc-
tion of heat during the period of febrile rise of tempera-
ture.
  As is well known, most of the heat  of  the  body is
liberated from  the skin  and from the lungs; from  the
former by radiation and conduction and by the evapora-
tion of moisture, and from the latter by evaporation of
moisture and warming the respired air.  It has been esti-
mated that in man about eighty per cent, of the total heat
dissipation is from the skin.
  The method of direct calorimetry, already described,
has been applied only to animals for the determination of
the total heat loss in fever.  Here Wood's  experiments
are the best which we possess.  Leyden and Liebermeis-
ter have furnished calorimetrical data which, although
unsatisfactory  in  many  respects, indicate  the  general
direction of febrile heat loss in human  beings.  All of
these experiments show that more heat  is dissipated in
fever than  under like conditions in health.   The fluctua-
tions of heat loss during a febrile paroxysm are so great
that the statement of an average for the entire period  has
little significance.  Such an average, according to Wood's
results on fevered dogs, would fall between twenty to thirty
per cent, excess of heat loss as compared with the loss in
health under like conditions of food.  The dissipation of
heat in fever, however, may be at times more than double
the normal amount, and again may sink below the norm.
We have not sufficiently accurate estimates either of the
total amount of heat produced or of that dissipated during
a febrile attack to enable us to strike a balance between
the two.  Some persons have been so impressed with the
large amount of heat lost  during certain periods of fever, 
•7 ~>
WELCH,
that they have concluded that there must be far greater
excess of heat production than previous investigations
have shown to be probable.  They suggest that there are
sources of febrile heat of which at present we have  no
idea.   Such conclusions seem to  me quite unwarranted,
when we consider  the  behavior  of heat-loss, not for a
limited time but throughout the different stages of a par-
oxysm of fever.   We have already seen that  we obtain
no  satisfactory conception  of febrile production of heat
unless we follow it during the  stages of fever, and this
is  no less true of heat dissipation.   The observation of
the condition  of the skin as regards temperature and
moisture must in all ages have afforded an insight into
the general behavior of heat dissipation during the differ-
ent periods of fever. It  does not require any instruments
of precision to make plain the fact that a cold, dry skin,
such  as we observe during a febrile  chill, liberates less
heat than normal, or that  a hot, moist skin, such as we
are likely to find at the defervescence, loses more heat than
normal.   Not quite so  evident is the direction of heat
loss during the hot stage or acme of a febrile paroxysm
or fastigium of a continued fever.  Here the skin usually
appears hot and dry.  The ordinary impression that more
heat than normal is dissipated during this  stage is sup-
ported by calorimetrical  experiments.   There can be no
doubt that the elevation  of the cutaneous temperature
which we  observe  in the  hot stage of fever  causes  an
increase in the amount of heat lost by radiation and con-
duction.  Similar elevations of  cutaneous temperature in
health, such as  those caused by muscular  exercise, are
accompanied by increased moisture of the surface.   Not
only is visible perspiration usually absent during the hot
stage of fever, but  the invisible perspiration is, as a rule,
relatively although  not absolutely diminished, as Leyden
has shown. The dryness of the skin, therefore, is a factor
which in the hot stage of a fever tends to lessen heat dis-
sipation.  Clinical observation, however, shows that fevers 
        THE CARTWRIGHT  LECTURES.     23

differ markedly from  each other as regards perspiration
during the hot stage, the skin being sometimes bathed in
perspiration without any depression of temperature.   It
would  undoubtedly be of great interest to possess trust-
worthy data as to the exact loss of water from the surface
of the  body in different fevers and at  different stages of
fever.  We cannot place much reliance upon  the indica-
tions afforded by Weyrich's hygrometer, which has been
repeatedly used for this purpose.  More is to be expected
from the method employed by Peiper1  in studying insen-
sible perspiration under physiological conditions.
  The  general impressions regarding febrile loss of heat
derived  from clinical  observations,  are supported  by
calorimetrical experiments.  The  dissipation  of  heat is
least during the initial stage of fever, and greatest during
the  period of defervescence.  During the hot  stage or
fastigium heat  dissipation exceeds the normal, but usu-
ally, on account of the dryness of the  skin, not so much
as one might infer simply from the impression of heat
received by the hand when placed upon the skin.
  During the initial  period the loss of heat, although on
the average less than  in the following stages, is  usually
greater than normal.   If,  however, the  rise of tempera-
ture be rapid the heat loss falls below the normal amount.
As there is now increased production of heat, there is evi-
dently a glaring disproportion between the two factors, heat
production and heat loss, and under these circumstances
the febrile attack is likely to be  ushered  in  by a chill.
During the febrile chill all the efforts of nature combine
to produce in the shortest time the greatest possible ele-
vation  of temperature.  Not only  is  heat loss reduced to
a minimum, but heat production is excited to the utmost.
  During the period of defervescence, on the other hand,
the  relation between  heat loss and heat production is re-
versed.  This is, of course, most apparent when the fever
1  Peiper:  Zeitschr. f. klin. Med., Bd. 12. 
24
WELCH,
terminates by crisis with rapid fall of temperature.  Then
the loss of heat is excessive, being sometimes threefold
that in the normal state, and the production is relatively
and often absolutely diminished.
  It is of importance to  remember  that there are con-
tinual and irregular fluctuations in the dissipation of heat
during the different  stages of fever.  These fluctuations
bear no definite relation either to the momentary produc-
tion of heat, or to the height of the internal temperature.
We deal in ordinary life so much more with units of tem-
perature than with units of heat that it is difficult for us to
keep constantly in  mind the fact that no  inference can
be  drawn as to the  height of the internal temperature
from  the knowledge of the momentary heat  production
and heat loss.   If the heat loss fall behind heat produc-
tion the temperature of the body rises, and it can remain
at this elevated point with either diminished or increased
heat production so long as the heat loss equals heat pro-
duction.
   No  correct  conception of the condition of the heat-
regulating mechanism in fever can be obtained without
taking into consideration these irregular variations in the
discharge of heat, and it is a merit of Senator and his
pupils to have  emphasized particularly this point.  These
variations are  made apparent  not  only by calorimetric
measurements and  direct observation, but also  by the
studies which have been made of the cutaneous tempera-
ture in comparison with the internal temperature in fever.
 Hankel's law  that the difference between the tempera-
ture in  the axilla and that of the surface  of the body in
the febrjle condition is less  than in the normal condition
 manifestly does not hold for the  chill, in which it has
 been proven that  the superficial temperature falls while
 the internal  temperature  rises.   Jacobson, Wegscheider,
 Schiilein,1 find that there  constantly occur in the course

   1 Jacobson: Virchow's Archiv, Bd. 65. Schiilein:  Ibid., Bd. 66.
 Wegscheider: Ibid., Bd. 68. 
        THE  CARTWRIGHT  LECTURES.     2$

of most fevers changes of the superficial temperature,
which stand in no relation whatever to alterations of the
internal temperature.   Schiilein thinks that he has dis-
covered some  facts in this regard which are available in
diagnosis.   However this may be, these observations in-
dicate that contraction and dilatation of the cutaneous
vessels are constantly occurring, and without any regu-
larity, in fever.   These irregular variations in the calibre
of the  bloodvessels are also apparent to the eye in the
vessels of the rabbit's ear during fever.  When  it is con-
sidered, furthermore,  that  these irregularities of cutane-
ous  circulation vary decidedly in different situations, no
further proof is needed that the mechanism which regu-
lates the discharge of  heat  from the surface of  the body
is profoundly disturbed in fever.
   These alterations in  cutaneous  circulation  are  such
striking phenomena that it is perhaps not surprising that
two  great  medical authorities  should  have  based upon
them  exclusively theories  of  fever, Traube assuming
excitation and  Marey paralysis of vaso-motor nerves as
the primal element in  fever.  We need not discuss these
theories, now  generally abandoned  in their  exclusive
form.   From what has been said concerning the loss 01
heat in fever, it is evident  that we cannot explain febrile
rise of temperature solely by  the behavior of  heat dis-
sipation any more than  we  can explain  it solely on
the  basis of increased  heat production.   In  rejecting
Traube's theory that fever is the result solely of  retention
of heat we must still recognize the fact that decrease in
the dissipation  of heat, at times absolute, at other periods
relative, is  a factor of the utmost  importance in  the
febrile process.
  From whatever point of view we consider the question
we cannot avoid the conclusion that it is the mechanism
which controls  the relation of heat  production to  heat
loss, which is disturbed in fever.
  Heat production is  increased in fever, but if the regu- 
26
WELCH,
lating mechanism were  normal, then the discharge of
heat would be proportionately increased and the tempe-
rature would  not be materially affected.  Nor would the
force of this argument  be changed if febrile  thermo-
genesis were twice as energetic as we suppose it to be.
  The loss of heat is increased in fever, so that on this
ground  alone we should be obliged to assume increased
heat production.   But,  even if  it were  proven  that
heat dissipation  is diminished, as  has been recently
claimed again by Rosenthal,1 and that fever is the result
of heat retention alone, it would  still be  necessary to
admit that  the regulating  mechanism is at fault, for
Pfliiger  has  demonstrated that when this is  normal,
changes in the temperature of the skin are attended by
such changes in heat production that the internal tempe-
rature remains within wide limits unaltered.
  I repeat then that the conclusion is forced upon us that
the fever-producing agents must act either directly or in-
directly upon the mechanism regulating the harmonious
relation of heat loss to heat production.
  That  the heat-regulating mechanism, although  pro-
foundly disturbed, is not entirely paralyzed  in  fever, is
proven by the effect of heat and cold upon fevered  indi-
viduals.  Although Colasanti  believed that his fevered
guinea-pig had  lost all power of heat regulation under
varying external  temperatures, a similar conclusion has
not been reached  by others who have investigated this
question.
  We can best  describe the condition of heat  regulation
in fever as unstable or  ataxic.   External cold  stimulates
to some extent  the heat  production of an individual in
fever, but by no means as much as it does in health.  A
person in fever is not able to maintain his bodily tempe-
rature under  the  influence of  heat and cold to the  same
degree that he can under normal conditions.  Lieber-

      1  Rosenthal: Deutsche med. Wochenschrift, 1888. 
        THE  CARTWRIGHT  LECTURES.     2J

meister, as is well known, held that heat regulation in
fever is simply adjusted for a higher point, although he
admits  not  perfectly  adjusted.  Experience shows that
this  so-called adjustment is so unstable that it does not
seem proper to compare it with that to  normal tempera-
tures in health, so that it is not clear what deep meaning
lies in Liebermeister's idea.
  We cannot imagine the heat-regulating mechanism to   *
be other than a nervous one.
  Some years ago this was about as far as the theory of
the mechanism of fever could be  carried.  All paths led
to this mysterious nervous apparatus, and beyond this
nearly all was speculation.  We stood, as has been said,
before imposing processes veiled in the  deepest obscurity.
Since then the veil  has been lifted here and  there and
we have caught glimpses of the nature of these processes.
I refer particularly to the results of researches which have
brought to light a more immediate and direct dependence
upon nerve  energy, than had been supposed, of chemical
processes concerned in the disintegration and construc-
tion of tissue, and, therefore, in the production of heat.
   With one side of the nervous mechanism concerned in
temperature regulation,  the classical  investigations  of
Claude Bernard have  made us tolerably familiar.  This
is the vaso-motor nervous apparatus presiding over the
circulation of blood in the superficial parts of the  body,
and thereby controlling  in great measure the discharge
of heat.  That the important part taken by the perspira-
tion in the dissipation of heat is likewise under  nervous
influence, has been demonstrated by Luchsinger.   The
facts concerning this side of the regulation of heat  are
too well known to require elucidation on this occasion.
   Heat regulation, however, is effected  not only by  varia-
tions in the  elimination of heat, but also by changes in
the production of heat.  Familiar as the fact is, it can
never cease to arouse our admiration that the tempera-
ture of the body remains the same in cold and in  warm 
28
WELCH,
 atmospheres.  Man  has become  so  dependent  upon
 clothing that in the naked condition his capacity of pre-
 serving his normal temperature in a cold environment is
 much less than that of most animals.  Pfluger has de-
 monstrated that  the  heat regulation under varying ex-
 ternal temperatures is accomplished by changes both in
 heat production and in heat  loss, so that in a cold atmos-
 phere more heat is produced and in a warm atmosphere
 less heat, provided the external temperature is not  so
 high  or  so low as to make it physically impossible to
 preserve the body temperature.  It is evident that this is
 the most rational and  economical method of retaining
 the internal  temperature of  the  body.   To regulate the
 body temperature simply by variations in the discharge
 of heat, as was formerly supposed to  be  the method,
 would be, as has been said, like regulating the tempera-
 ture of our  rooms summer  and winter by opening and
 shutting the windows without  controlling the source  of
 heat.
  A heat-producing or thermogenic apparatus, therefore,
 is no less apart of the heat-regulating  mechanism than
 is the heat-discharging or thermolytic  apparatus, to use
 the terms employed by Foster.  As  the thermogenic ap-
 paratus is less generally understood it is not permissible
 to dismiss its physiology  in  this  connection so briefly as
 I have the thermolytic, although our knowledge of the
 former is very imperfect.
  I can assume that the convincing reasons are known
to you which have led physiologists to conclude that most
 of the animal heat is produced in the  muscles and the
 glands, and that the muscles have the larger share in this
 function.  It is also well known that stimulation of secre-
tory and motor nerves causes not only visible physical
 alterations in the  glands  and muscles,  but also produc-
tion of heat.   This sort of dependence of heat produc-
tion upon innervation has been long admitted.  It may,
however,  not be  so  generally  known that  there  are 
        THE CARTWRIGHT  LECTURES.     29

reasons to believe that nervous impulses control chemical
changes which result in the production of heat indepen-
dently of visible physical alterations of the tissues; in
other words, that heat production or thermogenesis is at
least in considerable part under the immediate and direct
control of the nervous system.  The idea is  not a new
one, and was advocated especially by Claude Bernard.
Recent discoveries, however, have given it unexpected
support.
  This subject of the  relation of innervation  to thermo-
genesis is most pertinent to the pathology of fever, but it
is essentially a physiological one, and  as  I wish to con-
fine to a single lecture what I have to say concerning the
theory of fever, it is impossible for me to do more than
summarize the  most  essential points belonging  here.
This I can do the more readily as Dr. MacAlister,1 in his
admirable Goulstonian Lectures on the " Nature of Fever,''
which were delivered  last year, has clearly and forcibly
presented the main facts.
  The larger part of these facts relate to the chemical
changes and heat production of muscles under varying
conditions.
  That a large part of the chemical changes.in a muscle
in the condition  which we call repose is under the influ-
ence  of the nervous  system, is  made apparent by  the
great diminution in its consumption of oxygen and forma-
tion of carbonic acid,  which  follows the separation of the
muscle from  all connection with the central nervous
system.  This is conclusively shown by the experiments
of  Bernard,  Pfliiger,  von Frey, and others.   It  is, of
course, possible, and it has generally been supposed that
under these circumstances it is simply the withdrawal of
motor impulses which lowers the heat-producing energy
of the muscle.
  Far more suggestive as regards the point under consid-
1  MacAlister: The Lancet, 1887, vol 1. 
30                   WELCH,
 eration are the results of investigations which have been
 carried on in Ludwig's laboratory by Meade Smith, Mac-
 Alister, and Lukjanow. These experimenters have shown
 that heat production and contraction are in  a  measure
 independent properties of the muscle.  By various influ-
 ences the thermogenic property may be so impaired that
 a stimulus causes contraction with scarcely any develop-
 ment of heat.  The laws governing the restoration and
 the fatigue of the thermogenic  function differ from those
 controlling the mechanical function.   These researches,
 upon which I here  only touch, have made  it extremely
 probable that there are in the muscle chemical processes
 resulting mainly in the production of heat and chemical
 processes  causing  mainly contraction, and that these
 processes, although coordinate, are not identical.  A new
 light  is  shed upon the meaning of the term chemical
 tonus of muscle, which has  for some time  been used
 by some physiologists.  Great  caution is  properly exer-
 cised by Ludwig and his pupils in the interpretation of
 these interesting results.  They do not infer from them,
 necessarily, the existence of so-called thermic or  calorific
 nerves.   They suggest that it is possible to explain the
 phenomena upon  the supposition that there  are in the
 muscle two kinds of material, thermogenic and contrac-
 tile, and the  nervous impulses  acting upon these may
 pass through the same set of nerves.
  Proof of  the existence in  connection with  muscles of
thermic in distinction from motor nerves, would be afforded
if we could succeed, after paralysis of the motor nerves, in
exciting by nerve stimulation the thermogenic function of
the muscle. We possess, in curare, a drug which paralyzes
the terminations of  the motor nerves.  Meade Smith at-
tempted  by its aid to determine whether possible  thermic
 nerves may be differentiated from motor, but he reached
no positive  conclusion on this point.  There are, however,
on record some observations which suggest the possibility
that in moderate doses curare may leave intact  thermic 
        THE  CARTWRIGHT  LECTURES.     31

nerves  after the suspension  of the function of motor
nerves.  When an animal is profoundly under the influ-
ence of curare  the internal temperature falls, and  the
processes of oxidation are greatly reduced.   The animal
is no longer able to resist the changes of external tem-
perature, its own temperature rising and falling like that
of a cold-blooded animal when exposed to heat or cold.
This effect of curare poisoning is another  proof of  the
dependence of heat production upon nervous influences.
Claude Bernard in his early researches on the action
of curare noted elevation of temperature soon after its
administration.  Voison  and Lionville1  observed after
subcutaneous injections  of curare  in  man rigors, per-
spiration, headache,  and elevation of temperature to
104.70 F.   They attribute to curare the power of produc-
ing all of the essential phenomena of  fever.   Fleischer2
noticed in dogs and in rabbits  rise of  temperature after
curare injections, and the  same was observed in a rabbit in
one case  by Hogyes.3  Recently  Mosso4  claims that an
animal may be placed so far under the influence of curare
as to paralyze completely the voluntary muscles, and the
internal temperature either remain normal or rise.   He
infers that these moderate doses of  curare,  although  suf-
ficient to paralyze  the motor nerves, must have left intact
the thermic nerves.  That rise of internal temperature is
not due to retention of heat, he thinks is evident from the
normal or elevated temperature  of the skin.  Mosso is
strengthened still further in his conclusion as to the  ex-
istence of thermic nerves, by finding that after complete
paralysis  of the motor  nerves  by curare injections of
strychnine  cause  an  elevation  of  rectal  temperature,
which may  amount to three degrees centigrade.  Under

