ON
URJIIC   INTOXICATION.
       WILLIAM A. HAMMOND, M. D.,
PROFESSOR OF ANATOMY AND PHYSIOLOGY IN THE UNIVERSITY OF MARYLAND J SURGEON TO AND
  LECTDRER ON CLINICAL SURGERY AT THE BALTIMORE INFIRMARY | FELLOW OF THE
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       OF NATURAL SCIENCES OF PHILADELPHIA, OF THE AMERICAN
         PHILOSOPHICAL SOCIETY, OF THE PHILADELPHIA
           PATHOLOGICAL SOCIETY, ETC. ETC.
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UREMIC   INTOXICATION.
  When we consider how important a part the kidneys fulfil in depurating
the blood, we can readily believe that any serious interruption to the due
performance of their function must be attended by great disturbance in the
healthy action of the other organs of the economy.  We find that such is
actually the case.   Physiological experiments, together  with many  well-
established cases of disease, have taught us that suppression of the urinary
excretion is one of the most dangerous events that can happen in the whole
range of pathological occurrences.
  In the present memoir, I propose to consider the  subject of uraemia, or
that condition of system due to the accumulation in  the blood of matters
which in health are  removed by the kidneys, basing what I have to say
mainly upon my own investigations.
  When the renal  arteries of an animal—as, for  instance, a dog—are
ligated, or  the  kidneys removed, death ensues in from two  to four days
generally, though occasionally life is retained for  a longer period.  In one
of my own experiments, the animal, a small  dog, lived for twelve days;
and Marcband1 mentions a case in which a sheep lived for nearly a fortnight
after removal of the organs in question.
  At first,  the animal upon which this operation  has been performed does
not appear to  be seriously inconvenienced thereby.   It eats, sleeps, and
follows its other instincts  with but little irregularity.  After a variable
period, noticeable symptoms begin to manifest themselves.   These are loss
of appetite, nausea, vomiting,  and indisposition  to  exertion of any kind.
Occasionally  there is purging.  Finally, there is either coma  or  convul-
sions, or both, and the animal  dies in a state of  stupor,  or in epileptiform
convulsions.  If, previous to the death of the animal, the blood be exa-
mined, it is found  loaded with urea, and this substance can generally be
detected in the matters vomited and discharged per  anum.   Post-mortem

  1  De  l'existence de  Puree dans les parties de l'orgauisnie animal autres que
Purine.  L'Experience 183&, t. ii. p. 43. 
4
examination reveals the presence of urea in the contents of the stomach, in
the blood, the lungs, liver,  and other parts of the body.
  In Bright's disease, as it affects  the  human subject, we find that, owing
to structural changes in the  kidneys,  the urine is  imperfectly eliminated.
An element, albumen,  is separated from the blood,  which does not  nor-
mally exist in the urine.   The excretion,  upon analysis, is found to  be
deficient in urea, and may even,  as I have myself found, be almost  entirely
free from it.   Coma and convulsions at length appear, and death soon fol-
lows.   If, previously to the above,  the blood be analyzed, urea is discovered
in large quantity, and  a post-mor'em  examination reveals the presence of
this substance in nearly every portion of the system.   Such is the  natural
termination of Bright's disease.  Sometimes, however, the  retained ele-
ments of the  urine, by their action on  the brain and nervous system,  pro-
duce inflammations of important  structures, and death  ensues before the
stage of uraemic poisoning is reached.
   In  puerperal eclampsia,  in  the  latter stages  of  scarlet fever, in  yellow
fever, and  in  cholera, symptoms and appearances  similar to  those above
mentioned  are frequently present,  and  probably depend upon a like imme-
diate cause.
   To these symptoms,  taken collectively, the terms  uraemia, uraemic intoxi-
cation, and others of like import have been applied.
   Various theories have been propounded, relative to the immediate cause
of uraemia.  Thus, Osborne' considered it due to arachnitis ;  Prevost  and
Dumas'3 to effusion into the ventricles of the braiii;  Rees:i thinks it may be
caused by a watery state of the blood ;  and Bence Jones1 supposes  it to be
induced by an accumulation of oxalic acid in this  fluid.  There is no evi-
dence to support  any of these hypotheses; in fact,  each has been posi-
tively disproved.
   The view most generally held, has been that which ascribes uraemia  to
the direct  action of the urea  retained in the blood.  Later investigations
have called the correctness  of this hypothesis in  question, and much cogent
evidence has been adduced  against it.   Like most other physiological ques-
tions, the  present is not to be solved but  by the patient and thorough
research of numerous investigators.  I can only hope that the observations
and  experiments  which follow may prove to be contributions in the right
direction.
   The fact that urea is formed in the blood may be regarded as sufficiently
determined.  It is not present in the muscles, for analysis fails  to detect it;
but other substances, the immediate products of their destructive metamor-

  1 On the Nature  and Treatment of Dropsical Diseases.   London, 1837, p. 36.
  1 Annales de Chimie et de Physique, t. xxiii. p. 90 et  seq.
  3 On the Nature  and Treatment of Diseases of the Kidneys, &c.   London,  1850,
p. 67.
  4 Lectures on Animal Chemistry.  Medical Times, January 3d, 1852. 
5
phosis, and which admit of still further degradation, are found; and the
experimental  evidence, which establishes the fact that increased muscular
exertion leads to increased  elimination of urea, indicates these organs as
one, at least, of its sources of origin.  In  addition, we have the beautiful
researches of Bechamp,1 which are conclusive  as  to its production from
proteinaceous substances.
   Prevost and Dumas,2 Marcband,3 and numerous  other observers, have
shown that, after extirpation of the kidneys, urea accumulates in the blood,
and consequently these organs cannot be  regarded as forming this sub-
stance.   They, in fact, only separate it, as they do the other constituents
of the urine, from the blood brought to them by the renal arteries.  As the
healthy kidneys are constantly in action, urea never  normally exists in the
blood in any very considerable amount.  It is only when, through disease
or  other cause,  the  kidneys are prevented performing  their function  of
elimination,  or when large  quantities are submitted to examination, that
urea  is to be detected in the blood in any but very small proportion.
   The immediate cause of the production of the group of symptoms known
as  uraemia is  at  present,  as has been already  stated, a point upon which
there exists some diversity of  opinion, though  numerous researches  have
been  made with the view of elucidating the subject.   Urea has been injected
into the blood of animals,  and as death did not  often follow, this substance
has been regarded by some as non-poisonous.  Even  urine, filtered so as to
free it from  mucus and epithelium, has, under  like  circumstances, proved
harmless ; but when  injected unfiltered, death invariably ensued.   The in-
ference therefore from these last cited experiments is, that the urine, if not
eliminated, is  not, as such, capable of causing death, for the mucus and
epithelium  are not separated from  the blood by the kidneys, and conse-
quently are  not, properly  speaking, constituents of the urine.  As, bow-
ever,  the injection of unfiltered urine  has always  resulted  in death, the
further deductions must be drawn that epithelium, or mucus, or both, are
of themselves poisonous, or that one or both  are capable of so acting upon
the retained elements of the urine, as to cause the formation of some sub-
stance possessed of toxical properties.  These conclusions are, however, of
course only legitimate, provided that the experiments referred to have been
conducted with the care and accuracy so  absolutely essential in all physio-
logical investigations.  It  will be seen hereafter that it is more than  pro-
bable the experiments cited were not altogether  free from error.
   In  a philosophical treatise on the subject  of Bright's disease, Frerichs*
advances  the opinion that uraemia is not due  directly to the presence of

  1  Annales de Chim. et de Phys.   November, 1856.
  2 Annales de Chim. et de Phys., 1823, t. xxiii. p. 90.
  3 L'Experience, 1839, t. ii.  p. 43.
  4  Die Brightsche Nierenkrankheit und deren Behandlung. Braunschweig,  1851,
p. 111. 
6
urea in the blood, but to the conversion of this substance into carbonate of
ammonia, through  the  agency of a ferment supposed to be present in the
circulating fluid.   This view has been accepted by Braun,1 but has  been
controverted  by Schottin,a Zimmerman,3  Gallois,* myself,5 Bernard,0  and
others.
  The arguments relied upon  by Frerichs to support his  theory are based,
mainly, upon experiments on the lower  animals—dogs—but partly upon
observation of cases of  Bright's  disease which came under his notice.   As
this  hypothesis, from the source whence  it comes, from its apparent  sim-
plicity, and from certain facts which seem to give it support, has attracted
to a considerable extent the attention of pathologists, I deem  it important,
before proceeding further, to enter somewhat at length into its consideration.
  The fact that urea may be injected into the blood without ura>mia fol-
lowing, and that even filtered urine may be thus introduced with impunity,
are circumstances considered by Frerichs as incompatible with the hypothe-
sis which ascribes this condition to the retention  of the urea per se.   That
in animals, the kidneys of which have been removed,  there was vomiting
and  purging  of ammoniacal matters;  that ammonia was exhaled from the
lungs ; and that after death, as well in them as in persons dying of Bright's
disease, who  during life had manifested symptoms of uraemia, ammonia was
discovered  in the blood  and in the contents of the stomach and intestines ;
that urea has been frequently found in the blood  of persons suffering from
Bright's disease, in whom no uraemia  was present, and vice versa—consti-
tute, in his opinion, a mass of evidence strongly in favor of the theory he
has advanced.  Add to  all this the results of experiments performed by him
with direct reference to  the point in question, and we have the main points
before us upon which he has constructed the ingenious and beautiful hypo-
thesis, that uraemic intoxication is directly due to the presence of carbonate
of ammonia  in the blood, which substance has been formed from the re-
tained urea through the action of a ferment.  Of the nature of this ferment
he does not attempt to furnish an explanation.
  Two series of experiments were performed by Frerichs.  In the first,  a.