  1 Virchow and Lionville : Virchow u. Hirsch's " Jahresbericht,"
1886, I. p. 330.
  2  Fleischer: Pfliiger's Archiv, Bd. ii. p. 441.
  5  Hogyes:  Arch. f. exp. Path. u. Pharm., Bd. xiv. p. 136.
  4 Mosso: Virchow's Archiv, Bd. 106. 
32
WELCH,
these circumstances strychnine produces no  spasms or
other visible mechanical effect upon the muscles.  Mosso
brings forward a number of other experiments (decidedly
open to criticism) intended to demonstrate the existence
of nerves directly controlling heat production, but those
which I have mentioned are by far the most striking.  It
seems to me that the  natural interpretation of these ex-
periments is in  favor  of the view that there are nerves
controlling heat production in the  muscle distinct  from
motor nerves.  Far  more  conclusive as to this point
than  thermometric observations  would be  calorimetric
experiments determining the heat  production of animals-
under varying doses of curare.
  This  whole line  of experimentation directed  toward
the  differentiation of the mechanical and the chemical
functions of muscle is certainly most suggestive, but so
long as the interpretation of the results is not perfectly
clear, we should be very guarded in drawing far-reaching
conclusions.  I cannot refrain, however, from pointing out
that, as mentioned by MacAlister, all of these thermogenic
phenomena may be found eventually to depend upon
nerves whose chief function, on the one hand,  is the dis-
integration,  the metabolism of tissue, and, on  the other
hand, the restoration, the anabolism of tissue.  From the
study of the electrical  changes which stimulation of the
pneumogastric nerve produces in  the heart muscle,  Gas-
kell concludes that this nerve puts the heart in a condition
of relative rest during which the energy of the muscle is
increased.   During this period there is reason  to  believe
that  the material of the muscle, which, when  disinteg-
rated, gives  rise to heat and mechanical work, is in the
process of restoration.  Hence  Gaskell  speaks of the
pneumogastric or inhibitory nerve of the heart as ana-
bolic—that  is, it  directs  the  restorative,  formative,
anabolic processes in  the muscle.  On the other hand,
the accelerator nerve  of the heart  induces the opposite
electrical changes in the heart muscle.  Gaskell describes 
THE CARTWRIGHT LECTURES.
33
this nerve as katabolic—that  is,  its  stimulation causes
disintegration of  the muscle materials, and liberates
energy in the form of heat and of mechanical work.  If
it be found that  similar inhibitory  and accelerator nerves
preside over the chemical changes in  the voluntary mus-
cles and other tissues of  the body, then Gaskell's induc-
tion as to the existence of anabolic and katabolic nerves
must be regarded as one of the most important and pro-
found in modern  physiology.  Thermo-excitory nerves
we should then rank as katabolic, thermo-inhibitory as
anabolic.
   These investigations tending to  demonstrate the inde-
pendent  existence of thermogenic  properties in  the
muscles  and possibly  of nerves  directly controlling ►
thermogenesis, have prepared us for the consideration of
the relation of the  central nervous system  to the heat-
producing properties of the body.   Here you will willingly
permit me to confine my remarks  to  the more essential
and best established facts, without entering into  a  full
discussion of one of the  most perplexing subjects  in-the
physiology of the nervous system.
   The clinical basis  of the doctrine  that lesions of the
central nervous  system influence  directly the tempera-
ture of the body was laid by Sir Benjamin  Brodie, who
reported the well-known  case of fracture of  the cervical
vertebrae and injury of the spinal  cord followed within a
few hours by a rise of temperature to iii° F. measured
between the  scrotum  and the thigh.  Since then  many
similar instances have been  reported.  It is well  to re-
member, in  framing theories  on the basis of these  cases,
that there are also  on record not a  few instances in which
apparently similar injuries of the same parts of the spinal
cord have been followed  by equally striking fall of tem-
perature.
  The experimental basis for the acceptance of an in-
fluence of the nervous system on  temperature was laid
by Bernard, in his  celebrated experiments on  the effects
                          3 
34
WELCH,
of division of the sympathetic nerve in the neck.  Ber-
nard  interpreted  the  increased  temperature of the ear
following this operation as referable not only to the larger
amount of blood in the part, but also to increased tissue
metamorphosis and consequent heightened heat produc-
tion.  The latter part of this interpretation is not generally
accepted.  It may be said here that the common idea that
an  organ or tissue simply because it  receives a larger
supply of blood indulges in more active  metabolism is
opposed by the investigations of Pfliiger, who finds that the
amount of oxygen taken up by the cells depends in a far
higher degree upon the state of their innervation at the
time than it does upon the supply of oxygen. The demand
of the tissues for oxygen is not increased simply because
the supply is greater.  The arguments upon which Pfliiger
bases this line of reasoning,  although not without oppo-
sition, would dispose of the idea that when any consider-
able increase of heat production in the muscles  occurs
this can be explained simply by vasomotor changes.   I
mention this here, because the opinion has been advanced
that a large part of the increased  production of heat in
fever  and after certain  injuries to the nervous system is
referable simply to vasomotor changes in the muscles.
  In  1866 Tscheschichin1 published experiments which
he interpreted as indicating the existence in the brain of
centres which, when irritated, moderate the production of
heat,  and which he called heat-moderating or heat-inhib-
itory  centres,  and in the spinal cord  of centres which
when stimulated excite  the production of heat, heat-
excitive centres.  These  conclusions were not justified
by the experiments, but they have been  widely accepted.
  I may here say that, in this connection,  I use the term
heat centre as a convenient and generally  adopted  one.
There is a proper reaction against the prevailing misuse
  1 Tscheschichin: Reichert und Du Bois-Reymond's  Archiv,
1866. 
        THE  CARTWRIGHT  LECTURES.    35

of the word centre for all sorts of little understood locali-
zation of  nervous functions.  It would undoubtedly be
more accurate  to use some such expression  as therm-
ically active region instead of heat centre.
  It is not easy to  reconcile  the clinical fact that in
human beings lesions of the spinal cord may be  followed
at once, or in a very  short time, by extraordinary eleva-
tions of temperature with the results  of experiments on
animals.  That the rise of temperature in human beings
is not due to inflammatory fever is  apparent from the
rapidity with which it follows the injury.  It  cannot be
explained by vasomotor lesions, for the paralysis of the
vasomotor nerves accelerates the discharge of heat from
the surface of the body.  The  high temperature can be
explained  on Tscheschichin's assumption.  The lesion
either  stimulates the  spinal thermogenic centres or re-
moves  the  influence of the thermo-inhibitory  centres.
These  clinical  observations are  the strongest  support
which has been found  for the belief in  the existence of
centres in the spinal  cord which accelerate heat  produc-
tion.   Complete section of the cervical part of the spinal
cord in a dog or a rabbit is, under ordinary conditions,
always followed by a rapid fall of the internal temperature
and diminished oxidation.  These varying results in man
and in animals have been explained  by supposing that
after section of  the cervical  cord, on the one hand, the
discharge of heat is increased by dilatation of  the super-
ficial bloodvessels, in consequence of vasomotor paral-
ysis ;  and, on  the other hand, the  production  of heat is
increased by  withdrawal of thermo-inhibitory  cerebral
impulses.  If, as ordinarily happens in dogs and smaller
animals, the first factor predominates,  then, in conse-
quence of sinking of the internal  temperature, the heat-
producing processes are so reduced that the influence of
the second factor is  not manifest.  The attempt has been
made to test this explanation by placing the animal in a
warm  atmosphere.    If thereby the heat  discharge be 
36
WELCH,
reduced to a minimum, it is found that the internal tem-
perature of the animal often rises more rapidly than that
of a normal one under the same external conditions.  Here
thermometric observations are not conclusive as to the
point to be tested, for the more rapid rise can be explained
simply by failure of the  heat-regulating mechanism.
Wood's calorimetric experiments seem to show that there
is greater  heat production, under these circumstances, in
the animal with  cut cord.  These experiments admit of
various interpretations, but if  they be regarded as estab-
lishing the assumption from which we started, then  it is
evident that in man and in large animals  the increased
heat production  after  injury of the cord would not be so
readily  overcome  by the  increased  discharge  of  heat
from the surface, for, in proportion to its volume, a large
animal  has  less surface than a  small one.  The inter-
play, therefore, of these opposing tendencies might cause
different results,  according to  the size of the animals.
  Tscheschichin found that a transverse section made at
the junction of the pons and medulla  oblongata is fol-
lowed, in  a  short time,  by rise of internal temperature.
As the superficial temperature is  also elevated, he  con-
cludes that  there is no retention of heat;  moreover, the
section is  made  above the  dominant vasomotor centre.
Wood has shown by means of the calorimeter that after
this operation there is actual  increase  in the  production
of heat.   He, as well as  Tscheschichin, interprets the ex-
periment  as indicating thermo-inhibitory  centres above
the lower border of the pons.  Bruck and  Giinter1 re-
peated and modified  these experiments under Heiden-
hain's directions.  Out  of seven cases in which  they
separated the pons from the medulla, they observed in
only two  rise  of temperature; of eleven cases in which
they punctured the pons with a needle, in five they noted
increased temperature.  Heidenhain thinks these experi-
Bruck and Giinter: Pfliiger's Archiv, Bd. iii. 
        THE CARTWRIGHT LECTURES.     T>7

ments indicate heat-exciting rather than heat-moderating
centres, and it must be admitted that the evidence is not
conclusive in support of either view.
  By far the most interesting and conclusive experiments,
showing the influence of the central nervous system on
thermogenesis are those of Isaac Ott, followed by Richet,
Aronsohn and Sachs, Baginsky, and Girard.1  The ob-
servations of Ott, Richet, and Aronsohn and Sachs  were
made independently and at about the same time, but Ott
was the pioneer.   The  experiments of Aronsohn and
Sachs are reported  with  especial  fulness and  detail.
These investigators found that if the skull of a rabbit be
trephined  at the junction of the coronal  and  sagittal
suture, and a needle be passed vertically down so  as to
puncture the anterior part of the  caudate  nucleus  near
its median convexity, there follows a rise of temperature,
which may amount to three degrees or more, and which
may  persist for two or three days.   The rapidity and the
duration of  this elevation of temperature  vary  some-
Avhat with the depth of the puncture, parts  immediately
beneath the  caudate nucleus  being also thermically
active.  Puncture of  the overlying cortex  or  medullary
substance has no  such  effect  upon  temperature.  With
the exception of some increase  in. the frequency of the
respiration and of the pulse, the  animal after punc-
ture of the anterior median part of the caudate  nucleus
presents no  abnormal  symptom other than the rise of
temperature.
   I  have  several times repeated this  experiment   and
always with the result described.  That the pyrexia in-
duced by puncture of the caudate nucleus is not  due to
vasomotor changes causing retention of heat, is  proven

  1 Ott: lournal of Nervous and Mental  Diseases,  April,  1884;
Medical News, July,  1885.  Therapeutic Gazette, Sept. 1887.
Richet: Arch, de Phys., 1884.  Aronsohn and Sachs: Pfliiger's
Archiv, Bd. 37.  Baginsky  and Lehman, Virchow's Archiv, Bd.
106.   Girard: Arch, de  Phys., 1886, 
3§
WELCH,
  by Richet's and  Ott's calorimetric experiments, and by
  the determination by Aronsohn and Sachs that the con-
  sumption  of  oxygen and the elimination  of carbonic
  acid, and urinary nitrogen are increased.  Aronsohn and
  Sachs and Girard find that electrical stimulation  of the
  anterior median part of the caudate nucleus causes the
  same thermic phenomena as  the puncture,  and  they,
  therefore, conclude  that this region contains  a thermo-
  excitor heat centre.  This is the natural interpretation
  of their experiment, although  Baginsky and Ott regard
  the centre as thermo-inhibitory on grounds which cannot
  be considered convincing.
    Ott claims that there are four cerebral heat centres, one
  about the corpus striatum,  the  second in  the caudate
  nucleus, the third in the  anterior inner end of the optic
  thalamus, and the  fourth near the median line between
  the optic thalamus and the corpus striatum.  The greatest
  rise of temperature he found after injury of the thalamic
  centre.
     No adequate demonstration has been  afforded of any
  influence of  the cerebral  hemispheres upon thermo-
  genesis. Corin and van Beneden1 find that  pigeons, after
  removal of their cerebral hemispheres, exhibit no change
  of temperature, no failure of the heat-regulating mechan-
  ism, and no alteration in the excretion of carbonic acid.
     I have endeavored to present to  you the main  physi-
i  ological facts bearing upon the relation of the nervous
   system to thermogenesis.  It must be admitted that we
   are left to surmise  as to  the interpretations  of many of
   the facts, and  particularly as to their connection with
   each other.  But certain  important  points come  out
   clearly.  We have found  evidence of the existence in
   the body of  chemical  processes resulting  chiefly in  the
   production of heat energy.  We have learned that these
   processes are under the direct control of the nervous
i Corin and van Beneden: Arch, de Biol., 1887. 
THE CARTWRIGHT  LECTURES.     39
system, and possibly of nerves distinct from those now
recognized as motor or secretory.  We have seen that
there are  regions in the central nervous system which
are doubtless in some way connected with these nerves,
and through them control the chemical processes result-
ing in the production of heat.
  The bearing of these facts upon the theory of fever is
evident.   The study of heat production and of heat loss
in fever has led us, by arguments  which  need not  be
repeated, to the conclusion that the pyrogenic agent must
in some way act upon the heat-regulating mechanism.
The study of this mechanism, more particularly of its
thermogenic side, affords  some insight into the manner
in which the fever-producing  agent  may affect the regu-
lation of heat.  The main difficulty in the neurotic theory
of fever has been to understand how by any action  of
the  fever-producing agent  directly  upon  the  nervous
system the chemical processes leading to heat production
could be stimulated.  I have dwelt thus at length upon
the innervation of thermogenesis to show that this diffi-
culty has been in great part overcome.
  To some it seems more  reasonable to suppose that the
pyrogenic  agent circulating  in the blood  acts directly
upon the tissues, altering and stimulating their chemical
changes.  This  is  the  hasmic theory, which,  in some
form, has always stood over against the neurotic theory
of fever.  Although it may at first glance appear simpler,
the haemic theory is really the more complicated, for it
has already been set forth that we cannot explain fever
simply by increased heat production, so that even if-the
primary effect of the fever agent were upon the heat-pro-
ducing processes there  must be a  secondary influence
upon the nervous system,  for heat dissipation is no less
disturbed than heat production.
  If an animal be  thoroughly curarized so  that no im-
pulses from the nervous centres can reach  the  muscles,
the great heat producers, then it is found to be impossible 
40
WELCH,
to produce febrile  elevation of temperature by the injec-
tion of pyrogenic  agents.  This fact, first demonstrated
by Zuntz, is justly held  to weigh  heavily in  favor of the
neurotic theory of fever.
   Contrary to the  results of Murri,1 I have not been able
to induce rise of temperature or check its fall by the in-
jection of pyrogenic agents into the jugular veins of dogs
whose spinal cords have been cut in the lower  cervical
region.   In these  experiments I have employed various
pyrogenic agents, and especially pepsin and papoid.  One
specimen of the  latter which I  used possessed  very
striking pyrogenic properties.
   The pyrexia  produced  by puncture of the  caudate
nucleus in the manner already described, possesses  all
of the essential properties of fever, regarded as abnormal
elevation of temperature.  In this experimental condition
there are increased production of heat, increased dissipa-
tion of heat, excessive elimination of urea and of carbonic
acid, and excessive absorption of oxygen. The breathing
and the  pulse  are increased in frequency.   The eleva-
tion of temperature (usually after a  brief fall) begins
within half an hour after the puncture, attains  a febrile
height and persists sometimes for days.  As no obser-
vations exist  as to  the heat regulation  of these ani-
mals, I have made  experiments on rabbits after punc-
ture of the caudate nucleus, by placing them in a cold
environment and in a box heated to various temperatures,
and I find that their power of temperature regulation is
less than that of normal animals.
   These animals,  in a word, present all of the  essential
symptoms of fever, and I  do not know why we should
not call  the condition  fever.  If so,  we  must admit
that injury to a  circumscribed  definite  region of the
brain is  capable  of causing fever.   This  experiment,
therefore, is of the greatest  importance in support of the
1 Murri: Teoria della Febbra, Fermo, 1874. 
        THE  CARTWRIGHT  LECTURES.     4I

neurotic  doctrine of fever.  It indicates, of course, that
we may have fever of purely nervous orgin, without any
pyrogenic agent  in the  blood.   This experimental evi-
dence  is supported by the clinical cases collected  by
White in Guy's Hospital Reports, 1884.  It is. to be hoped
that by careful thermometric study of focal  brain and
cord lesions a more accurate  idea may be reached than
is  now possible  of the  topography  of the thermically
active  regions in the central nervous system of man.
   Admitting the dependence of fever upon the nervous
system, I  do not regard  as  particularly  profitable with
our  present  knowledge  the  discussion as to  whether
febrile thermogenesis  is excited by the withdrawal of
thermo-inhibitory impulses  or  by the stimulation  of
thermo-excitory nerves or nerve centres.  If we regard,
and there are  forcible arguments for doing so, possible
heat-inhibitory nerves as anabolic, and the heat-exciting
nerves as katabolic, then inasmuch as the formative or
anabolic processes  are manifestly in  abeyance  in fever,
we can reasonably infer that the function of the heat
inhibitory nerves or centres is impaired.  The phenomena
of the febrile chill  in which both the contractile and the
thermogenic properties of muscle are stimulated, speak
strongly in favor of direct irritation of the heat-exciting
nerves in fever.  We might infer, therefore, that both sets
of nerves or nerve centres are affected.
   But  my aim  in this lecture has been not so much to
construct a theory of fever, a  theory which, although it
may be  useful, must necessarily be largely speculative
if  it be coherent and rounded, but to bring before you
the main facts concerning heat production, heat loss, and
heat regulation in  fever, and to point out the physio-
logical basis on which their solution is to be expected. 
 
LECTURE   II.
THE EFFECTS OF INCREASED TEMPERATURE
                  OF THE  BODY.
  In  the last lecture I endeavored to bring before you
the main facts which we possess bearing upon the  ex-
planation of febrile rise of temperature.  After a review
of our knowledge  concerning heat production, heat dis-
sipation, and heat regulation in fever, we were led to
the conclusion that neither the changes hitherto observed
in the production of heat nor those  in the loss of heat
suffice to explain febrile temperatures.   Such an explana-
tion seemed possible only upon the assumption that the
fever-producing agents  act  either directly or indirectly
upon  the nervous mechanism controlling  the relations to
each other  of the production and the discharge of heat.
We then turned  our attention  to the relations of the
nervous system to these processes, and found that the in-
vestigations of recent years  have enabled us  to obtain a
much clearer  conception than was formerly possible, of
the  manner in which the complicated heat relations in
fever  may  be  brought about by an  action  upon the
nervous  system.   We  found even  substantial experi-
mental basis in support of clinical facts which show that
circumscribed lesions  of certain parts  of the central
nervous system may induce  directly febrile disturbances
of animal heat.
  To carry  the subject further, to consider whether pyro- 
44
WELCH,
genie agents act primarily or only secondarily upon the
processes concerned  in heat production  or upon those
concerned in heat dissipation, or  upon  the apparatus
regulating the relations to each other of these two sets of '
processes, to discuss  whether these agents act directly
upon the central nervous  system, and if so upon what
part;  or upon the  peripheral nerves or  their termi-
nations, or upon the  tissues; to  follow out more fully
than we  have done hitherto the themes here suggested
would lead us with our present knowledge  into a sea of
speculation.  We should find only here and there a faint
light of fact to  guide us.   Even upon foundations as in-
secure as this speculations have their legitimate uses.  A
good hypothesis is a most valuable incentive to scientific
work.  It is not my purpose, however, to  carry you with
me further in this  direction, although  I  realize that  a
single  lecture has been far from sufficient for a thorough
exposition of this subject.
  After dismissing the considerations bearing  upon the
so-called theory of fever, there still remains a host of
questions properly belonging to  our subject.  It is  evi-
dently impossible, even if it were  desirable, that these
lectures should include a discussion of all of these ques-
tions.  I have, therefore, selected certain ones, partly be-
cause they seem to me of immediate interest and partly
because I have given  some attention to their study.
  In the present lecture  I wish to present  to you some
observations  concerning the relation of  elevation of tem-
perature to other disorders of fever, and as  to the ques-
tion how far increased temperature is a source of danger
in fever ?
  Here I may repeat that the word fever is  used  as a
convenient name  for a group  of symptoms commonly
associated together in  febrile diseases. The association of
these symptoms, however, is so loose that we regard only
the dominant one—the increased temperature—as  the
essential  criterion of the existence of fever.  It  saves cir- 
       THE  CARTWRIGHT  LECTURES.     45

cumlocution to adopt this somewhat vague and common
signification of the term fever, although I think it would
be an improvement to confine the term to  abnormal
elevation of temperature.   The literature of fever is full
of misapprehensions resulting from the various meanings
attached to the word by different authors.
  All of the bodily functions maybe disordered in fevers.
The various symptoms or classes of symptoms which
are so commonly associated as to be  regarded by many
as belonging  to  the febrile process are, in addition to
heightened temperature, increased frequency of the pulse
and other circulatory disturbances,  increased  rapidity
of respiration, muscular weakness, lessened  secretions,
disordered nutrition and digestion, and nervous symp-
toms.
  What is the connection, if any, between these symp-
toms and  the elevation of  temperature ? What degrees
of  elevated temperature are  dangerous to  life, and in
what does the danger consist ? This subject can, at least,
claim the interest that attaches  to the questions of the
day.  The various  opinions which have been  held by
clinicians on these points are too  well known  to you to
require an  historical review.  I  need only remind  you"
that  until within a  few  years the views advocated with
especial force for nearly thirty years by Liebermeister
have prevailed, although not without  considerable oppo-
sition.  According  to  these  views, the chief source of
danger in uncomplicated essential fevers is the elevation
of temperature, and the main indication for treatment is
the  reduction of  temperature.  Above all, it was urged
with apparently convincing arguments that the weakness
of the heart, which is undoubtedly one of the gravest
dangers of fevers, is the direct effect of prolonged high
temperature, and is manifested  anatomically  by paren-
chymatous  or fatty degeneration of the cardiac muscle.
Liebermeister sharply defined his position when he said,
"A man whose temperature measures continuously 1040 
45
WELCH,
(400 C.) or more surely dies in consequence of the eleva-
tion of temperature, one  in a few days, another after a
somewhat longer time, according to the resistance of the
individual."  " If his temperature reaches 108.5° U2-5°
C.) or more, then is he irrecoverably lost."1
  At the present  moment there is  a decided reaction
against  these views, a reaction which in some quarters
goes to the extent not only of denying that there is dan-
ger in febrile temperatures which do not exceed a very
high point, but of asserting that the  elevation of tempe-
rature is a beneficent provision, a most important  vis
medicatrix natures, which should not be checked  by the
interference of the physician.   This  reaction of opinion
is plainly due, in great part, to the disappointment which
has followed the high hopes raised by the discovery of a
number of drugs which are admirable antithermic agents
and, nevertheless, do  not exert over febrile diseases that
controlling influence which had been anticipated.
  These questions, you  may  say, are clinical ones, and
not much edification is to be expected from their discus-
sion by  a pathologist.   So far as the  propriety of the use
of antipyretic agents or of any other mode of treatment
in fever is concerned, it is true that the decision must  be
reached at the bedside and cannot and never  should  be
controlled by the results of experimental pathology.  But
an appeal has properly been made to experimental path-
ology to  shed light upon such questions as the effects
of heat  upon the functions of the whole body and of its
various organs, and upon the causes of  parenchymatous
and fatty degenerations.  The arguments advanced in
support  of the view that  all of the characteristic symp-
toms of fever are directly dependent upon the increase of
temperature and that high temperature is the chief source
of danger, are derived no  less from experimental path-
ology than from clinical observations.
1 Liebermeister: Volkmann's Sammlung, No. 31, p. 240. 
        THE  CARTWRIGHT  LECTURES.     47

   Three methods have  been employed to determine the
 effects of increased temperature in fever :  one is to study
 the effects of external heat upon  man and animals;  the
 second is to examine in different fevers and in different
 cases of the same fever the relation of the temperature
 to the other symptoms,  and to  the general condition of
 the patient; and the third is to  note the influence of re-
 duction  of temperature upon these symptoms.  Each
 method has its limitations.
   The condition produced by exposure to external heat,
 even if it be called thermic fever,  is something quite dif-
 ferent from ordinary fevers, and we cannot transfer the
 results obtained by this method directly to the explana-
 tion of febrile phenomena.  On the  other hand, in the
 clinical study of fevers  it  is very difficult  and often an
 arbitrary matter to separate the  effects of increased tem-
 perature  from  those of  other  factors  nearly  always
 present.   Hence we find no agreement of opinion among
 physicians as to what symptoms or lesions in fever are re-
 ferable to the heightened temperature, and what are due
 to  infectious or other conditions often present.  Even
 the frequent or constant  association of certain symptoms
 with elevated temperatures and  their subsidence or  dis-
 appearance by reduction of temperature do not justify us
 in inferring  that the high temperature is the cause of the
 symptoms, for both may be coordinate effects of the same
 cause, and the so-called  antipyretic treatment may influ-
 ence other  conditions as well as the temperature.   As
 has  been frequently  said of late, the high temperature
 may be rather  an  index of the severity of the disease
 than a source of danger in itself.
  In hyperpyrexia and in many  cases of insolation there
 can be no doubt that the high temperatures, as such, are
the main elements of danger.  But both of these condi-
tions have important points of distinction  from ordinary
febrile processes.   In hyperpyrexia  there is probably
almost complete paralysis of heat regulation, and we shall 
48
WELCH,
 find that an analogous condition  with  similar dangers
 sometimes develops in animals artificially heated.   The
 cases of insolation  in which the high temperature  is so
 dangerous are  analogous to the condition which  may
 be  produced in  animals by brusque elevation of the
 bodily temperature  through  exposure to heat, and which
 differs from that resulting from more gradual increase of
 temperature.
  The most direct  way of determining the influence* of
 heat upon the body is to raise the internal temperature
 by  the  external application of heat.   Here we are not
 disturbed by the presence of other factors, such as infec-
 tion, which render  doubtful  so many of  the conclusions
 derived from clinical  observations as to the  effects of
 high temperatures.   For the solution of  many  problems
 it is evidently irrelevant whether the source of heat be
 within or without the body.
  These experiments,  if properly conducted, are calcu-
 lated to shed much light upon  many questions relating
 to the effects, of febrile  temperatures.
  According to the testimony  of  all experimenters, a
 mammalian animal, artificially heated, dies when its in-
 ternal  temperature  reaches  m.20 F. (44° C.) or 113° F.
 (450 C).  Death is  preceded by convulsions and imme-
 diately or soon after death rigor mortis appears.  At the
 moment of death the irritability of the heart and muscles
 ceases.   Death seems  to be due to heart paralysis, and
the cause of this  is  usually  set down as  heat rigor, but
this  is not probable' as death generally occurs  at a tem-
perature several degrees below that  at which rigor of the
heart muscle appears.
  It is generally argued that  temperatures several degrees
below those which are fatal must exert toxic effects, and
this conclusion seemed to be  substantiated by the majority
of experimenters, who  found that animals whose tempe-
ratures were artificially  raised to 1050 F. (40.50 C.) or 107°
F. (41.7° C), or even to a lower point, manifested  signs 
THE CARTWRIGHT  LECTURES.
49
of illness.   These latter results, however, are opposed to
those obtained by Rosenthal,  and especially Naunyn,1
who points out that the conditions in most previous ex-
periments were not favorable, as the animals were gener-
ally placed in small, dark,  poorly ventilated metallic
boxes.  Naunyn succeeded in  keeping a rabbit alive for
thirteen days with  an average temperature of 106.7° F.
(4i.5°C).
  Following Naunyn's example, I have had constructed
a wooden box, three feet long, two feet high, and two
feet broad, which fits closely  within a double-walled gal-
vanized iron box.  The wooden  box  is provided with a
perforated  movable bottom,  which allows the urine  to
escape.  The space between the two walls of the iron
box measures three  inches  across, and  is  filled  with
water, which, therefore, surrounds the inner box on all
sides, except at the top, which is  left open.  The dimen-
sions of this apparatus are somewhat larger  than those
of Naunyn's heating-box.  A  folded woollen blanket was
drawn over  each end of the box, so as to leave uncovered
at least one-third, and generally more of the top.   A rose
burner placed underneath served to  heat  the box.  At
first a thermo-regulator was employed, but this was found
unnecessary, as the temperature of the room varied but
little, and there was no difficulty in keeping a sufficiently
constant temperature in the box.   The experiments were
made upon  rabbits, and only a single one was placed in
the box at a time.   Corrected thermometers were used.
The temperature of the box  was taken a short distance
above  the  bottom, and that  of the rabbit at a depth of
three to four inches in the rectum.  This occasion does
not seem an  appropriate one to describe  these experi-
ments in detail with their protocols. I shall take another
opportunity  for that, and at present give only a general

  1 Rosenthal:  Zur Kenntniss der Warmeregulirung u.s.w., Er-
langen, 1872.  Naunyn:  Archiv f. exp. Path. u. Pharm.,  Bd. 18.
                          4 
50
WELCH,
account  of  those  results  which  relate to  the  subject
before us.
  In the box described I have  succeeded in keeping for
three  weeks two large  black rabbits,  the  one with an
average  rectal temperature  of 107.30 F, (41.80 C),  the
otherwith an average temperature of 106.6° F. (41.4° C.).
The rectal temperature fluctuated usually between 105.50
F. (40.80 C.) and 1080 F. (42.2° C), scarcely ever sinking
below 105° F. (40.50  C), but  occasionally rising as high
as  109.50 F. (43.i°  C).  The temperature of the box
varied between 960 F.  (35.50 C.) and 1060 F. (41.i° C).
The rabbits lay most of the time stretched out, breathing
very rapidly.  They took their food greedily, and  did
not appear  ill.  At  the end  of the  experiment the first
animal was  removed from the box,  and appearing per-
fectly well for  ten days afterward it was used for another
experiment; the second animal was  killed at the end of
the experiment, and presented marked fatty degenera-
tion of the heart, liver, and kidneys.  Both animals lost
weight while in the box.
  In  these  and similar experiments  the  rabbits were
given only  moist, green fodder,  and  were allowed  to
drink plenty of water, which they took eagerly.   It is
important for the success of the experiment that the tem-
perature should be gradually, and not suddenly, raised.
  Different rabbits offer varying degrees of resistance to
the effects of high external temperature.  It has seemed
to me that black and gray rabbits surpass, in this respect,
white rabbits.   The  same temperature of the box does
not produce, in all cases, the same rectal temperature in
different animals, or  in the same animal at different times
No factor is of more importance in determining the effects
of external heat than the animal's power of temperature
regulation.  Failure  of this power is  manifested by  a
sudden rise of internal  temperature, which may quickly
attain  a point incompatible with  life.  This  event may
take place without any alteration in the box temperature. 
        THE CARTWRIGHT  LECTURES.     51