  1  The Uraemic Convulsions of Pregnancy, Parturition, and Childbed.  Edinburgh
edition, 1857.   Translated by Dr. J. Mathew Duncan, p. 16.  I regret that I have
not the original work (Lehrbuch der GeburtshiiJfe u. s. w.  Wien, 1857) to refer to.
Dr. Duncan's translation,  however, appears to be very correctly rendered.
  2 Vierordt's Archiv., 1853, Heft 1, p. 170.
  3  British  and Foreign Medico-Chirurgical  Review. Am. ed., January, 1853, p.
223.   From Deutsche Klinik, No. 37.
  4  Comptes Rendus, No.  14, Avril,  1857.
  5  On the Injection of Urea and other substances into the Blood. North American
Medico-Chirurgical Review, April, 1858.
  6 Le<jons  sur les Proprietes Physiologiques et les Alterations Pathologiques des
Liquides  de POrganisme, t.  ii.  Paris, 1859, p. 36. 
7
solution containing from two to three grammes of urea (thirty-one to forty-
six grains) was injected  into the veins of dogs, the kidneys of which had
been previously removed.  The animals remained for some hours  to all
appearance unaffected;  a circumstance which  Frerichs regards as indicat-
ing that the urea,  as such, exerted no detrimental influence upon the nerv-
ous system.   After a longer or shorter period (from  one and a quarter to
eight hours), the  animals became  restless, and vomited  acid chyme, or  a
mucous matter of a yellow colour, according as  the stomach was. full  or
empty, at the commencement of the experiments.  Under the latter condi-
tion, the vomited  matter was of decided alkaline reaction.   Convulsions
occurred, and, at the same time, ammonia was expelled with the expired
air.   Finally, the  animals fell into a state of coma, the respiration became
stertorous, and death soon  followed.  Occasionally  the  convulsions were
absent,  coma being the first symptom of cerebral disturbance.  After death,
which generally occurred in from two and a half to ten hours after the in-
jection of the urine, ammonia was always found  in the blood.  The con-
tents of the stomach, in most instances, gave off a strong ammoniacal odor,
and contained carbonate of ammonia in large quantity.   In one case they
were feebly acid, and even then ammonia was present.  This substance was
also found in the bile and other secretions.
   In the second series of experiments, a solution of carbonate of ammonia
was injected  into the circulation, the kidneys of the animals remaining in-
tact.   Immediately afterwards convulsions  ensued, which, in some cases,
were very violent, but were soon succeeded by a comatose condition.  The
respiration was laborious, and the expired  air was loaded with ammonia.
There was also vomiting of biliary matters.   The stupor lasted for several
hours ;  so long as it was present, ammonia continued to be exhaled from
the  lungs.   Gradually  it ceased to be expired,  and the animals  slowly
recovered their senses.   If,  during the coma,  an additional amount of
carbonate of ammonia was injected, convulsions again occurred, the vomit-
ing was renewed, and the urine and feces were involuntarily evacuated.   In
from five to six hours, the ammonia again disappeared from the blood, and
the animals regained their ordinary liveliness.1
   There are  several objections to be urged  against  these experiments of
Frerichs, and the  inferences drawn from  them by him and those who coin-
cide with  him in  his uraemic theory.  In order to present these more con-
nectedly and with  greater clearness, I quote  Frerichs' own  details of the
first experiment of each series, which may be taken as  the type of the others
of its class.   The  first series  consisted of six experiments.
   » No. 1.—Both  kidneys were extirpated from a young full-grown dog, at 3
o'clock P. M., by opening the abdominal cavity.  On  the  following morning, the
animal appeared to be perfectly well; it ate, and wagged its tail when spoken
1 Op. cit., p. Ill et seq. 
8
to.  The posterior extremities, however, appeared to be paralyzed.   At 3 P. M\,
a solution of two grammes of urea was injected into the left jugular vein.  The
animal remained in the  same state as before, its condition not being altered in
the least.  At 4 P. M., it  became restless, seemed to be choking, and vomited
several times.  The matter thus ejected consisted of a slimy yellow fluid, with a
strong alkaline reaction.  Soon  afterwards convulsions supervened, the animal
rolled from one side to the other.  Opisthotonos ensued in the posterior, alter-
nating with violent contractions of the other muscles of the  body.   From time
to time the animal was quiet, after which the convulsions returned with increased
violence.  In the meanwhile, the vomiting continued, and a glass  rod, moistened
with chlorhydric acid, and held to the nose, caused the formation of thick white
fames, showing the presence of ammonia in the expired air.  By degrees, the
convulsions abated in violence, and at length entirely ceased.  The animal now
lay in a state of sopor, the respiration being quick and  difficult.  Finally, the
respiratory motions became weaker, and at 5^ P. M. death ensued.
  " The cavities of the body were immediately opened, and the blood contained
in the heart and large vessels collected.  It was of a dark violet colour.  The
colour did not become markedly clear by heating, but by the following morning
it had assumed a bright scarlet hue.  After four minutes, the fibrin was strongly
coagulated.   The blood-corpuscles were  not changed from the normal form.
Ammonia in considerable quantity was contained in the blood—a glass rod pre-
viously moistened with chlorhydric acid giving rise to the  white fumes indicative
of its presence.
  " A part of the defibrinated blood was mixed with water, and distilled in the
water-bath.   A fluid with an alkaline  reaction came over, which, being neutral-
ized with chlorhydric  acid and evaporated, deposited  crystals  of  chloride of
ammonium.   To  another  part of the blood caustic potash was added, and an
ammoniacal odour was given off.
  " The  stomach was strongly  contracted, and  contained still a few corroded
pieces of bone, and a  small quantity of  a yellow, tenacious, ropy  fluid.  The
stomachal mucous membrane was of a livid red colour, partly through vascular
injection and partly through imbibition.  The fluid contained in the viscus ex-
haled a  sharp odour  of ammonia, reacted strongly alkaline, and formed thick
fumes with chlorhydric acid.  In  an alcoholic extract of the same, no traces of
unconverted  urea were discovered.  In the bile, also, urea was sought for, but
only compounds of ammonia were detected. The substance of  the brain, and
the membranes covering  it, contained the normal quantity of  blood, and the
fluid  in the ventricles was not increased  in amount.   The lungs were healthy,
except that posteriorly there was some  congestion.  The mucous membrane of
the trachea and bronchia was slightly reddened.  The liver and  spleen were, to
all  appearance, healthy.   In the  abdominal cavity, a small quantity of bloody
fluid was contained.  No evidences of intense peritonitis were visible."'

   The other experiments of this series do not differ in any material respect
from the one quoted, except that in  the third no ammonia was detected in
the expired air.   The  details of the fifth and sixth are not given.
   Xow, in these experiments there is not the  least evidence that carbonate
of ammonia was the cause of death, or even that this  substance was  present
in the blood in any abnormal amount.
   In the first place,  it is asserted that ammonia was  present in the pulmo-
nary exhalation.   This  statement  is doubtless correct, but the inference
which  Frerichs  draws from it is,  I think, unwarranted.   Ammonia  can
generally be detected in the  products  of respiration in healthy dogs, into
the veins of which no urea has been introduced, and ia which  the  kidneys
1 Op. cit., p. 278 et seq. 
9
are in healthy functional activity, by employing the test  made use of by
Frerichs.   It is, however, occasionally absent, and in several cases which
will hereafter be more specifically referred to, in which urea had been intro-
duced directly into  the  blood, ammonia was not to be found in the pulmo-
nary exhalation, though recourse was had not only to Frerichs' process,
but to others of far greater delicacy.
   In  the second place, the means employed by Frerichs  to establish the
existence of  ammonia in the blood were faulty in the extreme, and such as
will always  effect this  object if urea be present,  even though ammonia, in
the first instance, be altogether absent.   The defibrinated blood was dis-
tilled in a water-bath (at what temperature we are  not informed), and an
ammoniacal  fluid collected.   Now, no matter how carefully this operation
was conducted, if any urea was present, a portion of it would have under-
gone  decomposition, and  ammonia would  have appeared in the distillate.
   Thus, I took about thirty cubic centimetres of freshly-drawn dog's blood,
defibrinated it by shaking it in a bottle with  small strips of lead, and then
added to it  five grammes of urea.   It was  then placed in a small retort,
and carefully distilled  in the water-bath at a temperature of 85° Cent.
(185° F.), till a sufficient quantity had passed over.   A few drops of the
distillate were then placed on a strip of glass, and held for a few moments
over a vessel containing  chlorhydric acid.  Upon evaporation, and subse-
quent microscopical examination, crystals of  chloride of  ammonium were
found in large quantity.  A similar strip of  glass was then exposed to the
vapor of chlorhydric acid, and held for a short time to the ball of the retort
whilst the distillation was progressing, in such a manner that the vapour
was received upon it.  Thick white fumes of chloride  of ammonium were
produced, and crystals of the same substance were formed upon the glass.
   In  order further  to  establish the  presence of  ammonia, Frerichs added
caustic  potash to  another  portion  of  the blood.  This  proceeding  was
equally objectionable as the other, for this substance decomposes  urea into
carbonate of ammonia,  and, of course, therefore it was not surprising that
an ammoniacal odour should have been evolved.
   Now, I have no intention of denying that ammonia existed in the blood
of the dogs  submitted  by Frerichs to experiment.   On the contrary, I be-
lieve  it to be generally present in the blood of most animals.   The fact
that Frerichs detected  it by holding over the blood a glass rod moistened
with chlorhydric acid, is perhaps sufficient to establish the point.  But that
this circumstance is at all confirmatory of his theory is far from  being the
case.   Richardson1 has shown, by numerous  experiments, that ammonia is
a constant constituent of  the  blood  of dogs  and many other animals, and
by repeated observations  I have satisfied myself  of  the correctness of  this