The degree of internal temperature at which this paralysis
of heat regulation  occurs varies in different animals.
One may be able to hold his temperature, for a short
time, from further rise  at as high a point  as 109.50 F.
(43.i° C.); in another, after the temperature has reached
107.6° F. (41.50 C), there may occur, without any change
in the box temperature, a sudden, and often fatal, eleva-
tion of temperature. In general, temperatures between
108° F. (42.2° C.) and 109° F. (42.8° C.) may be regarded
as critical temperatures for these animals.  One is forcibly
reminded by these sudden and dangerous  elevations of
temperature of  the occurrence of  hyperpyrexia in certain
fevers of human beings, and there is reason  to believe
that this, too, is caused  by paralysis of heat regulation.
   It seemed to me of some practical interest  to determine
what effect upon the  rabbit's power of resisting high
temperature is exerted by exhausting influences, particu-
larly by anaemia.   For this purpose rabbits which had
been moderately bled, and others which had  been used
for some other experiments, were placed  in  the hot box.
It was found that these animals are, although not without
occasional exceptions, unmistakably less resistant to the
effects  of high  temperatures than are  robust animals.
They succumb  sooner, and at lower box temperatures.
  We may now consider what inferences may be drawn
from these and  similar  experiments as  to the effects of
high bodily temperatures.  It seems clear that a consid-
erable part of the current  arguments based upon expe-
riments concerning  the injurious effects of  high tem-
peratures  must be  revised in  the light  of  Naunyn's
experiments,  and of those which I have briefly related.
Because an animal may be killed by raising its tempera-
ture to  iii° F.  (43.90 C.), or 113° F. (45° C), it does  not
follow that an  increase of temperature up  to within  40
or 50 F. of this fatal point involves danger to life, or even
any  serious disturbance of the  functions of  the body.
Although experiments in hot-air  chambers show that in 
52                   WELCH,
man brusque  elevations of the temperature by only a
few degrees give rise to serious  symptoms,  Krishaber1
found that by habituation his temperature could be raised
to 106.50 F. (41.4 C), or 107.2° F. (41.8), without much
discomfort.  As small animals generally succumb more
readily than  large  ones to  artificial  heating, it is  not
likely that  the  power of resistance in human beings is
less than  that  found to exist in rabbits,  and there is
reason to believe that it  is greater.
  We  cannot  transfer  directly  to  human beings  the
highest temperature at which we found rabbits can exist
without serious  discomfort  save  increased respiration.
A rabbit's  temperature  is normally considerably higher
than that of man, and apparently slight causes suffice to
produce marked fluctuations.  The  normal rectal tem-
perature of the rabbits used in my experiments was gen-
erally between  1020 F.  (38.90 C.) and 103° F. (39.4° C).
The highest average temperature at which a rabbit was
kept for three weeks in  the hot box exceeded, therefore,
by 40 to  50 F. the average normal temperature.  Such
an increase would not correspond to a high febrile tem-
perature in man.   We  can,  however, with equal, and
probably greater propriety,  compare this temperature
with that  at  which death  surely occurs  in a condition
bordering on heat rigor.  This temperature (111° to 113°
F.) is probably about the same for  man as for rabbits and
other mammalians.  From this point of view the infer-
ence may  be  drawn,  although,  of course, with much
reserve, that human beings may tolerate temperatures of
107° F. (41.70  C), or  even  higher, for  a considerable
time.   This inference is supported by clinical observa-
tions, especially in cases of relapsing fever.
  As  already pointed   out,  the condition  produced  by
artificial heating is not directly comparable with that in
fever.  In the former the loss of  heat from the body is
1 Krishaber: Gaz. Med. de Paris, 1877. 
THE CARTWRIGHT  LECTURES.
53
 reduced to a  minimum;  the  superficial temperature is
 three or more  degrees  higher  than the internal, so that
 the average temperature of the whole body is higher than
 in fever with the same internal temperature. We cannot
 say, therefore, but that man  may tolerate considerably
 higher internal temperatures when the elevation is brought
 about under conditions in which  the discharge of heat is
 not checked than when the  temperature is forced up by
 stopping heat dissipation.  This would be proven if con-
 fidence  could  be placed in  the  enormous elevations  of
 temperature reported by Teale  and others.   In  these
 cases, however, even if authenticated, it is probable that
 heat is abnormally distributed  in the body, and we can-
 not infer that the internal temperature is uniformly raised
 to such paradoxical heights.
   It is of the utmost importance to bear in mind that, as
 my experiments have shown, not only do animals differ
 in their power of tolerating high temperatures of the body,
 but this  resistance may be weakened by various depress-
 ing causes.  Nothing would be more irrational than to
 conclude, because one individual  in a  certain  condition
 can tolerate very high temperatures, another in a different
 condition possesses the same power.  In fevers we have
 various factors,  particularly infection, which we may well
 believe can lower the  tolerance of high temperatures.
 That in some  fevers, particularly relapsing fever, this
 does not appear, or only partially, does  not disprove that
 in another fever, such as typhoid or pneumonia, the system
 may be placed by other factors of the  disease in such a
 condition that  even  moderately  high temperatures are
 injurious.  It does not seem to  me proper in these cases
 to lay, as some seem inclined to do, the sole stress upon
the element of infection.  This is in all likelihood the
 determining factor, but the practitioner cannot shut his
 eyes to the possibility that under its influence the high
temperature, as  such, is a source of danger to his patient.
  With these restrictions I  shall surely not be misunder- 
 54                   WELCH,

 stood when I assert that temperatures which are ranked
 as high febrile temperatures do not in themselves, inde-
 pendently of other factors, exert any such injurious influ-
 ence as has been usually attributed to them.
  Our attention up to this point has been directed to the
 effects of high temperatures upon  the  general  condition
 of the body.  It is of importance for the  proper under-
 standing of fever to determine the  influence of heat upon
 the structure and functions of the various organs. To
 what  extent can the febrile disorders of respiration,  of
 circulation,  of secretion, of nutrition,  of innervation be
 attributed directly to the elevated temperature ?  These
 are questions  which can be answered better by experi-
 mental methods than by  clinical observation, for the
 latter has to deal with the effects of heat complicated by
 other circumstances whose influence cannot be accurately
 determined.  The one method, however, should be made
 to control the other.
  The most striking immediate  effect of  heat  upon an
 animal is increased frequency of respiration.   When a
 dog or a rabbit is placed in an  atmosphere of ioo°  F.
 (37.8° C), it at  once begins to pant and the respiration
 may run up to  150° or more.  The causation of this in-
 creased respiration, to which the name heat dyspnoea has
 been applied by Ackermann,1 has  been repeatedly inves-
 tigated.  Goldstein2  in Fick's  laboratory found that by
 applying to the carotid arteries tubes through which hot
 water is flowing the respirations may be greatly increased
 in frequency.   Goldstein's experiment is usually cited  as
 the crucial one, showing that the increased breathing is
 due to the effect of the heated blood upon the respiratory
 centres in  the  medulla oblongata.  Sihler,3 working  in

  1 Ackermann: Deutsches Archiv f. klin. Med.,  Bd. ii.
  2 Goldstein: Wiirzburger Verhandl.,  1871.
  3 Sihler : Journal of Physiology,  vol. ii., and Studies from the
 Biological Laboratory,  Johns   Hopkins  University,   Baltimore,
vol. ii. 
        THE CARTWRIGHT  LECTURES.     55

the Biological Laboratory of the Johns Hopkins Univer-
sity,  however, has  demonstrated  that  the  increased
respiration of an animal exposed to heat is due to two
causes, warmed blood and stimulation of the skin by the
heat, and that probaby skin stimulation is the more im-
portant factor.  Some of Sihler's criticisms of Goldstein's
experiments  have been met by Gad and von Mertschin-
sky,1 who have made it evident that increased tempera-
ture of the blood stimulates the  respiratory centres,  or
increases their irritability.  Section of the vagi does not
check heat dyspnoea, so that this does not result primarily
from the action of the increased temperature upon the
terminal pulmonary expansion  of  these nerves.   The
removal of afferent impulses from the skin by section of
the spinal cord does, however, exert so  marked an influ-
ence that it  cannot be doubted that heat stimulation of
the skin is an important element in the causation.  I  have
convinced myself of the correctness of  Sihler's explana-
tion by observing that in the hot  box at temperatures of
90°-95°  F. (32.2°-35° C.)  rabbits often  preserve  their
normal temperature, and still their breathing is markedly
increased, and that, on the other hand, upon  taking them
out of the box the respirations may sink before the internal
temperature begins to fall.   In one striking experiment
the respirations fell immediately to about normal upon
removing from the hot box a rabbit whose skull had been
trephined on each side of the median line, and the  optic
thalami punctured with a needle.
  We cannot transfer directly to human beings the results
of experiments on heat  dyspnoea in animals, because in
the latter respiration has a far more important function
in temperature regulation than in the former.   To keep
cool  a  dog  pants under  circumstances  when  a  man
sweats.   As  heat regulation is largely influenced by the
cutaneous temperature, it is not improbable  that in  man

  1 Gad and v. Mertschinsky : Virchow u. Hirsch's  Jahresbericht,
1881, Bd. i. S. 197. 
56
WELCH,
heat stimulation of the skin is less* prominent than the
warmed blood acting upon the respiratory centres in in-
creasing the frequency of respiration in fever.
  Inasmuch as disturbances of the heart and of the cir-
culation in general are among the most important symp-
toms  of fever it is  natural  that  much attention  should
have been given to  the study of the  effects of heat upon
the organs of circulation.  The supposed injurious effects
of  prolonged high  temperatures in  fever  have been
usually attributed especially to some toxic action of heat
upon the heart.
  That the pulse-rate is quickened by artificially heating
rabbits and dogs has  long  been known.  The positive
demonstration that this acceleration is due to the direct ac-
tion of the heated blood upon the  mammalian heart itself
was first given by my colleague, Prof. Martin.1  By con-
ducting through the dog's heart, isolated physiologically
by  the ingenious  method which he  devised,  Martin
proved that the heart " beats quicker when supplied with
warm blood and slower when  cold  blood is  supplied to
it;  also, that the rate of beat depends much more upon
the temperature of  the blood in the coronary arteries
than on its temperature in the right auricle or ventricle."
These experiments make  it unnecessary to recur to any
action of  the heated blood upon extrinsic cardiac nerves
or nerve centres in order to explain the quickened pulse
of fever.   Moreover, Fick2 found  that the nervous centres
of the heart  and bloodvessels are unaffected by heating
the blood flowing  through the  carotid  arteries in the
manner adopted by Goldstein in  his experiments on heat
dyspnoea.
  Prof. Martin has kindly permitted me in this connec-
tion to mention certain  unpublished  results of  experi-

  1 Martin : The Direct Influence of Gradual Variations of Tem-
perature upon the Rate of Beat of the  Dog's Heart, Philosophical
Transactions of Royal Society, part ii. 1883.
  2 Fick:  Pfliiger's Archiv, Bd. v. 
        THE CARTWRIGHT  LECTURES.     S7

ments which he is jiow conducting upon the effects of
heat and cold on the isolated heart.  As these results are
pertinent to our subject I gladly avail  myself of this
privilege.  The table of an experiment  which  I  have
examined shows that the isolated  cat's heart beats regu-
larly and more  and more rapidly as the  temperature of
the blood is gradually raised to m.2° F. (44° C).  At
this point the beats become irregular, but are restored to
their  normal rhythm  by feeding  the  heart  with cooler
blood.   The temperature  of about  m°  F.  (439°  C.)
appears  to be a critical one for the isolated heart.  Above
111.20 (44°  C.)  to  1130  (45° C.) the pulsations become
slower instead of quicker as the  temperature is raised.
At 122°  F. (50° C.) the  heart's action ceased, but  the
heart was made to beat again by supplying it with cooler
blood, showing  that the cessation was not due  to heat
rigor.  This interesting experiment teaches among  other
things that very high  temperatures may produce results
differing not only in degree but also in kind from  those
of temperatures only  a degree or two lower.
   We may consider  it then established  that  increased
frequency of the pulse in fever is  referable to the direct
action of the  warmer  blood  on the nervo-muscular
substance of the  heart  itself.   Clinical  observation of
cases of fever makes  it evident that there may be and
often  are present other circumstances which influence
the rapidity of the  heart's pulsations,   circumstances
which in themselves may slow or may quicken the p ulse
Large series  of statistics, therefore, are required to  bring
out the ratio between  the pulse-rate and the temperature
in fever and even then for any given temperature  the
maximum and the minimum pulse-rates lie so far apart
that the statement of the  average increase  in the fre-
quency of the pulse for each degree of rise of tempera-
ture, such as has been computed  by Liebermeister, has
very little value.
  Not only is the pulse-rate quickened in fever, but there. 
58
WELCH,
are often other and more serious circulatory disturbances.
In  the  fever  produced in  rabbits by  injection of the
swine plague bacillus  I find a reduction of the blood-
pressure measured in the carotid artery, and others have
obtained similar results in  the artificial fevers of animals.
The determination of the blood-pressure in fevers of
human beings by means of Basch's sphygmomanometer
has given, in the hands of different experimenters1 such
contradictory results, that  no conclusion can be drawn,
unless it be the very probable one that the blood-pressure
varies, being sometimes high, sometimes low, and some-
times normal in fever.   That the arterial tension is often
reduced is made evident by  the marked dicrotism of the
pulse wave.   This dicrotism, however, characterizes par-
ticularly septic and typhoid  types of fever  and is absent
during the chill of intermittent fever and  often in exan-
thematous and some other fevers,  so that we cannot con-
sider the blood-pressure and arterial  tension as having
any such definite relation to  fever as does the pulse-rate.
  It has been observed by Paschutin, Senator, and Men-
delson,2 that the blood pressure rises with increasing
bodily temperature, produced by exposure to heat.  Men-
delson found that the pressure begins to sink as the tem-
perature  approaches a point incompatible with life.   In
these experiments the animals were  subjected to rapid
elevations of temperature.   I find that when a rabbit is
gradually and cautiously heated in the hot box  used in
my experiments, the rise of  temperature is less marked,
and may not surpass even  for temperatures of 107° F.
(41.7° C), the normal limits of variation which may be
found in the blood-pressure of the same animal examined
at different  times.  These measurements, however, are

  1  Von Basch, Zadek, Arnheim, Wetzel.
  2  Paschutin, Ludwig's  Arbeiten, 1873.  Senator,  DuBois-Rey-
mond's Archiv,  1883, Supplement-Band.  Mendelson,  On the
Renal Circulation during Fever,  Amer. Journ. Medical  Sciences,
October, 1883. 
        THE  CARTWRIGHT  LECTURES.     59

 not very conclusive, for, as has been already remarked,
 rabbits which have been operated upon do not stand well
 artificial heating.
   I have observed that the rhythmical contractions  of
 the bloodvessels of the rabbit's ear are  feeble or absent
 when the temperature is much elevated by artificial heat-
 ing ; whereas, it will be remembered that in experimental
 septic  fever  these contractions are irregular and exag-
 gerated.
   Upon  the  whole, I think that we are  justified  in con-
 cluding that the variations of arterial tension in fevers are
 much  less dependent upon increased temperature than
 upon other factors, such as infection.
   But  the corner-stone of the doctrine which teaches that
 a chief source of danger in fevers is the elevation of tem-
 perature, is not the effect of increased temperature  upon
 the pulse-rate or the  arterial pressure, but it is the belief
 that prolonged high  temperature exerts a directly para-
 lyzing influence upon the  heart.  The  main support  of
 this belief is not the  admitted fact that extremely high
 temperatures paralyze the heart, for these critical tempe-
 ratures lie far above  the ordinary high temperatures  of
 fever, and in a region where all admit the dangers of the
 excessive internal  heat.   The  stately superstructure has
 been built up chiefly on the basis of experiments showing
 that when the internal temperature of animals  has  been
 maintained for some time at a high point by  exposure  to
 external  heat,  parenchymatous or  fatty degeneration  of
 the heart muscle ensues.   It is true that all experiments
 are not  in accord upon this point, and that, as a rule,
 pathological anatomists have not given adherence to the
 doctrine  that parenchymatous degenerations are chiefly
 dependent upon high temperature, still this doctrine has
gained a wide acceptance  among clinical men, and  is
advocated with especial force by Liebermeister.   I have,
therefore, thought it desirable in my experiments to give
especial attention to this question. 
6o
WELCH,
  Among previous experimenters on artificial heating of
animals, Iwaschkewitsch, Wickham Legg,  and Litten
may be mentioned as finding  parenchymatous or  fatty
degeneration of the heart, liver, and kidneys ; and Wal-
ther, Obernier, and Naunyn  as obtaining only negative
results.
  It is not necessary here to enter into a criticism of these
different experiments, which  are of very unequal value.
Litten's1 experiments  on the one side, and Naunyn's2 on
the other,  appear to  be the most carefully conducted.
Litten, whose experiments  are  those usually cited,  kept
guinea-pigs in a double-walled metallic box which was at a
constant temperature of 98.8° F. (37° C.) with dry air, or of
96.60 F. (36° C.) with moist air.  He never failed to find
fatty degeneration at  the end of thirty-six to  forty-eight
hours.  The liver was first affected, and then the heart
and kidneys, which become fatty by the second or third
day.  The animals did  not  survive longer than five or
six  days, and by that time the fatty degenerations had
reached an extreme degree.  Von Recklinghausen3 urges
with apparent justice against these experiments that the
enforced inactivity of the muscles and the imperfect ven-
tilation  may have had  as much  to do in causing the
degenerations as had the high temperature.   These ob-
jections find support in the experiments of Naunyn, who,
making use of a much larger and  better ventilated heat-
ing box than Litten, failed to find any parenchymatous
or fatty degeneration  in his rabbits after they had  been
exposed for two weeks to higher temperatures than Litten
employed.
  As  my  experiments  confirmed in  other  respects
Naunyn's results, I was quite unprepared to find that my
rabbits, after a variable period  of artificial heating quite
  1 Litten, Virchow's Archiv, Bd. 70.      2 Naunyn, op. cit.
  3 Von Recklinghausen: Handb. d. Allg. Pathologie d. Kreis-
lause u. d. Ernahrung, p. 512, Stuttgart, 1883. 
        THE  CARTWRIGHT  LECTURES.     6l