  1  The  Cause of the Coagulation of the Blood.  Astley Cooper Prize  Essay for
1856.  London, 1858. 
10
conclusion.  I have frequently failed when using  Frerichs' test with  the
glass rod moistened with chlorhydric acid, which, besides its want of ex-
treme  delicacy, is liable,  from several  causes, to  yield erroneous results.
These, however, with  care, may generally be avoided.   I  have, therefore,
preferred either Reuling's1 process with logwood, or Richardson's, which
consists in moistening a slip of glass with chlorhydric acid, and exposing
it  to the vapour  arising from the blood, when, if  ammonia be present,
minute crystals of chloride of ammonium will be formed, and may be rea-
dily  perceived under  the  microscope, with  an object  glass  of moderate
power.   This  process has already been referred to as the means employed
during the present researches in examining for ammonia.
  I am aware  that Davy2 has not been able to detect ammonia in the blood
of the common fowl.  Not having access at present  to the original paper,
I know not what process he employed.  With Richardson's method, I have
never failed to find it in  the blood of this animal in the course of fourteen
experiments with  reference to this point.
  It will be seen, therefore, that  ammonia is not an abnormal constituent
of the blood,  as  Frerichs  evidently supposes.  There  is no proof, either,
that any  of the retained urea was converted whilst in the system into car-
bonate of ammonia.
  The fact that ammonia was found in the  contents of the stomach, which
consisted of  fragments of undigested bone  and of  mucus, should not have
the least weight in the matter, as it is well known that this latter substance
causes the decomposition of urea, and the consequent formation of ammo-
nia.   No urea was detected in the alcoholic extract of these contents, and
it  is  therefore probable  that it was, as  Frerichs supposes, entirely decom-
posed.  There is no evidence, however, to lead us to  infer that this change
was  effected  in the blood, but, on  the contrary, much to  warrant us in be-
lieving that it took place in the stomach, through  the action of the mucus
present in this viscus.
  In support of this view, I adduce the  following experiments :—

  Expt.  To a full grown dog, fasting, two  grammes  of urea were admi-
nistered  dissolved in water.   Fifteen minutes afterwards,  the animal was
killed by injecting a solution of woorara under the skin.   The stomach was
opened, and found to contain nothing but a quantity of  thick, tenacious
mucus, which  exhaled a strong ammoniacal  odour.  On bringing a glass
rod moistened with chlorhydric acid near it, the dense white fumes of chlo-
ride  of ammonium were  formed, and crystals  of this substance appeared on
a slip of  glass used in the manner before specified.
  Expt.  To another dog, somewhat smaller than the other, five grammes
of urea were given in the same  manner as  before,  and  at the end of ten

  1 Archiv des Vereins fur gemeinschaftliche Arbeiten, Zweiter B. 1856, S. 120.
  2 North  American Medico-Chirurgical  Review, vol. iv. No. 1, 1860, p.  149.
(From Dublin Quarterly Journal of Med. Science, Nov.  1859, p. 425.) 
11
 minutes the animal was  killed by dividing the medulla  oblongata.  The
 stomach was immediately opened.   It contained a few fragments of bone,
 some pieces of undigested meat, and a quantity of thick mucus.  The mass
 was of feeble alkaline reaction, and evolved a barely perceptible ammoniacal
 odour.  The  presence of ammonia was further established, as in the first
 instance.
   The contents were then  examined for urea by the process hereafter de-
 tailed, and this substance was shown to be present in considerable amount.
 Owing to an accident, it was not weighed.

   If, however, the animal  has eaten largely a  short time previous to the
 injection of the urea, the change into carbonate of ammonia does not occur,
 and if  the animal be killed soon after the administration of the urea, this
 substance is found  intact in the stomach.   If, however, sufficient time has
 elapsed, it is absorbed into  the circulation and excreted  by the kidneys.
   The following experiments are adduced, as  tending to establish  these
 propositions :—

   Expt.  A full  grown dog  was fed largely on  animal food, and thirty
 minutes afterwards two grammes of urea  were administered to it.   Fifteeu
 minutes after  taking the urea it was killed by  section  of the medulla ob-
 longata.  The contents of the stomach were of  acid reaction.   On testing
 for  ammonia by  Richardson's method, a negative  result  was  obtained.
 Neither were fumes of chloride  of ammonium formed by the proximity of
 chlorhydric acid.
   Expt. A full grown dog  was confined and fed during three  days  on raw
 beef, two  and  a  half pounds  being given to him in the twenty-four hours.
 A uniform  quantity of water was allowed.   The urine of each  period of
 twenty-four hours was  collected, and tested for urea by Liebig's  process
 with the nitrate of mercury.  On the fourth day, the animal was fed as be-
 fore, but with  each meal two  grammes of urea were  administered.   Six
 grammes were  administered in all.   The immediate  effect was to increase
 to a considerable extent the amount of urine eliminated, which contained
 an augmented quantity of urea. The following table exhibits the results:—

                       1st day.        2d day.        3d day.       4th day.
  Quantity of urine .   815 c. cm.    795 c. cm.    891 c. cm.   1073 c. cm.
  Urea  .....  15.25 gram.  14.75 gram.  15.10 gram.  20.22 gram.

  Grallois,1 from  experiments  on rabbits, arrived at a  similar conclusion,
 and  has also  shown that urea acts  as a violent poison on these animals
 when injected  into the stomach in sufficiently large amount.  A train  of
 symptoms was induced similar  to those of uraemia, of which  the animals
 died.   During  the progress of these symptoms, there was no ammonia in
 the breath.
  I  cannot  therefore perceive, from  a  consideration  of Frerichs'  experi-
 ments,  and from those performed by myself, as well as  from the other evi-
 dence adduced, that  there are  any facts to warrant  us  in concluding that
urea  is transformed whilst in the blood into carbonate of ammonia.
1 Op. cit. 
12
  As has been already stated, Frerichs performed another series of experi-
ments, in which the carbonate of ammonia was directly introduced into the
blood.  In this  series,  a  filtered solution  containing from  one  to two
grammes of  the  carbonate  was employed.   The first experiment, from
which the  others do not  materially differ,  is  detailed by  Frerichs  as
follows :—
  " No. 1.—Into the jugular vein of a strong, full-grown dog, the solution was
very slowly injected.  The dog moaned and fell into deep stupor, broken occa-
sionally by convulsions.  The respiration was  quickened, and the  expired air
was loaded  with ammonia.  The coma lasted for three hours, after which the
animal regained its ordinary liveliness.  During the coma, ineffectual efforts to
vomit twice occurred."
  The experiments of this series amounted to six in number.  None of the
animals subjected to  them died—a fact which, to  say the least,  is not one
calculated to  support Frerichs' hypothesis.
  That carbonate of ammonia, when introduced  directly into the circula-
tion, produces considerable disturbance in the phenomena of life is doubt-
less correct.  It  is,  however, excreted so rapidly by the lungs, that  the
most  enormous  quantity may be injected without death ensuing.  Thus
Dr. Steiner,1 late  of the United States Army, performed some years since a
series of  experiments, some  of  which  show this  very strikingly.  In one
instance,  two ounces of strong aqua ammoniae,  diluted with an  equal
amount of water, were introduced into  the circulation of a  horse, and
although the animal suffered severely for a few minutes,  it soon rose from
its feet, and trotted about  as though nothing bad  happened.
  I have myself2  also experimented with  reference to this point, and have
injected as much as sixty grains of carbonate of ammonia into  the jugular
vein of a dog in normal condition.   Convulsions ensued, and ammonia was
exhaled from the lungs.  The animal, however, recovered perfectly in  a
short time.   Urea was also injected  with  a like  ultimate  result.  The
symptoms observed were, however, by no means identical  in both cases.
  In  a second  series of experiments performed,  and  detailed  in the same
memoir, the kidneys  were  removed,  and in these animals  death  followed in
a few hours after the injection  of ammonia and  other substances.   From
these experiments it is apparent that carbonate  of ammonia possesses no
pre-eminence as a toxical agent over substances not regarded as poisonous.
The investigations, however, are not sufficiently extensive to warrant the
formation of decided conclusions  from them.   It is  perceived, however,
that when  urea  was injected it was  not  decomposed into  carbonate  of
ammonia either in unmutilated  dogs or in those  deprived of their kidneys.
  In  Bright's disease, there is a condition  of system present  very similar
to that existing  in animals the kidneys of which have been removed.   In

       1 Medical  Examiner, vol.  v. No. 11, N. S., 1849, p.  644.
       2 North American Medico-Chirurgical Review, vol.  ii. p. 291. 
13
persons, therefore, suffering from  this affection, carbonate of ammonia, if
injected in  large  quantity into the blood, might  cause death,  or, even if
retained in this fluid to any very great extent, the same result might follow.
As, however, we have no proof that there is any accumulation of  this sub-
stance in the blood during the progress of the disease in question, we cannot
ascribe uraemic intoxication to its influence.
   In  the breath of persons labouring under Bright's disease, Frerichs con-
stantly detected ammonia, and this circumstance  is advanced as an addi-
tional argument in favour of his hypothesis.   Allusion has already been
made to the fact that ammonia  can generally be found in the  pulmonary
exhalation of dogs.   It is perhaps even a more constant constituent of the
human breath, even in that of persons who, as far as can be perceived, are
in perfect  health.   Richardson,1 in many examinations, failed to find it
only in one person.   Schottin2 detected it in the breath of persons suffering
under other affections than Bright's disease, and in sixteen cases of uraemic
poisoning  found ammonia in the breath  but  once, and then, he thinks, it
was probably derived from the mouth.
   Mettenheimer3 found white fumes produced by  a  rod moistened  with
chlorhydric acid, as readily with the breath  of healthy persons as with that
of subjects of uraemia ; and, in a note to  his memoir, Beneke states that he
has arrived at similar results.   Yiale and Latini,4 by numerous  delicate ex-
periments,  have also shown  that with  each act of expiration ammonia is
exhaled from the lungs of the healthy human  subject.
   From  my own  investigations, it has resulted  that  I have scarcely ever
failed to find ammonia in my  own breath, or in that of very many healthy
persons whom I have examined.
   I have thus considered, at  some length, the arguments and experiments
brought  forward by Frerichs in support of his theory, and have, I think,
sufficiently shown that it is not tenable.    It is because, if generally adopted,
it may lead to  very grave errors in diagnosis and practice, that I  have
deemed it  important to  show how many facts tend to disprove the hypo-
thesis in question.
   Another view of the cause of uraemia, inferentially supported by  Ber-
nard,5 requires some notice.   According to this hypothesis, the condition in
question is produced by decomposition of the tissue of the kidneys, and the
retention in the blood of the elements  arising from their putridity.   The