 constantly presented fatty degeneration of the heart, liver,
 and kidneys, and sometimes of the diaphragmatic and
 intercostal muscles.  I never found the degeneration at
 so early  a period  as  did Litten.   It was not until the
 rabbit had been kept for at least a week with an average
 rectal temperature of io6° F. (41.1° C.)  that the degener-
 ation was noticed, and then only in  moderate degree.
 The higher and the less fluctuating the internal tempera-
 ture, the  more certain was the degeneration  to appear.
 I could reckon -upon obtaining rabbits with well-marked
 fatty degeneration of the  heart, by keeping them  for ten
 days with a rectal temperature between  io7°F. (41.70 C.)
 and 108°  F. (42.20 C).   I am not prepared to account
 for the discrepancy in this  respect between Naunyn's
 and my  experiments.  The  box  used  was larger than
 that employed by him, and every care was taken to keep
 it well ventilated by leaving  at least one-third and often
 one-half of the top open.
   I do not think that my experiments altogether do away
 with the force of von Recklinghausen's criticisms.  The
 fact that in these experiments the degeneration made its
 appearance at the end of a  week or ten days, and in
 Litten's in forty-eight hours, to say nothing of Wickham
 Legg finding it at the end of twelve hours, would suggest
 that if the rabbits were  heated in a still larger and better
 ventilated apartment, the degeneration  might not occur
 at all, or  might be  deferred to a much  later period.  In
 my opinion, however, even if full allowance be made for
 this line of argument, we must still admit that prolonged
 high temperature is a  factor in the causation of fatty
 degeneration.
  That it  is not the sole factor no one can doubt.   As is
 well known, fatty degeneration is  produced by anaemia
 and by a  variety of poisons, and even in fevers most
 pathologists are convinced that it bears a closer relation
to the kind and  the degree  of infection than it does to
the height of the temperature.   It is more  frequently 
62
WELCH,
 absent  than present  in pneumonia,  even where there
 have been symptoms of heart failure.
   The kind of degeneration  present  in my rabbits was
 fatty and not parenchymatous.  Probably all who make
 many post-mortem examinations  will  agree  with von
 Recklinghausen, that altogether too liberal use has been
 made of the diagnosis of parenchymatous degeneration,
 and not sufficient  account has been  taken  of the ana-
 tomical changes of the  parenchyma produced by post-
 mortem chemical changes, such as acid formation, etc.
   In order to determine what  influence is exerted by in-
 fection combined with high temperature, I inoculated a
 rabbit, which had been in the hot box for four days, with
 the bacilli of swine plague. These bacilli, if not identical
 with, are closely allied to those of rabbit septicaemia, and
 are extremely virulent for rabbits.   In thirty-six hours
 the animal, which had remained at a high temperature in
 the box, was dead, with  characteristic lesions of the dis-
 ease,  and  the  most  extreme fatty  degeneration  of the
 heart and other  organs was found.  As in other experi-
 ments the  degeneration  had not made its appearance at
 this early date, there can be no doubt that the infection
 was an important element in the causation.  That it re-
 ceived powerful support in the high  temperature, how-
 ever, is  proven by the fact  that little or  no degeneration
 of the heart is observed after infection with this organism
 when the animal is kept at  ordinary temperatures.
  Admitting, then,  that high temperature aids in the
 causation of fatty degeneration of the heart in  fever, the
 question arises, What do we know of the  effects of this
 degeneration upon  the functions of the heart ?  I will say
 nothing of the growing tendency to transfer a large part
 of the classical symptomatology of Quain's fatty heart to
other conditions, particularly to disease  of the coronary
arteries  and chronic myocarditis; we are concerned  at
 present  only with the  occurrence of this degeneration  in
fever.  Have we not  been somewhat  hasty in  assigning 
        THE  CARTWRIGHT  LECTURES.     63

to degenerations of the heart's muscle so large a share in
the production of heart failure in fevers?  One cannot
look at a muscular fibre in which the striated substance
is all replaced by fatty globules, and suppose  that  its
functional activity was unimpaired ;  but into what serious
errors should we fall if we attempted to deduce from the
anatomical changes in the liver cells or the renal epithe-
lium the corresponding functional disturbances ?  Certain
it is that symptoms which are usually considered those
of heart failure are often enough present in fevers without
finding at  the autopsy any degeneration of the heart;
and, on the other  hand, such degeneration may be dis-
covered without any history of these symptoms, although,
of course, the  two  are often associated.
   In the face of these doubts it seemed desirable to deter-
mine,  if possible, experimentally the damage inflicted
upon the cardiac functions by the presence of fatty  degene-
ration  of the heart muscle.  That this degeneration may
exist without apparent injury is rendered probable by the
fact that a rabbit which has been kept for three weeks in
the hot box at a  high temperature, and in which there is
every  reason  to suppose that  fatty degeneration has
occurred, may present no  symptoms of heart paralysis,
and when removed from the box appear and remain per-
fectly normal. An instance has already been mentioned
where  one rabbit  at the  end of three weeks was killed
and presented marked fatty degeneration of the heart;
and another, which had possessed a higher average rectal
temperature, was removed from the box at the end of the
same period, and appeared for ten days perfectly normal,
when it was  used for  another purpose.   That  this de-
generation can be recovered from is, moreover, rendered
probable by clinical experience, and is  universally ad-
mitted.
  Once in teasing out, in a warm room, a bit of fatty heart
muscle  from one of the rabbits, I made a curious obser-
vation.  Near the edge of the  cover glass, where there 
64
WELCH,
was a slight current  in the physiological salt solution,.
rhythmical contraction was observed in a group of mus-
cle-fibres.  This interesting spectacle could be watched
under the microscope for ten minutes.  These contract-
ing fibres were filled  with fatty globules, and  only here
and there, and then indistinctly, could any trace of stri-
ation be detected.  This observation teaches that a fatty
degenerated muscular fibre is capable of contraction,
but, of course, warrants no further conclusions.
  Far more  important than any inferences which can be
drawn from  such observations  is the measurement of the
actual blood-pressure in  animals whose hearts  have
undergone fatty degeneration.  This  I  have  done in
three instances.  The rabbit was removed from the box
at the end of ten  days  to  two weeks, and  the pressure
in the carotid  artery was measured by a mercury  man-
ometer attached to Ludwig's kymograph.  In no instance
was the blood-pressure found to be lower than that nor-
mally present in rabbits.  In an  experiment recently
performed, the average pressure was  125 mm. of mercury;
the pulsations were  regular;  the  heart responded to
stimulation of the  vagi  in  an  entirely normal  manner.
After such stimulation the pressure in one case rose to
176 mm. of mercury.  Immediately after the measure-
ment of the  blood-pressure the rabbit, as in the previous
instances, was killed, and marked fatty degeneration of
the muscular  fibres was found.  In  many of  the fibres
the striation could not be made out, and only fatty globules
were visible; in others, which  also contained fatty  gran-
ules,  the  striation  was distinct.  The  degeneration  in-
volved the whole  muscular substance of the  heart.  A
similar appearance in a human  heart would be considered
to indicate well-marked fatty degeneration.
  These  experiments show that a rabbit's heart which
has undergone marked fatty degeneration from exposure
to heat, may perform its functions, to all appearances,
and for the time being, in a perfectly normal manner. 
       THE  CARTWRIGHT  LECTURES.     65

  There is at least one consideration which should make
us cautious in  drawing far-reaching  conclusions from
these experiments.  There are diseases of the heart—I
need only refer to lesions of the coronary arteries—in
which the functions of the organ  are performed for  a
longer or shorter  time, apparently in a perfectly normal
way, and then heart failure suddenly appears.   It is
probable that here too the blood pressure would be found
normal at a certain period of the disease, and  still it
would be an error to suppose that  the lesion does not
damage the heart.
  Whatever force there may be in this analogy, I still
think that these experiments, as  well as careful patholo-
gical and clinical observations, necessitate some revision
of the current  opinions concerning the significance of
fatty degeneration of the heart in fever.
  So much time has been devoted to  a consideration of
the effects of heat upon the respiration and the heart that
the limits of the present lecture  will permit hardly more
than a summary of the effects exerted by heat upon other
functions and  organs  of the body.  On account of the
great clinical importance of the subject it seemed desir-
able to treat with especial  fulness  the influence  of in-
creased temperature on the heart.
  What  part  has increased temperature  in  producing
febrile consumption of tissue ?  In the  first lecture men-
tion  was  made of Pfliiger's experiments showing that
animals with elevated temperature, produced by exposure
to heat, absorb more oxygen and excrete more carbonic
acid than at the normal temperature.  This  is in con-
formity with the general law that within certain  limits
cell activity is more energetic  at high  than at  low tem-
peratures.   It was also  shown  in  the first lecture that
only a comparatively small part  of the increased oxygen
absorption and carbonic acid elimination in fever can be
referred to the immediate effects  of high temperature.  It
has not been demonstrated that  the respiratory gases in
                        5 
66                   WELCH,
human  beings  are  increased  by artificial elevation  of
temperature.   Indeed, Voit1 was unable to find any such
effect of increased temperature in human beings on the
respiratory gases as  both  he and  Pfliiger observed in
animals.
  Inasmuch as increased disintegration of nitrogenous
material is such  a prominent disorder in fever,  much
attention has naturally been given  to  determining how
far this  can be explained by elevated temperature.  That
it cannot all be so explained is proven by  the interesting
observation of Sydney Ringer, that excessive elimination
of urea  antedates the  rise of temperature in intermittent
fever, and Naunyn has found  the same to be true of the
septic fever of dogs.  The experiments which have been
made to determine the influence of artificial heating on
the amount of urea  excreted by man and by animals
have  yielded contradictory results.   A number of these
experiments are of little or no value, because no attention
was given to establishing beforehand  nitrogen equilib-
rium.   Schleich's2  experiments may be  mentioned as,
perhaps, the most accurate of  those showing an increase
in the urea excreted under the influence  of exposure to
heat.    The more recent experiments of Simanowsky3
were made in Voit's laboratory upon a dog with especial
precautions  as to the establishment of nitrogen equilib-
rium.   He failed to find  any increase in the excretion of
urea as  the result of exposure to external heat,  While
then this question must be left at present sub judice, there
can be no doubt that  only a part at least of the excessive
disintegration of  nitrogenous substance in fever can be
assigned to the influence of the increased  temperature.
  The  loss  of weight exhibited by animals  kept  for a
long time in a hot atmosphere is  usually explained by
the excessive  evaporation of water from  the  body.  In

        1 Voit: Zeitschrift fiir Biologie, Bd. xiv.
        2 Schleich  : Arch, f. exp. Path. u. Pharm., Bd. iv.
        8 Simanowsky:  Zeitschr. f. Biologie, Bd. 21, 
        THE  CARTWRIGHT  LECTURES..     67

 many of my experiments the rabbits were freely supplied
 with food and water, and still the loss of weight was very
 noticeable.   I  am  inclined, therefore, to attribute to  the
 increased temperature under  these conditions a decided
 influence upon the consumption of tissue.
   Senatorx found the  urine of rabbits artificially heated
 to contain more albumen than is ever found in the urine
 of healthy rabbits.  This observation I have not been
 able to confirm on  the  rabbits in my experiments, and
 probably this difference is to be explained  by the  more
 rapid and intense heating  employed  in Senator's experi-
 ments.  Senator explains  the heat albuminuria- by  the
 rise of arterial  pressure  in the renal vessels, but this is
 not  in conformity with the  interesting experiments of
 Mendelson,2 who found by  means of Roy's oncometer
 that both in thermic  and in  septic  fevers  of dogs  the
 kidney is anaemic, while the general blood-pressure is
 elevated.
  No  satisfactory explanation has yet been offered of
 the  diminution  of perspiration   which   distinguishes
 fever so strikingly from  the condition produced by  ex-
 posure  to  high  external  temperatures.    Luchsinger's
 assertion that this is the result of lessened  irritability of
 the sweat centres in the spinal cord remains to be proven,
 and at the best is not a satisfying explanation.
  Bokai,3 in a recent experimental research on intestinal
 peristalsis in thermic and in  septic fevers, comes to  the
 conclusion that the constipation of fever is to be explained
 by the  heated  blood stimulating  the nerves inhibiting
intestinal peristalsis.  If this should be confirmed, then
it would be proven that at least three  symptoms of fever,
  • Senator:  Du Bois-Reymond's  Archiv,  1883, Supplement-
Band.
  2 Mendelson : Op. cit.
  3 Bokai:  Archiv f.  exp. Path. u. Pharm., Bd.  23. 
68       -             WELCH,
the quickened respiration and pulse and the constipation,
are direct effects of elevated temperature.
  When we consider the important nutritive changes in
the muscles accompanying increased thermogenesis, we
shall  be inclined to attribute in part, at least, to these
alterations  and  the  associated  abnormal  innervation,
rather than to increased temperature, the muscular pains
and weakness which  form such  an early and frequent
complaint in many fevers.
  The investigations  hitherto published  of changes  in
the blood  produced  by increased temperature  within
febrile limits are not of sufficiently definite and satis-
factory nature to warrant any consideration on the present
occasion.
  Nor am I acquainted with any experimental  evidence
(save Bokai's work  already mentioned) that increased
temperature is concerned in the production of the digestive
disorders of  fever.  It has already been said that the
rabbits with high internal temperatures in the hot box ate
greedily, but these voracious animals cannot be considered
favorable subjects to test this  question.
  Especial emphasis has been laid by Liebermeister and
those who accept his teachings upon the dependence of
the nervous symptoms of fever, particularly the so-called
typhoid  symptoms, on the  elevation  of temperature.
There is, however, abundant clinical evidence to disprove
this doctrine.  Reference need be made only to relapsing
fever, and especially to the aseptic fever  described by
Genzmerand Volkmann, in which there is entire absence
of  the  whole  group of so-called nervous symptoms.
Moreover, Liebermeister's opinion in this respect is  not
supported by adequate experimental evidence.   Unless
the temperature of the  brain or of the entire  animal be
brusquely raised to a high  point  by coarse methods,  no
disturbance of the cerebral functions is noticed until the
temperature reaches a critical point, beyond which further
increase is likely to prove rapidly fatal.   At this  critical 
       THE  CARTWRIGHT  LECTURES.     69

point the animal, which before has lain quietly, becomes
very uneasy, and if the temperature rise higher it has
convulsions and coma and dies.
  I have endeavored to bring before you in this lecture
the experimental evidence relating  to the effects of in-
creased temperature upon the  general condition of the
body and upon  the functions of its various organs.   I
have given account, as  briefly  as possible,  of some ex-
periments which perhaps shed additional light upon this
important subject.  In the course of this lecture emphasis
has repeatedly been laid upon the necessity of controlling
the results of the experimental method by clinical ob-
servation, and here and  there I have endeavored to in-
stitute this control.  Further than this I shall not attempt
to set before you the clinical evidence regarding the effects
of increased temperature in fever.   There are those here
more competent than I to deal with this side of the ques-
tion.  We may feel assured that when all  the facts are
before us and are properly interpreted, there can be no
lack of harmony between the results of experimental and
those of clinical investigations. 
 
  LECTURE  III.

THE ETIOLOGY OF  FEVER.
  We considered in the last lecture  the experimental
evidence concerning the effects of increased  bodily tem-
perature.   An advantage of the experimental over the
clinical method of investigating this subject  is that it
enables us to study  the  effects of  heat upon the whole
body and its various functions without the intervention
of disturbing factors, such as infection, which complicate
the clinical analysis of febrile phenomena with reference
to this question.
  We found that animals may be kept at  high febrile
temperatures for at least three weeks  without mani-
festing  any serious  symptoms.   The only functional
disturbances which could be attributed  directly to the in-
fluence of the elevated temperature were increased fre-
quency of respiration and quickened pulse.   The rapid
respiration  was found to be due  partly  to stimulation of
the skin by external  heat and by the warmed blood, and
partly to the action of the warmed  blood on the  respira-
tory centres.  The quickened  pulse could be  positively
referred to  the effect  of the warmer blood upon the heart
itself.  No  definite relation could be established between
the variations of arterial tension which  occur in fever
and the height of the temperature.
  Although the  experiments narrated  showed that  pro-
longed high temperature is an element in the  causation 
72
WELCH,
of fatty degeneration of the heart, they also indicated
that other factors, such as infection, are concerned in the
production of this  lesion.  Moreover, experimental evi-
dence  was found  in  support of clinical facts showing
that this alteration  may exist without serious interference
with the  functions of the heart, so that  the conclusion
seems justified that failure of the heart's power in fever is
less an effect of high temperature than of other concomi-
tant conditions.
  Of the other disturbances in fever we learned that the
increased consumption of tissue can be  explained  only
in relatively small  part by the elevation of temperature.
The lessened perspiration, the renal disorders, and the
digestive disturbances (with the  possible  exception of
constipation)  are referable  also  chiefly  to  other causes
than the increased temperature.   Both experimental and
clinical observations  strongly  support  the  view  now
widely accepted that  the disturbances of the  sensorium
which constitute so prominent a part of the group of so-
called  typhoid  symptoms, are dependent in far  higher
degree upon infection or intoxication than  upon  the
heightened temperature.
  Although no  attempt was made to analyze in detail the
clinical evidence relating to the  effects of high tempera-
ture, attention was called to the fact that the absence of
all serious  symptoms in  many cases of relapsing fever,
and in the  so-called aseptic  fevers in spite of  prolonged
high temperatures, strongly support the conclusions de-
rived from  the experimental study of the effects of heat
upon man  and animals.  Even in fevers, such  as typhoid
fever and pneumonia, where the height of the tempera-
ture is undoubtedly  a  most  important index  of  the
severity of the disease, there exists no such parallelism
between the temperature  and the nature and the severity
of the other symptoms  as we should expect if these
symptoms  were caused  by  the increased  heat  of the
body. 
        THE  CARTWRIGHT  LECTURES.     73

  It was emphasized that the results of experimental in-
vestigations should not be permitted to control the treat-
ment of fevers, more particularly  the  use  of  so-called
antipyretic agents.  These agents,  whether  hydrothera-
peutic or medicinal, influence, as is well known, many
functions besides  reducing the temperature.   I need
only refer to the powerful influence of cold  baths upon
the circulation and the nervous system, and to the action
of antipyrin and other antithermic  drugs upon the ner-
vous system.
  Reasons were given for assigning to hyperpyrexia and
insolation a position separate from other febrile condi-
tions in the discussion as to the effects of elevated tem-
perature.
  Before leaving  this subject of the effects of increased
temperature, I wish to call attention to one consideration
which should perhaps influence our opinion on this much
disputed question.  Is it a  matter of. indifference,  so far
as the  effects of febrile temperatures are concerned, in
what  manner  the  increase of temperature  is  brought
about ? We have seen that heat regulation, heat produc-
tion, and heat loss are disturbed in  fever; but, as experi-
ence shows, not always in the same manner  or the same
degree.  In one case the incoordination of  the  regulat-
ing mechanism may be most apparent, the temperature
fluctuating strangely up and down ; in another  case  the
heat-producing processes are excited to the utmost; and
in another the circulatory changes in the skin, the vaso-
motor disturbances, are the most prominent phenomena.
Now this varying interplay of the  factors which  cause
febrile rise of temperature doubtless corresponds to vary-
ing conditions of innervation, of structure and of function
of certain tissues of the body.  May we  not  reasonably
suppose that these  varying conditions of the tissues di-
rectly associated with the rise of temperature may influ-
ence their tolerance of increased body heat ? We have
not the experimental or the clinical data which would 
74
WELCH,
enable us to give a definite answer to the question here
propounded, and it would lead me too far from the theme
of the present lecture  to  attempt to  sift the equivocal
evidence which might be gathered.  I  suggest this ques-
tion, however, as one worthy of more attention than  it
has hitherto received.
  I wish now to invite your attention to some considera-
tions concerning the etiology  of fever.  In this era, when
etiological studies occupy the foremost rank  in medical
science, it will naturally be expected that a discussion of
the general pathology of fever, even  though it does not
aim at completeness, will not  leave wholly untouched the
etiological aspect of the subject.
  The general etiology of fever relates mainly to a con-
sideration of the agents producing fever, the so-called
pyrogenic substances.  It is, moreover, only certain gen-
eral characters of these agents which can be  properly
considered here.   Most  of the questions which at present
engage so prominently  the attention of physicians con-
cerning the specific  causes of individual fevers  belong,
of course, to the special etiology of fevers, and therefore
do not  lie within the  limits of our subject.  But even
with these limitations we cannot in treating of the gen-
eral etiology of fever consider the febrile processes  so
much in the abstract as we have done hitherto.  We
must come into closer contact with the individual  forms
of fever.
  At the start it should be  said that probably in no in-
stance are we acquainted  with the actual substance or
substances upon which  the  febrile disorder of animal
heat immediately and directly depends.  We deal  here,
as elsewhere in medicine, not with direct but with remote
causes.   But in no department of  etiology have we ad-
vanced nearer the proximate  causes than in many of the
infectious fevers.   To  be convinced  of the immense
progress which  has been brought about  by the etio-
logical study of fevers, Jet one glance over some of the 
        THE  CARTWRIGHT  LECTURES.     75

 older  books on fevers, such as Percy's or Selle's,1 with
 their endless divisions into symptomatic genera and spe-
 cies, and their barren speculations.   Percy, for instance,
 describes no less than one hundred and fifteen different
 kinds of  fever.
   In all ages it has been customary to divide fevers into
 two great groups, viz. :  those  which are secondary  to
 some  local cause, usually an inflammation,  and  those
 which cannot  be explained by the presence of any local
 lesion.  The explanation of the symptomatic  seemed  so
 much clearer  than  that of the essential  fevers that
 attempts have  repeatedly been made to place  all fevers
 in the symptomatic  group.   It is a curious fact that the
 two methods which  have been of  the greatest  service  in
 the study of fevers, each, when first introduced, led to an
 entire misconception of the nature of fever. Boerhaave,
 who was the first to  make any extensive use of the ther-  «
 mometer at the bedside,  supposed that this instrument
 indicated a reduction of the bodily  temperature during
 the febrile chill.  He therefore taught that increased fre-
 quency of the pulse  and not  the elevation of temperature
 is the  constant and  essential symptom of fever.  If we
 except de Haen's correction, which never became widely
 known, it was  not until the  middle  of the present cen-
 tury that Boerhaave's error was overthrown.  A no less
 serious misconception  sprang  from the  study of the
 pathological anatomy of fevers in  France during the
 early  part  of  the  present   century.   The  exaggerated
 ideas of the immediate followers  of Bichat as to  what
 can be accomplished by pathological anatomy led them
to the belief, for a long time widely accepted, that there
is no such  thing as an essential fever, that all fevers are
symptomatic of some local disease. This error  of Brous-
  1 Percy : Die gesammte Fieberlehre, Pesth, 1820. The original
is in French.
  Selle:  Rudimenta Pyretologiae Methodicre, Berolini, 1773. 
j6                   WELCH,
sais, one of the  most influential  and eloquent medical
teachers of this century, is plainly traceable partly to the
fact that his autopsies were chiefly of typhoid fever, and
partly to the belief that the lesions found at the autopsy
suffice to explain all of the manifestations of the disease
during life.  But we need not stop to trace the fate of the
various  attempts to overthrow the doctrine of essential
fevers. I have mentioned one attempt chiefly on account
of the suggestive lessons it conveys rather than  from a
desire to enter into historical details which! have hitherto
purposely avoided.
  The division of fevers into symptomatic and essential
fevers is one of undoubted practical utility, and is  not
likely to be abandoned.   But it cannot truthfully be said
that this popular classification  has been of much assist-
ance in advancing our  knowledge.  Close inspection
shows that the boundary lines between the two groups of
fevers are vague and  shadowy.   Probably no one any
longer believes that traumatic fever, the principal type of
the symptomatic group,  is due to increased production of
heat in  the seat of inflammation, which, acting like a
furnace, was once thought to warm  the whole organism,
or to the irritation of nerves connected with the inflamed
region.  The opinion of Billroth  and of Weber  is  now
generally  accepted, that traumatic fevers are caused by
the absorption of pyrogenic substances from the inflamed
district.   Symptomatic fevers as well as essential fevers,
therefore,  are  dependent upon the  presence within the
blood of fever-producing agents.  Many essential fevers,
moreover, resemble the symptomatic ones in the  exist-
ence of inflammation, or necrosis  at the  portal where
there is  reason to believe that the pyrogenic agents gain
access to the general circulation.  A distinction in  these
cases cannot be based on the ground that in  sympto-
tomatic  fevers only chemical  substances, although pos-
sibly the products of bacteria,  enter the  circulation, and
in essential fevers microorganisms invade the blood, for 
       THE  CARTWRIGHT  LECTURES.     77

such  a distinction would place cholera and possibly
tetanus and typhoid fever among the symptomatic fevers.
These considerations show how vague and unsatisfactory
are the distinctions between symptomatic and essential
fevers.  Still, similar criticisms can be made of many of
our artificial classifications which nature is under no com-
pact to observe, and we should undoubtedly  be  put to
great inconvenience if we attempted to dispense with the
epithets symptomatic  and essential as applicable to dif-
ferent forms of fever.   There are, however, other points
of view which seem to me more fruitful in the study of
the etiology of  fever than  those embodied in  these dis-
tinctions.  I refer to the differences in the nature of fever-
producing agents,  concerning which  our  knowledge,
although  still  very imperfect, has been materially in-
creased within recent years.   And  here again  we are
greatly indebted to  the  results of  experiments upon
animals.
   Much light has been shed upon the causes of a  certain
class of fevers  by a series of experiments, which received
their impulse from the important studies of Alexander
Schmidt and his pupils upon the physiology of the blood.
A particular direction was given to these experiments by
the often repeated observation  that fever and  other in-
jurious effects  may follow the  transfusion  of  blood,
especially  when the  blood of one species of animal is
transfused into an animal of another  species.   In order
to test the supposition  that these bad  symptoms are due
to an excess of fibrin  ferment  Kohler1 injected into the
vessels of animals blood made rich in fibrin ferment and
fibrino-plastic substance, and found that this blood when
injected in large  amount into the jugular vein causes
sudden death by  rapid coagulation of the blood in the
right heart and pulmonary arteries, but when injected in
  1 Kohler: Ueber Thrombose und Transfusion, u. s. w. Inaug.
Diss., Dorpat, 1877. 
78
WELCH,
smaller amount or  in  a different manner produces  a
typical febrile attack bearing a close resemblance to that
following  the injection of putrid  fluids.  Angerer1 then
found that a similar fever, although less intense and more
gradual in its development,  may be produced by the in-
jection of blood into the peritoneal cavity or the subcu-
taneous tissue, or  even by  an extravasation of blood.
Although  in these experiments it was believed that fibrin
ferment is the  pyrogenic agent, Edelberg2 was the first
to produce fever and other symptoms of intoxication by
the  injection of this  ferment  isolated   according  to
Schmidt's method.
   In the light of these experiments it was to be expected
that other ferments would be examined with reference to
their pyrogenic  power.   Schmiedeberg3 discovered that
injections of  histozyme into the blood of dogs produced
high fever associated with general illness, and particularly
with diarrhoea.   The ferment to which Schmiedeberg has
given the  name histozyme he believes to be present nor-
mally in small amount in the body, and to  be concerned
in the dissociation  of the nitrogenous constituents of the
tissues.   He  concludes from his experiments that an ex-
cessive accumulation in the  body of this normal ferment
gives rise  to fever with increased metamorphosis of nitro-
genous materials.  Schmiedeberg ^thinks it  probable that
the fibrin-ferment solutions employed by Edelberg in his
experiments  contained  also histozyme,  and  that  the
pyrexia was due to the latter substance.
   Following these observations concerning the pyrogenic
power  of  fibrin-ferment  and histozyme comes  the dis-
covery of  von Bergmann and Angerer* that injection of

  1 Angerer:   Klin.  u. Exp. Untersuch. lib. d.  Resorption  v.
Blutextravasate, Wiirzburg, 1879.
  2 Edelberg:  Arch. f. exp. Path. u. Pharm., Bd. xii.
  3 Schmiedeberg: Ibid., Bd. xiv.
  * Von Bergmann u. Angerer:  D. Verhaltniss d. Fermentintoxi-
cation. Festschrift, WUrburger Universitat, 1882, i. 135. 
        THE  CARTWRIGHT  LECTURES.     79

pepsin  and of trypsin into  the blood of dogs causes  a
well-marked fever with characters like those of the other
ferment  intoxications  described.   A valuable  calori-
metrical study of pepsin and trypsin fevers has been
made by Wood, Reichert, and Hare.1  These authors, as
well as Ott,2 have demonstrated that it is not the pepsin
and the trypsin ferments themselves which constitute the
pyrogenic  agents, but some  contaminating substance,
which seems to be a peptone.   That peptones artificially
prepared contain poisonous  principles has been  known
for some time, and Brieger* has succeeded in isolating  a
crystallizable  poisonous ptomaine,  called  pepto-toxin,
from commercial peptone and from that formed by the
artificial digestion of fibrin.   This ptomaine, however, is
not identical with the pyrogenic agent found by Ott and
by Wood and his colleagues in commercial pepsin.  To
this list of pyrogenic  substances obtained from  impure
ferments  may be  added leucin, and, according to Ott,
papayotin and neurin which produce marked fever when
injected into the blood in small quantity.  The substance
sold under the name of  papoid possesses marked pyro-
genic power when  its filtered aqueous solution is injected
into the blood.   This substance contains principles  be-
longing to the peptone  or albumose group.  Dr. Mall,
Fellow in Pathology at  the Johns Hopkins  University,
has isolated from commercial papoid a bacillus, which in
pure cultures  exerts a powerful  peptonizing  action on
fibrin  and  on  connective  and  elastic tissues.  The
bacillus itself is not pathogenic, but an albumose or some
similar substance produced by its activity, has pyrogenic
power when injected into the blood.
   It does  not appear  that any one  has actually isolated
the pyrexial agent from the  various  ferments  employed
in these experiments.   Certainly no such  agent has been

  1 Wood, Reichert, and Hare:  Therapeutic Gazette, 1886.
  2 Ott:  Journal of Physiology, vol. viii,
  3 Brieger: Ueber Ptomaine, Berlin, 1885. 
8o                   WELCH,
obtained in a crystalline form, which is the test of its
purity, if we except Brieger's pepto-toxin, the pyrogenic
capacity of which has not been established.  It has been
alleged that the fever-producing agent is the same in all
these ferment intoxications, but this has not been proven
nor does it seem probable.
  On better grounds it has been urged by von Bergmann
and Angerer, that all of the substances in  the group of
pyrexial agents now under consideration, cause fever by
producing the same change in the blood.  These authors
claim that this change is  the formation in the circulating
blood of an excessive amount  of fibrin ferment, which
leads either  to coagulation or to stasis in the capillaries,
particularly those of the lungs and of the intestines.  One
of the main arguments for this  view  is the fall of blood
pressure which von Bergmann and Angerer  observed
after  injections of  pepsin and  of  pancreatin,  but  this
fall can be explained in  other ways  than  by supposing
that the pulmonary capillaries are  occluded, and, more-
over,  Wood, Reichert, and Hare find that the blood pres-
sure often  rises in the course of pepsin fever. It does not
seem  to me that we are any more  able  to explain in
exactly  what manner the pyrogenic substances act in
this class of fevers than in other fevers.  The idea, how-
ever,  that the  liberation  of  fibrin ferment  in abnormal
quantity is capable of causing fever, finds support not
only in experiments which have been mentioned, but also
in the fact that injections of haemoglobin solutions, and
of large quantities of water into the blood, produce fever.
  But you, perhaps, by this  time have asked yourselves
what bearing all  of these experiments with various pyro-
genic substances have upon the etiology of human fevers.
They have,  in my judgment, an  important bearing on
this subject.   However obscure may  be the  explanation
of the  mode  of action  of these substances, however
doubtful may be their exact chemical composition, they
have certain common characteristics which are calculated 
        THE  CARTWRIGHT  LECTURES.     8l

 to shed light upon the causation of some obscure febrile
 disorders of human beings.  In the first place, the mem-
 bers of this group of pyrogenic substances, if not  identical
 with certain physiological ferments, are readily produced
 by them,  quite independently of the action of bacteria
 or other microorganisms.  In the second place,  some of
 these substances are present normally in small amount in
 the  body, and if their elimination is impeded,  or their
 formation  is excessive, there is reason to believe that they
 become  efficient causes of fever.  In  the  third  place,
 these pyrogenic substances may be produced, again with-
 out  the action of bacteria, in extravasated blood, or by
 the  abnormal  disintegration of tissues, and if they are
 absorbed from these sources in such a condition, or in so
 large an amount that nature cannot  render them harm-
 less, they are capable of producing fever.   It is customary
 to call the morbid  condition produced by the absorp-
 tion of these substances, ferment intoxication in  analogy
 with the term  putrid intoxication, applied to the  diseases
 caused by the  absorption of the products of putrefactive
 bacteria.   The term ferment intoxication seems to me to
 imply  more than our knowledge warrants, but it  is not of
 much  use  to contend against names  which have gained
 currency.  It  is  probable  that some  of  the  pyrogenic
 agents in  this group belong to the class of leucomaines,
 but our present information regarding these bodies does
 not justify  any positive statements on  this point.
  Although the  etiology  of  individual fevers does not
 belong to our subject, I cannot forbear calling your atten-
 tion  to certain febrile conditions which  seem to  be pro-
 duced  by the accumulation of substances that are either
 normal constituents of the body or  are the result  of
 chemical processes, differing but little from physiological
 ones.
  To this category probably belongs the so-called aseptic
fever, first described by Genzmer and Volkmann.1  These
  i Geiumerand Volkmann: Volkmann's Sammlung, No. 121.
                         6 
82
WELCH ,
surgeons have established the fact that there are traumatic
fevers not caused by the absorption of septic material,
and that  severe injuries and  wounds which pursue an
entirely aseptic course, are not infrequently associated
with considerable elevation of temperature.  This aseptic
fever is usually to be observed with extensive wounds or
injuries in which there is much lacerated tissue or extrava-
sated blood to be disintegrated and absorbed.  It occurs
not only  with wounds  correctly treated  by  antiseptic
methods, but also with subcutaneous injuries, particularly
fractures of the large bones, where  there can be no sus-
picion of the action of bacteria.  Aseptic traumatic fever
differs by  such marked characteristics from septic  fever,
that there can be no doubt that the two types of fever are
etiologically  distinct.  Aseptic  fever has no prognostic
significance; its only symptoms are  the elevation  of the
temperature, which may mount to 104° (40° C), or even
105.8° (41° C), and the increased frequency of the pulse.
The entire absence of  all the  intoxication symptoms of
septic and infectious fevers, such as the benumbed senso-
rium, the  dry tongue and skin, the lessened secretion of
urine,  I have already referred to in  confirmation  of the
belief that these symptoms  are not  dependent upon the
rise of temperature.  Genzmer and Volkmann assign as
the cause of aseptic traumatic fever,  the  absorption of
substances  resulting from  the  disintegration of the
wounded tissues and of the extravasated blood,  and state
that these substances  probably  do  not differ markedly
from  those  produced by physiological tissue metamor-
phosis.  This explanation certainly has received decided
support by the experiments which  I have described in
this lecture, a large part of which have been performed
since the publication of Genzmer and Volkmann's article.
It has  been suggested that  aseptic traumatic fever is a
reflex neurosis, and this suggestion cannot be absolutely
rejected as a possible explanation, but for various reasons, 
        THE  CARTWRIGHT  LECTURES.     83