  1 Op. cit.
  2 Vierordt's Archiv. 1853, Heft i. s. 170.
  3 Archiv des Vereins fur gemeinschaftliche Arbeiten u. s. w.  Band 1, Heft iv.
1854, p. 605.
  1 American Journal of the Medical Sciences, April, 1855, p. 4S8.   From L'Union
Medicale, t.  viii. No. 98, Aout 1854.
  5 Lecjons sur les Proprietes Physiologiques et les Alterations Pathologiques des
Liquides de l'Organisme.   Paris, 1859, t. ii. p. 34 et seq. 
14
 experiments of Miiller and  Peipers,1 and of Marchand,3 are adduced  as
 tending to establish the correctness of this theory.   These observers induced
 mortification of the kidneys by ligating the renal nerves, and though it is
 asserted that death ensued from uraemia, it is by no means clear that this
 condition was not due to the cessation of  the function of the kidneys,
 rather than to the entrance into the blood of  septic matters from the mor-
 tified organs.   Moreover, when the kidneys of an animal are removed, there
 is certainly no retention in the blood of putrid matters arising from their
 decomposition, and yet death  invariably follows.   The entrance into the
 blood of  substances in a  state of putrefactive  fermentation  would  more
 probably induce a pyaemic or typhoid condition of  the system than one of
 uraemia.  Finally, in Bright's disease, of which uraemia so frequently forms
 a  prominent concomitant, pathology shows that the existing condition of
 the kidneys is not one at all  analogous to putrefaction.
   It is perhaps unnecessary to consider other objections which are applica-
 ble to this hypothesis.
   The theory which much observation and numerous experiments have led
 me to think most probably correct, is that which  ascribes uraemic intoxica-
 tion to the direct action of the  elements  of the urine retained in the blood
 upon  the brain and nervous system, in a manner which we do not at pre-
 sent understand.   Of  these  elements,  we have strong reasons for deeming
 urea the most poisonous.
   It  is true, that urea has been directly introduced into the circulation of
 healthy animals without death ensuing.  Thus Yauquelin and Segalas3 in-
jected a solution of this substance  into the veins of  dogs and cats, without
 the production of  any remarkable  effect other than an increase in  the
 amount of urine  excreted.  They  then injected  urine, and death followed
 with symptoms of uraemia.   Hence they drew the conclusion, that it is the
 urine  as a whole which, when retained in the blood, induces toxication.
   Frerichs* thinks that death in these cases arose from the urine being un-
 filtered ; that  is, from  the mucus and  epithelium derived from the urinary
 passages.   He has repeatedly injected from twenty to forty grammes of
 filtered urine, sometimes even adding urea to it, into the veins of animals,
 without causing  death.   An increased quantity of urine  was evacuated,
 but the normal condition of the organism was not otherwise disturbed.  A
 warm  saturated solution of urate  of soda, likewise produced no  untoward
 result.  The amount of urea  excreted by  the kidneys was, however, greatly
increased.
   Other observations have also  been made relative to the point in question,

              1 Archiv  fur Physiologie, 1836.
              2 Journal fur practische Chemie, Band xi. s. 149.
              3 Journal de Physiologie de Magendie, t.  ii. p. 354.
              1 Op.  cit., p. 106. 
15
 and leading to the same general conclusions.   It may therefore be regarded
 as a well-established fact, that urea, in considerable amount, may be intro-
 duced into  the blood of healthy animals, without death being necessarily
 produced.
   It has been  definitely shown  that  urea  is a  normal constituent of the
 blood.   It has been found in the chyle, the lymph, the  saliva, the bile, the
 aqueous and vitreous humours, the perspiration,  the liquor amnii,  the fluid
 of blisters, in dropsical effusions, in fecal evacuations, and even in the milk.
 It cannot therefore be regarded  as poisonous, unless when, from defective
 excretion, it accumulates in the blood.
   The amount of urea formed within  the organism is, as has already been
 shown, subject to very great variation ; but so long as the kidneys continue
 to perform the function  of elimination  in accordance with the requirements
 of the  system, the  normal balance between the  urea and the blood is not
 disturbed.   Thus it is that urea, and even urine, may be directly introduced
 into  the circulation without inducing continued uraemia ; for so  soon as
 these substances reach the kidneys (as Vauquelin  and Segalas, Frerichs, and
 many other investigators have shown), there is an increased  elimination of
 urine, they  are  expelled from  the body, and the coma,  convulsions,  and
 other accompaniments of toxication cease.
   Occasionally, it happens that when the kidneys do not properly depurate
 the blood, other organs  assume their  office,  and then uraemic intoxication
 does not occur.
   Several cases are on record in which, from total suppression of the func-
 tion of the kidneys continuing for a long time, this condition existed. One
 of the most remarkable of these is that reported to the French Academy of
 Sciences, several years  since, by Monte-Santo,1 of Padua, the  accuracy of
 whose statements was confirmed by MM. Graefe  and  Frank from personal
 observation.   In the case in  question, there was complete constipation of
 the bowels and suppression of urine for fourteen  years.   There was always
 vomiting in from two to five hours after each meal, and about .once a month
 a large  quantity of fecal matter was discharged in the same  manner.   Al-
 though it  is stated that there was no odour of  urine in these egesta, it is
 more than probable that the stomach vicariously performed the function of
 the kidneys, and perhaps  the  skin also shared  with it this  office.  Some
 years previously, a case  had been reported to the Academy,  in which there
 had been no discharge of feces or urine (by the ordinary channels, at least),
 for a period of seventy-two years.
  Whatever  doubt  may be attached to  such cases as the above, it is very
certain that in several diseases it frequently happens that other organs than
the kidneys  eliminate some of the elements of the urine from the blood.
This is especially the  case in Bright's disease, in  yellow fever, and in cho-

      ' Medico-Chirurgical Review, July, 1833 (American edition), p. 236. 
16
lera.   Immediately previous to the accession, and during the continuance
of the stage of collapse, in this last named disease, the cutaneous transpira-
tion often contains urea, which is deposited by evaporation on the skin.   I
have frequently had occasion to notice this circumstance, and in  one case in
particular,  which  fell under my charge, the  skin  of the  face, chest, and
arms  presented the appearance of being  dusted with a fine white powder
from  the large quantity of urea which covered it.  The  urine contained
scarcely a trace of this substance, but it was found both in the fluid vomited
and that discharged per anum.  I do not cite this case as one at all singu-
lar, but merely for the bearing which it has  upon the  subject  under con-
sideration.   In the numerous cases of cholera which  have fallen under my
observation, I  have generally, whenever  an  examination was  instituted,
detected urea in the rice-water discharges from the stomach and  bowels.
  The experiments of Bernard and Barreswil,1 which show that when  the
kidneys are removed from an animal urea is excreted by the gastro-intestinal
canal, may also be adduced.   These observers extirpated the kidneys from
dogs, and found that  in  those  animals which survived but a short time no
urea was to be  detected in the blood, but that the matters ejected by vomit-
ing and purging contained large quantities of ammonia, the product of the
decomposition of the  urea through the action of mucus and other gastro-
intestinal secretions.  If, however, death did not soon follow, the stomach
and intestines  lost their vicarious  office, and then  urea was found in the
blood.
  The fact that urea may occasionally exist in large quantity in the blood
without giving rise to uraemic intoxication, is no proof that this substance
is not generally poisonous.  No one will deny the  poisonous properties of
arsenic.  Dr. Taylor2 gives  the opinion, that a  medical witness would be
justified in  stating it to  be fatal in doses of  two or  three grains, yet subse-
quently refers  to cases  in which half an  ounce, an ounce and a half, and
even two ounces,  had been taken without  causing death.   In  the first of
these instances, there  was not even vomiting.   So in  relation to opium, as
small a quantity as four  grains  produced  death in a robust man, whilst on
the other hand, as much as five ounces of laudanum has been taken with-
out even causing sleep.  Similar instances might be  brought forward in
relation to  almost every  other poisonous substance.
  It may perhaps be objected, that in such cases the poisons were not ab-
sorbed into the blood; but  toxic agents have been introduced directly into
the circulation, and like  differences in the extent of their action have  en-
sued.   I might bring forward numerous examples in support of this asser-