which cannot here receive further consideration, the usu-
ally accepted explanation is the more probable one.
  An instructive case of ferment intoxication  has been
reported by Cramer.1   There existed in a young woman
a cyst, the size of a goose's  egg, between the fibres of the
semitendinosus muscle. The cyst was developed from a
cavernous angioma, and was filled with dark fluid blood.
The patient had had fever for almost two years up to the
day of the operation.   The cause of the fever could not
be discovered.   Immediately after  the  removal of the
cyst the fever stopped and  did not return.  In  this case
the cavernous structure of the cyst wall  accounts for the
ease with  which we must suppose a considerable quan-
tity of  the  pyrogenic  substance was continuously ab-
sorbed from the bloody contents of the cyst. The results
of Angerer's experiments, already mentioned,  enable us
to explain the source of the fever in this case.
  Another instance may be cited in which fever is prob-
ably  to be explained  by  the  accumulation within the
body of products of normal metabolism.   More or less
fever appears to be a constant  accompaniment of the
agonizing method  of treatment known as the Schroth
cure.   In  this treatment the patient is kept  for a number
of successive days on dry food  with scarcely any fluids.
Both  Bartels and Jurgensen,2 who have investigated the
nutritive changes  of  individuals under  this  treatment,
believe that the body becomes so poor in water that some
of the products of  regressive  metamorphosis cannot be
carried  out of the system.  This certainly seems very
probable,  and, if true, it affords in the light of recent ex-
periments an explanation of the accompanying fever.
  I believe that good reasons can be adduced in support
of the opinion that the febrile conditions sometimes asso-
  1 Cramer: Verhandl. d.  Deutschen Gesellschaft f. Chirurgie,
13th Congress, 1884.
  2 JUrgensen : Deutsches Arch. f. klin. Med., Bd. i. 
84
WELCH,
    ciated with leucocythaemia, profound anaemias, and chlo-
    rosis belong  to  the group of fevers we are now  consid-
    ering. It is probable that some of the obscure ephemeral
    fevers are also to be included here.  But to consider these
    febrile disorders in detail would lead us into the domain
    of special  etiology upon which we have already perhaps
    encroached too far. My purpose has been to bring before
    your attention only a  few clinical examples in illustration
    of the experimental results.
      I think that you will  agree  with me in  the conclusion
    that experimental and clinical evidence justify us in rec-
J   ognizing as a distinct group  of pyrogenic agents, sub-
    stances which have no necessary connection with micro-
    organisms, and which are either not foreign to the healthy
    organism or are readily formed by unorganized ferments
    from  normal or abnormal  constituents   of  the  body.
    These substances may  be described  as  homologous in
    distinction from the heterologous agents concerned in  the
    production of septic and infectious fevers.
      A class of pyrogenic agents of far greater clinical im-
    portance than those previously considered is formed by
    the products of  microorganisms which in  themselves are
    not pathogenic. A  considerable number of bacteria,
    which when inoculated in pure culture into the body  are
    not capable of further invasion or of multiplication, pro-
    duce in culture  fluids  and  in dead animal or  vegetable
    material poisonous substances often  of great virulence.
    Exception may  be taken  to the description  of  these
    organisms as  non-pathogenic, inasmuch as the products
    of their activity are poisonous, but the epithet pathogenic
    is usually assigned by bacteriologists only to such micro-
    organisms as are capable  of multiplication  within  the
    body.  If  we called  all of the microorganisms patho-
    genic  which  produce  poisonous  ptomaines  we should
    have to include  in  this  category a far  larger number of
    the known species of bacteria than has  hitherto been
    customary. 
       THE  CARTWRIGHT  LECTURES.     85

  The best known and most important of the fevers pro-
duced by chemical products of saprophytic bacteria are
those grouped under the name putrid intoxication.  Until
the introduction of the modern era in bacteriology by
Koch nearly all of the experimental work on the etiology
of fevers related to the causation of the septic and putrid
fevers.  It is instructive with our  present knowledge to
follow the experiments on this subject from the  period of
Gaspard,  Magendie,  and  Sedillot up to recent times.
What light has been shed upon the mass  of contradic-
tory and perplexing results  of experiments with putrid
fluids by the recent chemical and biological studies of
putrefactive processes ?  Some of the  putrid substances
experimented with undoubtedly contained parasitic micro-
organisms, and others  contained  only obligatory sapro-
phytes.  Some were  rich  in poisonous ptomaines, and
others were nearly devoid of them.  The whole doctrine
of the parasitic nature of infectious fevers seems to have
hinged in the  minds of some upon the determination of
the question  whether septic  and  putrid fevers are pro-
duced by the  absorption of chemical substances, or  by
the invasion of pathogenic bacteria. The ideas concern-
ing putrid intoxication dominated  at one time the whole
field of fever etiology, and were applied not only to sep-
ticaemia but to typhoid fever, typhus fever, yellow fever—
in fact, to nearly all  infectious  fevers.   Nor  have the
echoes of this period even now entirely died out.
   Panum was the  first to isolate from putrid materials
some chemical substance or substances in tolerable purity,   A
certainly  free  from  bacteria.   This  substance, when
injected  into  animals, produced symptoms  of  putrid
intoxication.   Subsequently, von Bergmann and Schmie-
deberg isolated from putrefying yeast a poisonous crystal-
line substance, their celebrated sepsin.  For a time the
opinion prevailed that this  sepsin is  the  source  of  all
putrid intoxications.   Thanks to  the investigations of
Nencki and others, and particularly of Brieger, we now 
86
WELCH,
   know that many alkaloidal substances can be separated
   from  putrefying  materials.   Some of  these  so-called
   cadaveric alkaloids or ptomaines are poisonous, fever-
   producing, others are harmless.  There  is no reason to
   suppose that the list of the ptomaines of putrefaction has
   been exhausted, nor is it necessary to believe that all of
   the poisonous  constituents of putrefying  materials are of
   an alkaloidal nature.
     Most of the bacteria concerned in ordinary putrefactive
   processes are purely saprophytic.  They are incapable of
   multiplication  in the living animal tissues.  In a mixture
   of putrefactive bacteria it is not, however, uncommon to
   find genuine pathogenic or parasitic bacteria.  It was from
   such sources that the bacilli of mouse septicaemia and of
   rabbit septicaemia (Koch)  were obtained.  The bacillus
   of malignant oedema is  also  often found in the  early
   stages of post-mortem decomposition.
     There  is, of course, no doubt that the absorption of
/^  the chemical products of putrefaction may produce fever
   with septic symptoms, quite independently of the pene-
   tration and multiplication within living tissues of bacteria.
     Here belong certain cases usually described as septic,
   in which fever and other bad  symptoms subside  upon
   the thorough cleansing and disinfection of a foul wound,
   or of a puerperal uterus.   The majority of cases of septi-
   caemia are not to be included here, for they depend upon
   the invasion of pathogenic bacteria.   But, excluding the
   cases of genuine septicaemia, there remain  the  putrid
   intoxications which result from the absorption of poisonous
   substances produced in necrotic  or disintegrating tissues,
   or exudations,  or extravasated blood, by  the  action of
   purely saprophytic bacteria.   The ideas which  I  have
   expressed on this subject  are now so generally admitted
   that they require no further elucidation.
     It is probable that  fever, with symptoms of intoxica-
   tion, although generally of a much milder nature than in
   the class of cases just considered, may be produced by 
        THE CARTWRIGHT LECTURES.     87

abnormal fermentations  and  putrefactions  caused by
saprophytic bacteria in the alimentary canal.  But Here
the essential morbid conditions seem to be abnormalities
in the gastric and  intestinal contents, due partly to the
character of the ingesta, but chiefly to alterations of the
digestive juices.   Fermentative and putrefactive bacteria
are normally present in the intestinal canal, and  have
abundant opportunities to gain access to this situation.
The number, however, which can multiply and thrive
there is quite limited, for under normal conditions, accord-
ing to Escherich, only such bacteria can multiply to any
extent in the intestinal  canal  as are capable of growing
with little or no  oxygen, and  of deriving their nourish-
ment from  the anaerobic  fermentation of the food sup-
plied to them in this situation.  Suitable conditions for
the excessive multiplication of putrefactive or fermenta-
tive bacteria may, however, be furnished by abnormali-
ties of the gastric or intestinal contents.
  Of a far more  serious nature are the putrid or ptomaine
intoxications which result from the ingestion of sub-
stances which  have undergone outside of  the  body
putrefaction, or  changes which lead to the formation of
poisonous ptomaines.   To this group of cases  belong at
least many of the instances of poisoning which have been
caused by  eating certain  kinds of meat, sausage, fish,
cheese, etc.   In  some of these instances poisonous pto-
maines have been isolated from the suspected substances,
but we know scarcely  anything of the microorganisms
which are concerned in their production.
  It is important to bear in mind that it is not stinking
putrefaction alone which gives rise to poisonous products.
Brieger has found that  such  products may be absent in
very  advanced  decomposition,  and that in  general the
most  virulent products  are formed  in the early stages of
putrefaction.  We know,  furthermore, that putrefactions
and fermentations differ in the character of their products.
There are differences according to the kind of bacteria 
88
WELCH,
 present, according to the substances decomposed, and
 according to various  other conditions, such as the pres-
 ence of oxygen, the temperature,  etc.  This is  not the
 proper occasion to discuss these details.
   Enough has been said to prove that we are justified in
 recognizing as a second  class of pyrogenic agents sub-
 stances which are the products of bacteria in themselves
 not pathogenic.  These pyrogenic agents may be formed
 on or within the body,  or they may be produced outside
 of the body.  I would not by any means have you infer
 that it  has been proven  in all of the special examples
 which I have mentioned,  that the bacteria involved are
 not pathogenic, or capable of multiplication within the
 living  tissues.   We  have not  sufficient knowledge to
 assert or to deny this  in every instance, but I do not think
 that it is likely exception  will  be taken to the classifica-
 tion which I have adopted for most of these cases.  As
 has repeatedly been  mentioned, our purpose here is not
 an analysis of individual  cases of fever,  but  an attempt
 to  classify systematically the various  pyrogenic sub-
 stances.
   We come now to the  third and most important  group
 of fever-producing agents, the pathogenic microorgan-
 isms.  So  overshadowing is their importance that it has
 been claimed that they are the sole  causes of fever.  In
 contrast with former times it is no longer the symptom-
 atic fevers  whose etiology is clearest.  We  have  much
 more definite ideas as to the mode of production of some
 of the essential fevers which were once the most obscure,
 than we have of symptomatic fevers.   It does not seem
 to me worth while to go  over the chain of evidence which
 establishes the doctrine that  the infectious fevers are
 caused by microorganisms.  There  is  probably  no one
 who has  thoroughly  investigated  the  subject, and  is
competent to form an  opinion on it,  who does not to-day
admit that a number of infectious  diseases have been 
        THE  CARTWRIGHT  LECTURES.     89

proven to depend upon  specific microorganisms, and
that it is a logical  inference that all infectious diseases
are caused by parasitic organisms.
  It is not germane to our subject to enter into a morpho-
logical or biological description of the different species of
pathogenic  organisms which  are causes of  febrile dis-
eases. The  only question which concerns us in this con-
sideration of  the  general  etiology  of fever  is how the
microorganisms produce fever. Are they themselves the
pyrogenic agents, or do  they produce chemical  sub-
stances which are  pyrogenic ?   A number of other pos-
sibilities might be  mentioned.   These and similar ques-
tions have  suggested themselves to  investigators since
the  beginning  of any knowledge of  parasitic  micro-
organisms.  Our  information  is far  from sufficient to
enable ws to answer these questions in a  positive manner,
and still we are not left wholly to  vague  surmises in
attempting to  form some sort of an opinion.
  That bacteria can  produce mechanical effects by plug-
ging up  capillaries and in other ways is certain, but the
wide differences presented  by  the various infectious dis-
eases cannot be reconciled with the idea that pathogenic
bacteria  act chiefly by mere mechanical  interference with
the fluid and  the  solid constituents of  the body.   Not-
withstanding the fact that Strieker and Albert succeeded
in producing  fever by the injection  of starch granules
into the blood, probably  no one will be  inclined to
attribute the pyrogenic activity of  bacteria in any con-
siderable extent to occlusion of bloodvessels.
  In a certain number of infectious diseases, particularly
of  animals,  bacteria are  present  in  such  enormous
number in the blood and tissues that  some are inclined
to refer  the disastrous effects of the organisms .to the
withdrawal of oxygen and  other nutritive pabulum from
the cells of the body.  So far as  the  appropriation of
oxygen is concerned, this  idea is not supported by the
results of most of the examinations  of the blood in cases 
90
WELCH,
of anthrax.   This explanation was more  popular in the
early days of bacteriology  than  it is at present, and at
the best its value is limited, for it cannot be applied to a
large number of infectious diseases, such  as cholera or
typhoid fever where  the circulating  blood is not largely
invaded by the  parasites.  Furthermore, it  is not clear
how the appropriation by bacteria of nutriment intended
for the tissues would  help us to explain the production of
fever.
   It has been suggested  that the  increased temperature
in infectious fevers may be explained by  the heat pro-
duced  by oxidation  or  other chemical changes in  the
microorganisms  themselves.   But this is not at all  a
satisfactory  explanation.   Not  only is  the quantity of
heat which can come from this source in all probability
very small compared with  that constantly  produced in
the body, but such an explanation of febrile rise of tem-
perature is not in harmony with what we know concern-
ing the mode of production of fever (see Lecture I.).
   The  failure to explain the pathogenic power of bacteria
in these and  similar  ways led to the supposition  that the
morbid activity of pathogenic bacteria is exerted chiefly
by means of  injurious chemical products.   The  demon-
stration of such  products leaves no room for doubt as to
the correctness  of this  supposition for some infectious
diseases.  This  explanation is probable for most such
diseases, but  experience has shown that it is particularly
dangerous to indulge in hasty generalizations in this de-
partment of medical science.
   Sterilized and filtered cultures, particularly old cultures,
of various pathogenic bacteria are capable of producing
fever and other symptoms when injected into the blood
or tissues.  This, of  course,  makes it  evident that the
bacteria in  question  give rise to poisonous  substances.
It is necessary  to distinguish between the intoxication
produced by the injurious  products  of  bacteria and
the infection caused by multiplication of the  microor- 
THE CARTWRIGHT  LECTURES.     91
ganisms within the body.  That this distinction may be
readily overlooked is shown by the recent experiments
with the inoculation into animals of pure cultures of the
typhoid bacillus.   Small quantities of these cultures may
be inoculated without any apparent effect; if, however,
larger quantities are injected into the veins or the peri-
toneal cavity of a rabbit, the animal dies in a short time
and  the characteristic  bacilli  are  found in the blood,
spleen,  and elsewhere.  It was  supposed by Frankel and
Simmonds,1 to whom we owe this latter observation, that
actual infection took place, but it has been demonstrated
by Sirotinin and by Beumer and Peiper2  that under these
circumstances no  multiplication of the  injected bacilli
occurs,  and that the same results may be obtained by the
injection of sterilized typhoid cultures.
  The isolation in a chemically pure state of the poison-
ous  products of  pathogenic  bacteria  encounters  great
difficulties, and we owe to Brieger3 nearly all that has
been accomplished in this  direction.   Two substances
which he has obtained from cultures of pathogenic bac-
teria are  of great interest.  Brieger isolated from pure
cultures of the typhoid bacillus  a very poisonous ptomaine
or toxine, as he prefers to  call  this group of substances..
He  has given to it the name typhotoxine.  It may be
somewhat significant that  he failed to  find  typhotoxine
in a culture which had stood for twenty-four hours at a
temperature of  102.2°  F.  (39°  C).  The  injection  of
typhotoxine into  guinea-pigs  produced  great muscular
weakness, diarrhoea, increased frequency of pulse and
of respiration, and death.  Nothing is said as to the effect
upon the temperature of the animal.
  A toxine has been isolated by Brieger in a crystalline