  1  Sur les  voies d'elimination de Puree apres l'extirpation des reins.  Archives
GenSrales de Medecine, 1847,  t. xiii. p. 449.   Also, Leqons sur  les Liquides  de
l'Organisme, &c, t. ii. p. 36.
  2  On Poisons.   Second American edition, 1859, p. 341. 
17
tion, but it will probably be sufficient to recall the fact of the total insus-
ceptibility of some persons to the action of the vaccine virus.
   In Bright's disease, the  disorganization of the kidneys  is generally of
slow  progress.   They continue to perform  their function, though imper-
fectly, and consequently the amount of urea contained in the blood is not,
in the first stages, very excessive.   Its accumulation  is gradual, and there
is therefore time for the system to  become in a measure habituated to its
presence in such  an amount that, if suddenly introduced into the blood and
not  eliminated,  uraemia would in all  probability ensue.    We find this
ability of the system to adapt itself to gradual changes generally present in
all animals, and with reference to the action of poisonous substances ex-
ceedingly well  marked.   Thus, by progressively increasing the doses, large
quantities of arsenic,  opium, strychnia,  hydrocyanic acid, and other toxical
substances may be taken without  the  production of the  least  poisonous
effect.
   When, however, in Bright's disease, the structure of the kidneys becomes
so greatly disorganized as to unfit them  entirely for depurating the blood,
the elements of the  urine continue to accumulate, and if not otherwise ex-
creted, almost invariably give rise to uraemia.
   As  to the assertion that uraemic intoxication may  exist without  the
accumulation of  urea in the blood, I have only to say that there is no  evi-
dence whatever to support such a conclusion.
   The  following investigations were undertaken with the  hope of  being
able to contribute somewhat to a fuller and more exact understanding of
the cause of uraemia.   I have endeavoured to avoid every source of fallacy,
and  though (knowing the difficulties which  attend researches of this cha-
racter) I can perhaps scarcely assume to have succeeded, I am, nevertheless,
unaware of  any circumstances which  would invalidate the conclusions
drawn.
   To say that I entered upon the  inquiry without certain preconceived
opinions would be far from correct.  That such views as I had conceived
have, however, blinded me to the truth, or warped my judgment of things
as they actually were, I do not believe.   Theories are true but for the time
being,  and physiological  hypotheses are even more ephemeral  than any
others.   We should therefore be prepared to yield our convictions without
regret, when they do  not  accord with the  results of experiments better de-
vised and more accurate than our own, for only by so doing can we entitle
ourselves to be considered useful labourers  in the fields of science.
   The chemical  processes  used in  the  several  determinations  were  as
follows :—
   In examining  the blood for urea,  a weighed portion was mixed  with its
volume of strong alcohol, and evaporated over sulphuric acid or chloride of
calcium, in vacuo, to dryness.   The  residue was pulverized, and extracted
       2 
18
with cold alcohol.   The alcoholic extract was filtered, and carefully evapo-
rated to dryness at a low temperature in  the water-bath, and the residue
washed repeatedly with small portions of  ether.  The ether extract was
filtered and evaporated to dryness.   Nitric acid was then added  to- the resi-
due,  the  whole thrown upon a filter of known weight,  and subjected to
strong pressure.   It was then dried at  100° C,  and  weighed.   The differ-
ence between the weight  of the whole  and that of the  filter gave  the
amount of nitrate of urea, and from this the quantity of urea was calculated.
  Whenever the amount of urea was too small to determine quantitatively,
the  dried ether  extract last obtained,  as  in  the foregoing process, was
placed upon a glass slide, and nitric acid added to it under the microscope.
The  production of rhombic and hexagonal tablets, the opposite acute angles
of which measured  82°, was deemed sufficient evidence of the  presence of
the substance sought for.
  The same  methods were used to determine the existence of urea in  the
vomited and fecal matters,  whenever they were examined for it.
  For ascertaining  the amount of urea in  the urine, Liebig's  volumetric
process with the proto-nitrate of mercury was always employed.
  In the determination of ammonia, Richardson's process, already detailed,
or Reuling's, was made use of.   Whenever  negative  results were  obtained
by the one, recourse was always had to the  other.
  In the first place, I was desirous of ascertaining more definitely than had
hitherto been done, the action of urea when  injected into the blood of sound
and healthy animals.

  Expt.  A large adult dog, weighing 65 pounds, was fed for three days on
fresh meat.   During this  period,  ammonia was constantly found in  the
breath.
  On the fourth day the jugular vein of the left side was opened, and a
sufficient quantity of blood abstracted.  100 grammes of this contained
0.019 gramme of urea.  Ammonia was present, as it was likewise in  the
expired air.
  The urine  passed on this day amounted  to 1025 cubic centimetres, and
contained 11.28  grammes of urea.
  The food was the same as on the preceding days.
  On the morning of the fifth day, at & A.M., 3 grammes of urea  dissolved
in -30  cubic cen. of distilled water,  were injected.into the jugular  vein.
The  animal, from the very first, appeared to suffer pain.   It moaned;  the
breathing became laboured; and it trembled violently, as if from  fright or
cold.   At the end of about 20 minutes, the animal became more quiet, and
even  appeared to be  somewhat stupefied.  After  nearly an hour had
elapsed, convulsions ensued.  These were confined almost entirely to  the
posterior extremities, though at times the other portions of the body were
in spasms.
  At 10 o'clock, whilst the convulsions were still present, I abstracted 100
grammes of blood.   It contained 0.135 grammes of urea.   Ammonia was
also  present, though in  no larger  amount  than on the  previous  day.
Examined microscopically,  the red blood-corpuscles were found  to  be of 
19
normal size, shape, and colour.   They appeared, however, to be diminished
in quantity.  The white corpuscles were very evidently increased in amount.
   The animal continued to be convulsed till  about 2 o'clock P.  M., when
coma ensued.   This lasted 3^ hours.  The dog then awoke, and passed a
large quantity of urine.   It amounted to 280 cubic centimetres, and con-
tained 2.15 grammes of urea.
   Before, during, and after the convulsions, ammonia was exhaled with the
breath.
   Immediately on the dog awaking, I  again  abstracted 100 cubic centi-
metres of blood from the.jugular vein.  This contained 0.014 of urea.
   The total amount of urine voided on this day was 1381 cubic centimetres,
containing 14.63 grammes of urea.
   The dog ate as much on this day as on any previous one.  It recovered
perfectly.
   Expt.  For this experiment, a dog, weighing 38|- pounds, was used.   As
in the preceding experiment, it was fed  for three  days on fresh meat.
During this period, at only one  examination  (at 10 o'clock A.M., on the
second day), was ammonia detected in the expired air.  On the fourth day,
100 grammes of blood were abstracted from the jugular vein, and found to
contain 0.027 gramme of urea.   Ammonia was  also present, and likewise
in the pulmonary exhalation.
   The urine voided  on this day amounted to 834 cubic  centimetres, and
contained 4.09 grammes of urea.
   On the fifth day, at 10 o'clock A.  M., 5 grammes of urea dissolved in 30
cubic centimetres of distilled water,  were injected into the jugular vein.
No  immediate  effect was  produced.   After the lapse of 45 minutes, there
were slight spasms of the muscles of the eyelids ;  and 50 minutes after tl»e
injection, a severe general convulsion ensued.   The vein was now reopened,
and 100 grammes of  blood taken.  Upon  analysis, this was found to con-
tain  0.254 grammes of urea.  The convulsions continued with  great vio-
lence for 15 minutes.   Coma followed, and lasted till 6 o'clock P. M., when
the animal died.  There was no excretion  of urine after the injection of the
urea.  The breath was  examined every  hour for ammonia, but at no time
was it detected; neither was it  present on this  day before the  urea was
injected.   It was, however, found in the blood  last drawn.  There was
neither vomiting nor  purging.
   Immediately after death the post-mortem examination was commenced.
   The substance of the brain appeared to be perfectly healthy; but there
was considerable injection of the vessels of the meninges.   The ventricles
contained  about 15 cubic centimetres of serous fluid.  Urea was detected
in this by the process mentioned, and microscopical examination.  It was
likewise found in the blood from the sinuses.
   The vertebral canal was laid  open, and the spinal  cord  examined.  Its
substance presented a normal appearance,  but there was some congestion of
the vessels of its membranes.
   The chest contained  a small  quantity of serous fluid.  The  lungs were
congested, but were otherwise healthy.  The heart was of normal size, and
did  not  appear to be in the least diseased.   It contained a considerable
quantity of fluid blood ;  100 grammes were collected from it and the large
vessels.  The urea in this quantity amounted to 0.873 grammes.
   Upon microscopical examination  of  this blood, the red  corpuscles were
found to present a crenated margin, and to be in decidedly less  than  the 
20
normal quantity.  The white corpuscles were very much increased in quan-
tity ;  as much as in well-marked leucocytbemia.
   The cavity of the peritoneum contained a small quantity of serous liquid.
The membrane was in places slightly congested.
   The  liver was healthy in  appearance, but the spleen  was considerably
enlarged, and  contained much  more than the normal quantity of blood.
The tissue  of  this latter organ, when examined microscopically, was found
to  present several  important deviations from the normal structure.  The
Malpighian corpuscles were  almost entirely absent, and  there was a very
great increase in the number  of parenchyma cells.   These latter were much
larger than I have ever found them in the spleen of the dog.    The red
blood-corpuscles in the splenic blood were generally aggregated in  groups,
and were of irregular forms.
   The  stomach was  opened, and presented nothing  abnormal.  The con-
tents, consisting of mucus with a few pieces of bone, were of alkaline reac-
tion,  and  contained  both  urea and  ammonia, the latter in considerable
amount.
   The kidneys were enlarged and very, much congested.  Upon cutting into
them, the blood poured out from innumerable orifices.   There was  no  ob-
struction to either the  renal arteries or veins  that was discovered after
death.  The tissue of the kidneys, when submitted to microscopical exami-
nation,  showed excessive congestion of the capillaries, and enlargement of
the Malpighian bodies.  Into many of these latter extravasation of blood
had taken place, and  the tubes were gorged with this fluid.
   The bladder contained a small quantity of bloody urine.

 ^Death in this case was,  I think, obviously due to  non-elimination  of
urea,  and perhaps of the other elements  of the urine, through  excessive
hyperaemia of the  kidneys.  The  cause of the  kidney affection  I  do not
know.  It  was  undoubtedly caused either  directly or indirectly by  the in-
jection of the  urea, for up to the  time of that  operation the function of
these organs was perfectly effected.
   The experiment cannot but be regarded as exceedingly instructive.  There
was complete  arrest of excretion from the  kidneys, and the  blood, besides
retaining the elements of the urine, received in addition a large quantity of
urea,  which remained in the organism.  In  many  respects,  therefore, the
experiment resembled those in which the kidneys have been extirpated, and
urea subsequently introduced into  the blood.   In  all such  experiments,
death has  invariably taken place within a few hours.  There is, however,
this important difference, that the system was saved the shock of a serious
operation,  and therefore one source of error was eliminated.
   In  relation  to the  alteration in  the form of  the blood-corpuscles, it can
scarcely (having Kolliker's experiments in view) be  ascribed to  the direct
physical action  of the urea, as the  proportion of this substance present in
the blood was altogether too small (less  than 1§)  to effect the  change.
Kolliker1 found that a solution containing 30§ of urea caused the  red cor-

  1 Zeitschrift  fur wissenschaftliche  Zoologie, B. vii.  s. 183.  Also, Quarterly
Journal of Microscopical Science, vol. iii. 1855, p. 289. 
21
 puscles of the frog to assume the form of stellate  cells, and finally to melt
 down and disappear.   These alterations were also produced, though much
 more slowly, by solutions of 15§  and 12§.   When weaker solutions were
 used, they were not caused.   Human blood-cells were only rendered smaller
 and colourless.  The phenomenon observed in the  case under consideration,
 taken in connection with the diminution of the number of red and increase
 in that of the white corpuscles, must probably be ascribed to some defect in
 the process of sanguification.
   For the purpose of ascertaining the effect of introducing repeated quan-
 tities of urea into  the blood, I proceeded as follows :—