  1 Frankel and Simmonds:  Die  yEtiologische Bedeutuhg des
Typhus-bacillus, Hamburg und Leipzig, 1886.
  2 Sirotinin : Zeitschrift f. Hygiene, Bd. i. 465.
   Beumer u. Peiper: Ibid., p. 489.
  3 Brieger:  Untersuchungen iiber Ptomaine,  Berlin, 1886. 
92                   WELCH,
form from an  impure culture of the tetanus  bacillus.
This substance, called tetanin, produces, when injected
into animals, the characteristic symptoms of tetanus.
  It  is evident that these important  discoveries render
far more definite than was formerly possible, the belief
that bacteria  produce fever by means of their chemical
products.
  A dangerous  influence exerted by poisonous ptomaines
is that under their agency the power of the body of re-
sisting the invasion of various microorganisms may be
impaired or overcome.  Thus, Wyssokowitsch has shown
that the immunity of some animals against certain species
of bacteria may be destroyed by ptomaine poisoning.
  In order to observe the effects upon the temperature, I
have injected into rabbits sterilized cultures of the typhoid
bacillus.   Injections of very  small  quantities  of these
cultures produce  no effects,  somewhat larger  amounts
cause a rise of temperature without other marked symp-
toms, still larger quantities produce increased tempera-
ture, diarrhoea,  weakness, and other manifest symptoms
of severe illness, but the animal may recover ; relatively
large amounts are followed by fall of temperature, grave
illness, and death.  I have also obtained results similar
to those of Sirotinin, who inoculated two rabbits with the
same amount of a typhoid culture.  In  one rabbit fever
developed and the animal recovered; in the other, the
temperature  fell  after the  injection,  and  the animal
died.   This certainly does not indicate that the rise  of
temperature in itself is an unwelcome  attendant of in-
toxication with the poisonous  products of bacteria.  My
experiments certainly showed that the animals were more
likely to die after injection of typhoid cultures when the
temperature fell than when it  rose, independently of the
quantity of material injected.   One is reminded here of
the very malignant cases of typhoid fever  reported  by
Frantzel, and others, in which the temperature throughout 
        THE  CARTWRIGHT  LECTURES.    93

a great part of the  disease was  subfebrile, or  even at
times subnormal.
  In no disease is the dependence of the febrile paroxysm
upon the presence of bacteria so apparent as in relapsing
fever,  where,  according  to  the   statements of  most,
although not of all,  observers the spirilla appear in the
blood at the beginning of a paroxysm and disappear at
the end. Whether or not, here and in malaria, the pyro-
genic agent is a chemical product  of the microorganisms
causing the disease, we do not know.
  I must content myself with having brought before you
evidence showing that at least in  some of the infectious
fevers the specific bacteria produce pyrogenic substances.
We have  no  right to say that this is  the only way in
which pathogenic bacteria can cause fever.
  We have considered now three  groups of agents con-
cerned in the production of fever, viz.: first, unorganized
ferments and other  relatively  homologous substances;
second, ptomaines and other chemical products  of sapro-
phytic  microorganisms; third,  pathogenic microorgan-
isms and their chemical products.
   It is not to be understood that these groups correspond
to  sharply defined  classes of fever-producing agents.
The same  substance may be produced  by the  action of
unorganized ferments, as well as by saprophytic bacteria
or  by parasitic bacteria; hence, we may  find the same
fever-producing agent in each of  the  three groups.  As
has already been mentioned,  our knowledge  does not
justify  us  in regarding these various substances as the
immediate  and  direct  pyrogenic agents. The  epithet
pyrogenic  is applied to them only by a certain latitude of
signification.  It is possible that these various substances,
which we  are  in the habit of describing as pyrogenic,
may produce in the body some common  change which
gives rise to the real fever-producing agent.  This is the
view of von Bergmann and Angerer,  who believe that
this common change is a liberation of fibrin ferment by 
94
WELCH,
destruction of leucocytes.  While we cannot  consider
this view as more than an hypothesis,  it is, nevertheless,
well  to  remember that  apparently heterogeneous sub-
stances, which are usually designated as pyrogenic, may
produce similar changes which are to be regarded as the
real source of the febrile disorder of animal  heat.  But,
notwithstanding these limitations and  these elements of
uncertainty, it seems to me that some  such classification
as that suggested of the agents producing fever 'is more
useful than that  usually employed in  the  discussions of
the etiology of symptomatic and of essential fevers.
  There  is one  point which  must be impressed upon
every one who makes many  experiments  with pyrexial
agents.   This is, that once in  a while a substance of un-
doubted pyrogenic power causes a fall  instead of a rise of
temperature.  This occurs frequently when the substance
is injected in large quantity and under these circumstances
there is usually  produced a condition of collapse.  But
in exceptional cases the  same dose which will  cause in
one animal a rise of temperature may give rise in another
animal of the same species  to a distinct reduction of
temperature.  In these latter  cases there must  be some
idiosyncrasy  on the part of the animal.   Aronsohn1
refers this unusual  phenomenon  to some peculiarity of
the heat centres in the brain, and he draws an interesting
parallel  between this contrary  effect  of pyrogenic sub-
stances and the  exceptional  cases in  which  antipyretic
drugs give rise to elevation instead of lowering of tem-
perature.
  The causes of fever which  we have thus far discussed,
have been substances which exert a pyrogenic effect when
introduced into the circulation.   We suppose that these
substances act in some way  upon the nervous system,
but whether or not this action is a primary one  it  is im-
possible  to say.   Even  if we assume, as  is often done,
1 Aronsohn:  Deutsche med. Wochenschrift, 1888. 
        THE CARTWRIGHT LECTURES.     9$

that these  substances  incite directly in  the  blood and
tissues chemical changes which lead to increased produc-
tion of heat, we must still have recourse  to some action
upon the nervous system, as has already been sufficiently
set forth in the previous lectures.
   It cannot be  doubted that fever may be  caused by
other agencies than pyrogenic  substances present in the
blood  or tissues.  The  effects of exposure  to external
heat have  already been  considered.  We found  experi-
mental  evidence in support of the  view ably advocated
by H. C. Wood, that in typical cases of thermic fever or
sunstroke,  the strain  placed upon  the  heat-regulating
centres by  exposure to excessive heat results in paralysis
of  these centres with rapid  elevation  of the internal
temperature.
   The cause of  the elevation of temperature in tetanus
is not altogether clear.  In this disease the  temperature
may vary but little from the  normal, but it is not un-
common to find  excessive  elevations  of  temperature
toward  the  termination.   Temperatures  of U3°F. (45°
C), or  more, have  been  recorded.   The  idea  would
naturally suggest itself that the  rise  of temperature is due
to the tetanic muscular  spasms, which  we know to  be
accompanied by production of  heat.  Leyden was led to
adopt  this   explanation  by the results  of experiments
made upon animals.   He succeeded by producing violent
tetanic  contractions of the muscles of a dog, in  raising
the internal temperature in the  course of  one hour and a
half from 103.30 F.  (39.6° C.) to  112.6° F.  (44.80 C).
Clinical observations, however, do  not support the sup-
position that the hyperpyretic temperatures of tetanus are
dependent  upon the muscular  contractions.  In spite of
violent  and prolonged tetanic  spasms, the internal tem-
perature may remain  normal or be  but slightly elevated.
There is a decided similarity between the hyperpyrexia
of tetanus and that which occurs in rheumatism and some
other diseases, particularly in  affections of the central 
96                    WELCH,
nervous  system, and it certainly seems probable that in
all of these cases  there is a profound disturbance of the
heat-regulating centres.  As the elimination of urea in
tetanus is  not excessive, we  find  additional reason to
separate tetanic hyperpyrexia from ordinary febrile con-
ditions.  Recent investigations of the etiology of tetanus,
have rendered it certain that at  least some forms of this
disease are caused by infection  with  a special micro-
organism.   This has been demonstrated not only in the
tetanus of  animals  but  also  in that of human beings.
The tetanus bacillus has been found wide-spread in the
ground in Germany, and I find it abundant in the ground
in Baltimore  and its  neighborhood.   In  experimental
tetanus, the bacillus, which has not yet been obtained in
perfectly pure cultures,  develops  chiefly  in the tissues
near the seat of inoculation, and  does  not  invade other
parts of the  body and  the blood to any  great extent.
This indicates that the symptoms are referable chiefly to
poisoning  by some  chemical products of  the  specific
microorganism.  As has already been  mentioned, this
view is sustained by Brieger's discovery in cultures con-
taining the tetanus bacillus of a peculiar ptomaine which
he has called tetanin, and which produces  tonic spasms
of the  muscles.  It  is, therefore, reasonable to believe
that the hyperpyrexia of tetanus  is  caused by the action
of poisonous  products  of the tetanus  bacillus on the
nervous  centres concerned in  temperature regulation.
Our present knowledge, however, does not warrant us in
asserting that  all forms of tetanus  in human beings are
of an infectious nature.
  In the first lecture of this course, evidence was pre-
sented to show that pyrexia may be caused by affections
of the  nervous system without the agency of any pyro-
genic substance.  It  may jar upon the sensibilities  of
some to call this form of pyrexia fever; but this hesita-
tion can  be due only to  the  idea  that symptoms which
are referable to infection  or  intoxication are essential to 
        THE  CARTWRIGHT  LECTURES.     97

the conception of fever.  In my judgment, we shall be
led into confusion if we attempt to incorporate into our
definition of fever, more than  properly belongs  to  the
febrile disorder of animal heat, and from  this point of
view there can be no impropriety in designating as fever,
the pyrexia dependent directly upon  affections  of  the
nervous system.
   It is  not  necessary to repeat here the conclusive ex-
perimental  evidence  for  the  existence in  the nervous
system of centres or  regions which control the dissipa-
tion of heat and the chemical processes concerned in the
production of heat.  Those who are not much impressed
by experiments upon animals, can hardly fail to be con-
vinced by the clinical evidence which demonstrates that
lesions  of the nervous system may cause elevation of
temperature, which cannot be referred to the action of
any pyrogenic substance.  Such evidence must, of course,
be collected from cases where the fever cannot  be ex-
plained by  inflammation,  bed-sores,  or other  lesions
which can give rise to absorption fever.  W.  Hale White,1
in the interesting article already referred to,  has collected
a  number of cases  of tumor, hemorrhage,   softening,
sclerosis, injury and functional disturbance  of the spinal
cord and brain, in which  the  pyrexia or hyperpyrexia is
to be  explained only by the lesion of the nervous system.
The number of such cases might  be  considerably  in-
creased.   These cases show that lesions of the cervical
part of the cord, of the pons, of the corpus striatum, and
of the neighboring white matter,  are most likely to be
associated with high temperature, but the cases hitherto
reported hardly justify positive  statements as to the exact
situation in man of thermically active nerves or regions
in the brain and spinal cord.  As might be expected, not
only focal lesions, but also diffuse diseases such as occur
  1 W. Hale White:  The Theory of a Heat Centre from a Clini-
cal Point of View. Guy's Hospital Reports, vol. 42, 1884.
                           7 
98
WELCH,
in general  paralysis of the insane,  locomotor ataxia,
multiple sclerosis  may give rise to pyrexia which some-
times assumes the form of temperature crises.   It is in
harmony with what we  know of  other disorders of the
nervous system, to find that  not only demonstrable ana-
tomical lesions, but  also  functional  disturbances may
produce  nervous pyrexia.  Such  functional disturbance
furnishes the most probable  explanation of the singular
and  erratic  elevations of temperature  which  have been
occasionally observed in hysteria.
  A  question which merits more consideration than it is
possible to give to it  on  the  present occasion, relates to
the possibility  of  the  occurrence  of  fever as  a reflex
neurosis.  The advance in  our knowledge of the etiology
of traumatic and inflammatory fevers, has  pushed aside
almost wholly the  old doctrine of irritative fever.   There
are,  however, cases of fever where still the simplest, and
apparently most rational, explanation of the causation,
is peripheral nerve irritation.  As examples may be men-
tioned, the fever resulting from teething in children, that
sometimes accompanying  the passage of gall-stones  or
urinary calculi, and that occasionally following the inser-
tion  of a catheter into the urethra.   It  must be admitted
that  the evidence on this  point is not conclusive.   Espe-
cially is there lack of satisfactory experimental evidence.
Electrical irritation of the exposed  sciatic nerve is, under
ordinary circumstances, followed  by a moderate fall  of
temperature, although Ott1 finds that in atropinized cats
such irritation is followed by a decided rise of tempera-
ture.  But these experiments cannot  be  held to weigh
for or against  the  doctrine of irritative fever.  Observa-
tions on human beings  indicate  that peripheral nerve
irritation, if  ever a cause of  fever, is so only in certain
situations and under certain forms of stimulation, and in
certain individuals.  In infants temperature regulation is

         1 Ott: Therapeutic Gazette, August, 1887. 
         THE  CARTWRIGHT LECTURES.     99

 more labile than in adults, so that  it may be that nerve
 irritation can more readily disturb the temperature in the
 former than in the latter.   The chief controversy as to
 the question now before us, has been as to the explana-
 tion of  certain  forms of urethral or catheter  fever.  It
 cannot be doubted that a large number, probably most,
 of the cases of so-called urethral fever, are instances of
 genuine absorption fever.   Even if  we exclude all cases
 with diseased kidneys, or with cystitis or other inflam-
 matory disease of the urinary passages, there remains a
 certain number of cases in which the gentle insertion of
 a disinfected catheter is followed by distinct febrile reac-
 tion.   It seems unwarrantable to assume that in all of
 these cases the catheter has caused a laceration of the
 urethra through which pyrogenic substances are absorbed.
 What is the nature and whence the  source of these sub-
 stances ?  In the  cases now under consideration, they
 can be sought only in the normal urine, and of their ex-
 istence there no proof has been afforded.   In these cases
 it is certainly very difficult to understand how the fever
 can  be  interpreted as  due to the absorption of  some
 pyrogenic  agent, and failing this explanation,  the idea
 that the  fever is dependent upon nerve irritation is most
 plausible.
   I have now presented to you an imperfect survey of
 the general  etiology  of fever.   The attempt has been
 made to classify the  leading causes of fever, but  it can-
 not be  claimed that  every  variety  of fever can  be as-
 signed to one of these groups of causes.  Our knowledge
 of the  etiology of special fevers is still too imperfect to
 warrant  any such generalization.  This is an attractive
 field for much patient investigation.  I need only remind
 you of the uncertainty which still pertains to the  causa-
tion of many of the fevers of warm  countries.   There is
reason to believe that  there remain yet to be differentiated
etiologically, specific  types of fever  which occur among
us, and particularly in our Southern States.  It may be, 
100
WELCH,
that increasing knowledge will necessitate the recognition
of varieties of pyrogenic agents entirely distinct from any
with which we are now familiar.  It is certain that future
investigations will add clearness and precision to our
ideas of the nature and mode of action of causes of fever
which, at  the best, we  can now  understand only imper-
fectly.
  I cannot conclude this course of  lectures  without  say-
ing a few words on a subject which must engage the atten-
tion of every one who gives  much  thought  to the nature
of fever.  What is the significance  of fever, is a question
which  thrusts itself upon us no less than it has  upon
physicians in all ages.  Unfortunately, we cannot to-day,
any more than could our predecessors, give other than a
speculative answer to this question.  There  have been in
all  ages  enlightened  physicians  who   have held  the
opinion that fever is a process which aids in the elimina-
tion or destruction  of  injurious substances which  gain
access to the body.   Under  the influence of ideas which
sought in  increased  temperature the origin of the grave
symptoms of fever,  we have in recent times in great part
lost sight of the  doctrine  once prevalent, that there may
be  in  fever  a  conservative element.  There is much
which speaks in favor of this doctrine.  The  real enemy
in most fevers, is the  noxious substance which invades
the body, and there is nothing to prevent us from believ-
ing that fever is a weapon employed by nature to combat
the assaults  of this enemy.  The doctrine of evolution
indicates that a process which characterizes the reaction
of all  warm-blooded animals against the invasion of a
host of harmful  substances, has not been developed to so
wide an extent, and is not retained with such pertinacity
without subserving  some useful purpose. This is a point
of view from which many pathological  processes can be
regarded with advantage.   Even suppuration, which one
does not generally look upon as a beneficent provision,
is a most important instrument of nature in  forming  a 
        THE  CARTWRIGHT  LECTURES.    IOI

barrier against general infection of the body with certain
microorganisms.  It is impossible with our present knowl-
edge, to say in exactly what way  fever accomplishes a
useful purpose.  There  are  facts which suggest that in
some cases of fever the increased temperature as such
may impair the vitality or check the virulence of patho-
genic microorganisms, but there are many circumstances
which make it difficult to suppose that this is the agency
by which fever usually exerts a favorable action.
  The supposition seems  to  me more probable that the
increased  oxidation of fever aids  in the destruction of
injurious substances.  According to this view, the fever-
producing agents light  the  fire  which  consumes them.
It is not incompatible with  this conception of fever, to
suppose that the fire may prove  injurious also to the
patient and  may require  the controlling hand of the
physician.  Time will not permit me to elaborate further
the ideas here suggested.  In the course of these lectures
some facts have been  presented  and  others might be
drawn from clinical and experimental observations which
favor the hypothesis that  fever is  in  a certain sense
a conservative process.  Unproven and intangible as the
hypothesis may seem  to some, no apology is  needed for
bringing to your attention a conception of fever in favor
of which much can be adduced, and which, if true,  is of
fundamental importance,  both theoretically and practi-
cally. 
 
 
 
The Cartwright  Lectures.
ON THE
GENERAL  PATHOLOGY OF FEVER.
                        /
BY
\
     WILLIAM H. WELCH, M.D.,
PROFESSOR OF PATHOLOGY, JOHNS HOPKINS UNIVERSITY, BALTIMORE.
\1\Wt
        FROM

THE MEDICAL NEWS,

 April 7, 14, 21, and May 19, 1888. 
 
 
 
 
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