   Expt.  A clog  weighing forty-eight  pounds was fed as the  others for
 three days.  Ammonia was always found in the breath.
   On the fourth day, at 10 o'clock A. M., one hundred grammes of blood
 were abstracted, and upon  examination found to contain 0.021 grammes of
 urea.   The urine  voided during the twenty-four hours amounted to 1224
 cubic centimetres, and  contained  8.15  grammes  of urea.   Ammonia was
 present both in the blood and expired air.
   The following morning,  at 10 A. M., I introduced into the jugular vein
 five grammes of urea, dissolved in  thirty cubic centimetres of distilled water.
 No  immediate effect was produced, the  animal remaining perfectly  quiet.
 At  11.15 convulsions  ensued.  One hundred grammes of blood were now
 taken, and yielded 0.193 grammes of urea.  The convulsions, at first slight,
 became more  violent.   They continued about twenty  minutes, and were
 succeeded by stupor.  At 12 M., I injected, as before, five grammes of urea.
 Immediately afterwards, the animal voided 365 cubic centimetres of  uri^e,
 in which  were contained 3.17 grammes of urea.  The coma continued, and
 at 2 P. M. I again injected five grammes of urea into the blood.   At 3.20
 P.  M. the dog  passed  42.3  cubic centimetres of  urine,  containing  4.06
 grammes  of urea.   The coma was still present.  At 4 P. M., I injected ten
 grammes  of urea, dissolved in thirty-five cubic centimetres of distilled water,
 into the blood.  The stupor was now very  profound, the heart beat slowly,
 and the respiration was laboured  and  stertorous.   I again, at five P. M,
 abstracted one hundred grammes of blood  for examination.  It  contained
 1.683 grammes of urea.
   At 5.20, the dog evacuated per anum a small quantity of yellow, serous
 fluid.  Urea and ammonia  were detected  in it.
   At 5.45 the animal died, having in eight hours received directly into the
 blood twenty-five grammes  of  urea.
   Ammonia was found in  the breath during the whole course of this ex-
 periment,  and likewise in the blood.
   The urine voided from the commencement to the end of the experiment
 amounted  to 890  cubic centimetres, and contained 7.23  grammes of urea.
 In the  twenty-four hours, there were evacuated  1625 cubic centimetres of
 urine, in which were contained 12.37 grammes of urea.
   On  post-mortem examination, the brain and  spinal  cord  were found
 healthy; the membranes of  both  were  of perfectly normal  appearance.
 About five cubic centimetres of fluid were  collected from  the ventricles  of
 the former.  By simply  placing a  drop on  a glass  slide, and adding  nitric
 acid, crystals of nitrate  of urea were formed.
  The lungs were found congested, but there was no effusion into the pleural
cavities.   The pericardium was very much congested.  The heart contained 
22
a large quantity of blood.  Its lining membrane, both in the auricles and
ventricles, was redder than natural.
  One hundred grammes of the blood from the heart and large vessels con-
tained 1.385 grammes of urea.   The blood-corpuscles were of normal size
and shape, but, as  in  the former experiments,  were remarkably diminished
in number, whilst there was an increase in the number of  white corpuscles.
  The peritoneal membrane was found congested in  patches.  The spleen
was enlarged,  and  contained  a large quantity of blood.  Beycfnd this the
structure,  when examined with the microscope, exhibited  no abnormal
appearance.   The kidneys were healthy.
  The stomach contained about one hundred and fifty cubic centimetres of
fluid, resembling the  rice-water discharges of cholera.   The intestines also
contained  a  quantity of the same kind of fluid.  Both urea and ammonia
were present in it.

  For the purpose of  still further determining the action of large quanti-
ties of urea, when introduced into the circulation, the following experiment
was performed:—

  Expt.  A small adult dog, weighing thirty and a quarter pounds, was fed
as the others, for three days, on fresh meat, before any investigations were
commenced.   On the fourth day, at 10 o'clock A. M., one hundred grammes
of blood were drawn from the jugular vein.   This quantity contained 0.024
grammes of urea.  The total amount Of urine evacuated during the twenty-
four hours was  830 cubic centimetres, containing 5.12 grammes of urea.
On  this and the preceding days, ammonia was always found in the breath.
The food remained  the same.
  On the  fifth day, at 10 A. M., twenty-five grammes of urea, dissolved in
thirty cubic centimetres of distilled water (thus forming a nearly saturated
solution),  were injected into the jugular vein.  The animal lay down quietly
in its  box, and at first did not  seem  to be  greatly disturbed.  After a few
moments slight twitchings of the muscles ensued, and at 10.30 there was a
strong convulsion.  Some  of the  spasms,  subsequently,  were decidedly
tetanic.   During the convulsions, I reopened the jugular vein and allowed
100 grammes of blood to flow out.   The amount of  urea contained therein
was 2.005 grammes.   The convulsions  lasted with  undiminished violence
till  11.10 A.M., when 481  cubic  centimetres of urine,  containing  7.50
grammes of urea, were excreted.   They then  became slighter, and at about
12 M. were succeeded  by coma.  This continued, without intermission till
4.15 P. M., when the animal quietly died in  most profound stupor.   Two
hundred and twenty-five cubic centimetres of urine, containing 3.12 grammes
of urea,  were excreted a short time before death.  There was neither vomit-
ing nor purging.  Ammonia was constantly found  in the breath, but not
in greater quantity than during the previous  days.
  The blood drawn during  the convulsions was  examined with the micro-
scope.  The red corpuscles were altered in  shape, and had become much
paler  than natural.  Scarcely one could be found which was not more or
less irregular in outline.  They, besides, appeared to have lost their  ordi-
nary consistence, and when two or more came together they fused, forming
an  irregularly formed mass.   It was thus impossible to determine micro-
scopically their  relative numbers.   The white corpuscles were very much
increased in quantity.   The blood coagulated firmly.
  The cavities of  the body were opened  immediately after death.  The 
23
membranes of the brain were found in a state of intense congestion, and
the sinuses and large vessels  at  the base of the cranium were gorged with
blood.   The  substance  of the  brain, when cut into, exhibited  a uniform
pink tinge from excess of blood, and the red spots indicating the situation
of capillaries were greatly increased in number.   This was the first case in
which the substance  of  the brain  presented direct evidence of hyperaemia.
About twenty cubic centimetres  of  fluid were collected from the ventricles.
   The membranes of the spinal cord were likewise congested, especially in
the lumbar region, though  more  or less throughout their whole extent.
Into the  cavity  of  the arachnoid there  was an effusion  of serous  fluid,
amounting to fifteen or twenty cubic centimetres.
   The lungs were also congested, and  there was a considerable amount of
bloody fluid effused into the pleural cavities.   The pericardium contained a
quantity of liquid.   The  right side of the heart was distended with blood.
The left  contained but a small quantity.  The heart did not exhibit any
indications of pre-existing disease of any kind.  I was prevented examining
the blood chemically.  The blood-corpuscles presented the same appearances
as those in the blood abstracted before death.
   The peritoneum was  not diseased ;  there was no effusion.   The liver was
of normal appearance.   The spleen was enlarged, and contained a  large
quantity of blood.   The  red corpuscles were here found  almost entirely
broken down into a  liquid substance.   No Malpighian corpuscles were dis-
covered.  Large quantities of acicular  crystals  were scattered through the
substance of the spleen, and were visible by microscopical examination.
   The  kidneys were slightly congested, and some of the tubes contained
blood.  There were  no other appearances of disease:
   Two other experiments, similar to the last, were performed.  As the
results were almost identical, I refrain from detailed descriptions of them.

   Ffom the foregoing experiments, it  is perceived that there is a limit to
the power of the system to eliminate urea, and that when this substance  is
introduced into the blood in large  quantity, it causes death by uraemia. By
this I mean that the urea induces such an abnormal condition of the blood,
that the  brain  primarily, and subsequently other organs (the kidneys in-
cluded), are brought into  an  abnormal condition, and are thereby prevented
performing their functions.   From the results of the post-mortem examina-
tion, it is apparent  that  this state is one of  congestion.   I am therefore
disposed to think that if the brain had been able to resist the toxic power
of the urea for a considerably longer period, the kidneys would have elimi-
nated the surplus urea, and death in these latter experiments would not
have ensued.
   It is well known  that  in  Bright's disease  death frequently occurs from
congestions and inflammations of important structures.  Thus this termina-
tion may be caused by oedema of the glottis, by pericarditis,  by pneumonia,
by peritonitis, by apoplexy, &c.  Have we not reason to regard  these seve-
ral affections  as  due to an abnormal condition of the brain and nervous
system, induced  by the  retentiou in the blood of excrementitious matters
which in health are removed ?
  It is,  I think, very evident  that in neither of  the foregoing experiments 
24
was there the least reasou  to suppose that there was any decomposition of
urea into carbonate of ammonia.   In the second experiment, this substance
was not found in the breath after the injection of the urea into the blood,
although it.was present at two examinations before this operation.
  The alterations in the blood  observed with the microscope are very im-
portant, and constitute one link in the chain, connecting the retention of
urea with derangement of the  brain and nervous system.   They, perhaps,
show that it is not necessary that a toxic condition  of the blood  should
consist altogether in  disturbances of the chemical balance existing between
its several component parts.   The morbid  condition of the spleen which
was found to exist, is also  an interesting circumstance, taken in connection
with the changes in the form of the red, and alterations in the relative
number of these and the white corpuscles.
  Leaving, for the present, the further consideration of these experiments,
I proceed to the detail of those constituting the  second series, and having
relation to the effects following ligature of the renal vessels,  or removal of
the kidneys.

  Exp. A large adult  dog, weighing  68^ pounds, was selected.  At 10
A. M. the breath was examined for ammonia,  and this substance was found
to be  exhaled from the lungs  in considerable quantity.  100 grammes of
blood taken from the jugular vein contained 0.026 gramme of urea.
  At 3 P. M. the animal was placed under  the influence of chloroform,
and the kidneys  removed, the abdomen being  opened to the smallest possi-
ble extent.   Scarcely a drop of blood was lost;  the anaesthesia passed off
without the least untoward effect.
  The next morning the dog was in apparently good condition, but mani-
fested no desire to eat, or to move about.  At 3 P. M., twenty-four hours
after  ablation of  the kidneys, 100 grammes of blood were drawn,  and
found  to contain 0.083 gramme of urea.   The  animal refused all food;
ammonia was constantly in the breath.
  On  the third day, at 10 A. M., the dog seemed weaker.  Up to  this
period, however, there had been no convulsion, or coma, neither was there
any vomiting or purging.  At  about 2^ P. M. there was  a slight spasm,
succeeded in a few moments by a violent general  convulsion.  At 3 P. M.
100 grammes of blood gave 0.093 gramme of urea.  At 4 P. M. the ani-
mal vomited  a quantity of alkaline mucus, containing both urea and ammo-
nia__the latter  in large amount.  After the vomiting, the  convulsions
abated in violence, but soon  became as intense  as at  first.   At intervals,
however, the animal was free from spasm, and appeared  to be also free from
pain and uneasiness.  At about  8 P. M. coma ensued, alternating with the
convulsions till  10|.P. M., when it became persistent,  and very profound.
Death  ensued at  about 4 A.  M. the  next day, sixty-one  hours  after the
removal of the kidneys.
   The post-mortem  examination of the  body was commenced at 9 A. M.
The  membranes  of  the brain were intensely congested, and there was an
effusion of about twenty-five cubic centimetres  of serum into the cavity of the
arachnoid.   The substance of  the brain, when cut into, exhibited a pinkish
hue, and numerous bloody points appeared, showing enlargement,  and in-
crease in the number of capillaries.   The sinuses and vessels at the base of 
25
the brain were turgid.   Fifteen cubic centimetres of fluid were found in the
ventricles.
   The spinal cord was apparently healthy, but its membranes were slightly
congested.  There was no abnormal amount of fluid found.
   Both  lungs were congested, and both pleurae bore evidences of recent
incipient inflammation.  There was slight effusion.   The heart was gorged
with blood.  The pericardium was  healthy.   100  grammes of  blood from
the heart and large vessels contained 0.097 gramme of urea.
   When submitted to microscopical examination, the blood taken from the
heart exhibited appearances  similar to those previously noticed.  The white
corpuscles were increased, and the red diminished in number.  These latter
were also of irregular  shape, and decidedly paler than natural.
   The peritoneum exhibited traces  of recent inflammation; a small amount
of bloody serum was found  in its cavity.
   The  spleen was very much  enlarged, being at least three times the size
of the organ in its normal condition,  as noticed when the kidneys were re-
moved.   Upon cutting into it, the substance was found entirely disorgan-
ized, and of semi-fluid consistence.  No traces of  Malpighian corpuscles
were  to be found, and the  finer trabeculae and many of the larger, were
entirely  detached  from their  connections.  These, with masses of blood-
pigment, broken-down corpuscles, a few muscular fibre-cells, and numerous
acicular crystals of haemato-crystallin, were all the morphological elements
to be discovered.   The parenchyma cells, white corpuscles, free nuclei,  &c,
had been destroyed.
   The liver was also enlarged.  It was not examined microscopically.
   The stomach, on being opened, exhaled a strong ammoniacal  odour.  It
contained a quantity of yellow, alkaline mucus.  Ammonia was present in
large quantity, and  traces of urea.   The intestines contained  a like  sub-
stance.
   Exp.  At 9 o'clock A. M.,  100 grammes of  blood were abstracted from
the jugular vein of a large dog, weighing 60| pounds. The urea contained
therein amounted to  0.014 gramme.  Ammonia was present in the breath.
At 1 P. M. the renal arteries were  ligated, the animal being under the in-
fluence of chloroform.   As  soon as the anaesthesia passed off sleep ensued,
from which the dog did not awake  for several  hours.  At 10 P. M. it ap-
peared to be in good condition, and lapped a little milk.   It was quiet, but
when spoken to, manifested  undoubted signs of  intelligence.
   The following morning at 8 o'clock the animal was quite lively.  It stood
up, and  even walked a few  steps.   It ate a little  bread and milk.  At 4
P. M. it was somewhat drowsy, though it could be easily roused by speak-
ing loudly, or  knocking on the side  of its box.   100 grammes of blood
taken from the jugular vein  contained 0.038 of urea.  Ammonia was  pre-
sent in the breath.  The stupor continued to increase, and at about 8 P. M.
was profound.  When  last seen for the night, at 12 M.,  the animal was in
a very comatose condition.
   The next day at 8 A. M., the coma was still present.   100 grammes of
blood contained 0.043  gramme of urea.  Ammonia was exhaled from the
breath, but not io a very abnormal extent.  The dog remained in the same
condition till about 11^ P. M., when  it died, 58£ hours after the ligation
of the vessels.   There was no vomiting, nor purging, and no visible spasms
of any kind.
  The following morning, at 9 A. M., I made the post-mortem examina-
tion.  The membranes  of the brain were congested, and about twenty-five 
26
cubic centimetres of fluid were effused into the cavity of the arachnoid.
The substance of the brain likewise exhibited evidences of having been in
a hyperaemic condition.   The ventricles were  distended with  fluid, which,
however, owing  to an  accident, was not measured.  The sinuses and  ves-
sels at the base of the  cranium were turgid with  blood.   The spinal cord
was not examined.
  The pleurae, the lungs, the pericardium, and heart, were healthy;  100
grammes of blood collected from the latter, contained 0.069 of urea.  Exa-
mined microscopically,  the white corpuscles were found in largely increased
quantity, but no other  abnormal condition was discovered.
  The peritoneum was  congested in spots, and  exhibited evidences of recent
inflammatory action.   The spleen was large, and softer than natural.   No
Malpighian corpuscles could be  found.   Masses of extravasated blood, in
larger quantity than usual, were met with.  The liver was not markedly
affected.   The stomach and intestines contained  the residue of undigested
food,  with  some yellow, alkaline mucus.  Ammonia  and urea were both
present.
  From the foregoing  experiments, it is seen that, after the removal of the
kidneys, or ligature of the renal arteries, the amount of urea  in the blood
was increased threefold within a short period, and that  there was no reason
to suppose  any  conversion  of this principle into  carbonate  of ammonia.
The pathological changes are interesting, and congestion and inflammation
of important organs are seen to be produced  as well after ablation of  the
kidneys, as after the  direct injection  of urea into the blood, or during  the
course of Bright's disease.  The immediate cause, in each of these instances,
is probably the same—derangement of nervous influence through a morbid
condition of the blood.
  Four other experiments,  similar to the two foregoing, were performed.
In all, the quantity  of urea  in the blood  was greatly increased after  re-
moval of the kidneys, or simple ligature of their arteries, and the post-mor-
tem  appearances were in general the same.   In three  of these there were
convulsions and  coma,  in one coma alone—as in the second experiment of
this series.   In one experiment, the animal lived forty-nine hours after the
operation, in one fifty-three, in  one sixty-eight, and in  one seventy-three
hours.  Ammonia was  found in the breath  both  before and after the ope-
ration.   In none was there any vomiting or purging.
  But that these last-mentioned results do sometimes happen,  there can be
no doubt, and, in fact, judging from the  investigations of these observers,
they are usual concomitants.  In  one experiment which I performed sub-
sequently to the  above  cited, they were present  from the first, and doubtless
by these  means the urea was removed from the blood, and this fluid pre-
served in a comparatively normal condition.  In no other  way can we
account for the lengthened continuance of life  after the kidneys were extir-
pated.  As this  experiment is important in several respects, I  give the de-
tails of it in full.

  Expt.  A dog weighing thirty-eight pounds was  selected for operation. 
27
Before the extirpation of the kidneys, the breath was ascertained to contain
ammonia.  In 100 grammes of blood were 0.009 grammes of urea.
  The kidneys were removed at 9 A. M., the dog being under the influence
of chloroform.  After the operation, the animal fell into a quiet sleep, and
did not  awake for six or  seven hours.  At about 6 P. M. it ate a little
bread and milk.
  The following morning  at 8 o'clock it was in apparent good condition,
wagged its tail when spoken to, and ate quite freely of bread and milk.   It
remained in the same condition  all day, manifesting, however, no desire to
move  out  of its  box,  though it occasionally turned from one side to  the
other.
  The next morning it was found that in the night a little mucus bad been
vomited.   This contained ammonia, but no urea.  No other circumstances
worthy of note occurred during the day.
  On the fourth day, at 7 A.M., the animal seemed somewhat uneasy from
nausea.  Several  efforts to vomit occurred, but nothing was ejected.  At
about 4  P. M., there  was  a fecal evacuation of a thin, serous fluid, of a
yellow colour.  Ammonia was present, but no urea.  Crystals of ammonio-
magnesian phosphate  in large  quantities were visible by the microscope.
No food was taken on  this day.
  At  7  o'clock the following morning, it was found that there had been
both  vomiting and purging of ammoniacal matters during the night.  One
hundred  grammes  of blood were abstracted at 9 A.  M., and found to con-
tain 0.011  grammes  of urea.
   On the sixth day,  there were both vomiting and purging.  The animal
was sensible, but refused food.
  On the seventh, eighth, and ninth days, vomiting and purging occurred
several times.  Ammonia and  urea were present in each evacuation.   On
each of these days, a pint of milk was conveyed to the stomach through a
tube.
  On the tenth day,  at about 12\ P. M., a slight convulsion occurred.   A
pint of milk was  injected into the  stomach.  There was neither vomiting
nor purging.
  On  the  eleventh day, at 9| A. M., another convulsion took place, more
violent than the first.  The animal  was, however, still  sensible.
  On the twelfth  day,  at 7  A. M., the dog was found in a comatose condi-
tion.   One  hundred  grammes of blood were abstracted at  12  M.  This
quantity contained 0.041 grammes  of urea.  The wound in the abdomen
had nearly healed.   The ligatures on the renal vessels came away.  Coma
was present during the whole day, and death took place some time in  the
night after 11 o'clock.   The animal was cold  the following morning at 7
o'clock.
  Thus life had  remained for at least 278 hours after the kidneys were
extirpated.
  Ammonia was detected in the breath on every day but the last.
  The post-mortem examination was commenced at about 11 o'clock A. M.
The membranes of the brain were apparently healthy,  but there was slight
sub-arachnoidal effusion.  The substance of the brain was of normal  ap-
pearance.  The spinal cord and its  membranes were healthy.  The lungs
were  congested, and  there  were several recent  pleuritic adhesions.  The
pericardium was in several places adherent to the heart.  This latter organ
was in a state of incipient fatty degeneration.   It was  full of uncoagulated
blood, 100  grammes  of which contained 0.046 grammes of urea. 
28
  The red corpuscles, both in this blood and in that abstracted on the day
of death, were very much diminished in number, whilst the white corpuscles
were correspondingly increased.  The former were also  broken down, and
softer than is normally the case.
  The peritoneal membrane was congested, and several intestinal adhesions
had  taken place.  The spleen was enlarged, and felt  like a bag of  water.
When the enveloping  membranes were cut, the,substance flowed out, like
molasses in colour  and consistence.   Examined  microscopically, nothing
was  perceived but shreds of white fibrous  tissue, masses of  decomposed
blood-corpuscles, blood pigment, and large  quantities  of acicular  crystals.
The  liver was enlarged, and in a state of congestion.   The stomach and
intestines contained nothing but a little mucus.

  It is  seen from this experiment that so long as vomiting and purging
continued, there was  no accumulation of urea in the blood, and no conse-
quent uraemic intoxication.   It was only when these ceased that the latter
event ensued.  It  is therefore strongly confirmatory of the conclusion
arrived  at by MM. Bernard  and Barreswil, which has been previously re-
ferred to.   The connection between the retention  of urea in the system and
the occurrence of uraemia is  so well marked, that it is  difficult to deny to
these events the relation of cause and effect.
  In  the third and  last series of  experiments, the  kidneys were removed,
and urea or urine, subsequently directly introduced into the blood.

  Expt. From the jugular vein of a  medium sized dog, 100 grammes of
blood were abstracted  at 10 o'clock  A.M., and found  to contain 0.021
grammes of urea. Ammonia was detected in the expired air.  At 11 A. M.
the animal was placed  under the influence of chloroform, and  the kidneys
removed.   At 12 M., five grammes of urea dissolved  in thirty cubic centi-
metres of distilled water, were injected  into the jugular vein.   No imme-
diately noticeable effect was  produced.  At 1^ o'clock  P. M., convulsions
of great violence suddenly ensued.  One hundred grammes of blood from
the jugular vein yielded. 0.042  grammes  of urea.  A large  quantity of
highly ammoniacal fluid was vomited.  It contained urea. The convulsions
continued with undiminished violence  till about  five  o'clock, when coma
gradually ensued, and remained present till death, which occurred at about
8 o'clock P. M.
  Before death, and during  the height of the convulsions and coma, the
breath was examined for ammonia, which, although constantly found, was
not present in larger qnantity than before the kidneys  were removed.
  At 7 ^ o'clock the following morning, the post-mortem examination was
commenced.
   The membranes and substance of the brain were healthy, but there was  a
little sub-arachnoidal and ventricular effusion.
   The  lungs were highly congested, as  were also  the pleurae in  several
places.   The  pericardium was healthy, and  the heart was of normal ap-
pearance.  It contained a small  quantity  of uncoagulated blood.  One
hundred grammes  taken from  it  and  the large vessels,  yielded 0.032
grammes of urea.
   The  peritoneum  was anteriorly much congested, and there was about
one  hundred cubic  centimetres of bloody serum in its cavity.   The spleen 
29
was hyperaemic, and  its normal  structure disorganized, as in the previous
experiments.   The liver was not perceptibly diseased.
  The stomach and intestines contained a small quantity of  alkaline fluid.
It was highly ammoniacal.  Urea was not detected in it.

   Three other experiments, similar to the foregoing, were performed. The
results were almost  identical, and it is therefore, perhaps, unnecessary to
refer to them more in detail.
   In  the two following experiments, urine was introduced into the blood.

   Expt. A dog weighing somewhat less than forty pounds was used  for
this experiment.   The breath examined for ammonia gave distinct evidence
of containing it.   Previous to removing the kidneys, it was determined
that 100 grammes of blood from the jugular vein contained 0.017 grammes
of urea.
   Anaesthesia was induced by chloroform, and the kidneys extirpated at 9
o'clock  A. M.  As  soon as the insensibility had passed off, one hundred
cubic  centimetres  of fresh urine (voided during the induction of  the anaes-
thesia),  unfiltered, were injected carefully into the jugular vein.  No imme-
diate effect was produced.  At 12 M., thirty cubic centimetres more of  the
same urine were introduced into the blood.   The animal remained quiet in
its box till about  2  o'clock P. M., when a slight convulsion ensued,  lasting
only  a  few  seconds, and confined  to  the anterior muscles  of the body.
 Shortly afterwards,  another occurred more violent than the first.  This was
followed by others.   At about 4 P. M.  they ceased, and coma commenced
to make its appearance.   One hundred grammes of blood from the jugular
vein were found to  contain 0.030 grammes  of urea.   The coma  continued
till after 12  P. M.   The dog was found dead the ensuing morning at 5
o'clock.  There had been neither vomiting nor purging.  Before death,  the
breath was frequently examined for ammonia, and always with affirmative
results.
   The post-mortem examination was made  at 8| o'clock A. M.   The  ap-
pearances observed were not materially different from  those noticed in  the
case just detailed, except that the pericardium was congested, and there was
some little effusion  into its  cavity; 100 grammes of blood from the heart
and large vessels,  contained 0.036 gramme of urea.
   Exp. A dog, weighing 49| pounds, was  the subject of this experiment.
Ammonia was found in the expired air; 100 grammes of blood from  the
jugular vein  gave 0.027 gramme  of urea.  The animal was at 10 A. M.
brought under the influence of chloroform,  and whilst anaesthesia was pre-
sent,  the kidneys were extirpated.  When insensibility had passed off,  100
cubic centimetres of filtered urine—evacuated during the process of induc-
ing anaesthesia—were injected into the jugular vein.
   After the expiration  of about two hours, convulsions ensued.   These at
first were slight, but more violent ones soon followed.   They lasted till  a
few minutes before 3 P. M., when coma supervened;  100 grammes of blood
taken from the jugular vein were found to contain 0.035 gramme of urea.
The  coma persisted, and at  8£ P.  M.  the animal died.   There  was no
vomiting nor purging.   Ammonia was found in the breath throughout.
   The post-mortem appearances were not essentially different from those
observed in the preceding experiment.   The contents of the stomach were
however acid, and did not contain ammonia. 
30
  From the experiments, constituting this last series, it is clearly seen  that
the introduction of urea, or filtered  or unfiltered urine into the circulation
of animals deprived of their kidneys, induces death more speedily than if
such substances had not been thrown into the blood; for, we have perceived
from the experiments of the immediately preceding series, that animals, the
kidneys of which have been extirpated, or  the renal arteries ligated, live for
from  forty-nine to 218 hours  after the operation ; whereas, in the series
last  detailed, death occurred in from eight to fifteen  hours, in a condition
of system not  to be distinguished from that known as uraemia.   Taken,
therefore, in connection with the experiments of the first series, in which
urea was introduced into the blood of sound animals, and with those of the
second, in which, through extirpation of  the  kidneys, the  elements of the
urine were retained in the blood, and we have almost demonstrative proof
that the resulting uraemia was directly due to the operation of these causes.
  Taken as a whole, from an  attentive consideration of the foregoing in-
vestigations, I think the following conclusions are legitimately deductible :—
  1st. That the injection  of  urea, in limited  quantity, into the blood  of
animals,  produces  a certain amount of disturbance in the nervous system,
similar in its symptoms to the first stages of uraemia, but that this condi-
tion-even disappears, if the kidneys are capable of so depurating the blood
as to eliminate the toxic substance.
  2d. That urea,  when  introduced into the circulation  in larger quantity
than can  in a limited period be excreted  by the kidneys, induces death by
uraemia.
  3d. That by ligature  of the renal  arteries, or removal of  the kidneys,
the elements of the urine being retained in the blood, render  this  fluid
unsuitable to the requirements of the organism, and, consequently, induce
a condition  of system not essentially distinguishable from the uraemic in-
toxication of Bright's disease, or that caused by the direct introduction of
urea into the blood.  As, however,  was pointed out by Bernard and Barres-
wil, so  long as the urea, or  the products  of its metamorphosis, are dis-
charged by the stomach or intestines, uraemia does not take place, but, that
when these  channels become closed,  convulsions and coma are produced, and
death soon follows.
   4th.  That the introduction  of urea or urine  into the circulation of ani-
mals, the kidneys of which have been ablated, shortens the life of such ani-
mals, as Frerichs and others have already shown.
   5th.  That there is reason to believe that the urine, as a whole, is  more
poisonous than a simple solution of urea, for, in those cases in which  urine
was injected into the blood, the amount of  urea thus introduced was  much
smaller than that  previously thrown in, in a pure state, and yet symptoms
of  as great intensity followed.
   6th.  That urea, or the elements of the urine, as a whole,  induce such a
condition of the nervous  system, as strongly to predispose  to congestion 
31
and  inflammation of the viscera, especially the lungs, pericardium,  and
spleen.
   7th. That urea, when directly injected into the blood, or suffered to ac-
cumulate  in  this fluid  by extirpation of the kidneys, deranges,  in some
manner, the process of  sanguification, so as to disturb the normal relation
of proportion existing between the white and the red corpuscles, and either
to hasten the decomposition of these latter, or to interfere with the  due
removal from the blood of such as are broken down and effete.
   8th. That there  is no  reason to suppose that, under the circumstances
specified, urea undergoes  conversion into carbonate of ammonia, but that,
on the contrary, there  is  sufficient evidence to warrant the conclusion that
no such  process ensues.   The fact  that in  the foregoing experiments a
larger amount  of  urea was generally found in the blood taken from the
body after death, than in  that abstracted during life, is, of itself, conclusive
against any such hypothesis.