THE INFLUENCE OF FEVER ON THE ELIMINATION OF

THE INFLUENCE OF FEVER ON THE ELIMINATION OF CREATININE.

BY VICTOR c. MYERS AND G. 0. VOLOVIC.

(From the Laboratories o.f Physiological Chemistry, Albany Medical College, ~rld o-f Pathological Chemistry, New York Post-Graduate Medical School

and Hospital.)

(Received for publication, April 26, 1913.)

It has long been recognized that the rate of body metabolism is intensified in the various febrile diseases, resulting in an increased elimination of the nitrogenous waste products in the urine. The study of the urine under these conditions has been of considerable service in the interpretation of intermediary processes which take place in the bodyduring this disturbed state. Metabolism in fever, especially in typhoid fever and pneumonia, has recently received extonsive consideration at the hands of a number of investigators, viz., van Hoogenhuyze and Verploegh,l Klercker,2 Ewing and ‘\\‘olf,3 Shaffer and Coleman,4 and Wolf and Lambert.

That the elimination of total nitrogen andof its chief constituent, urea nitrogen, paralleled the rise in body temperature in various acute infections was noted long ago. The excretion of ammonia was found to be increased by some of the older investigators, though its excretion as determined with more reliable methods would indicate that the ammonia is not ordinarily greatly increased in fever, and further, that acidosis is not a prominent feature of this condition. Uric acid has quite generally been found to be increased during the height of fever, followed usually by a decline with the fall in temperature. Fever was likewise claimed by the older observers to increase the elimination of creatinine, though

1 van Hoogenhuyze and Verploegh: Zeitschr. j. physiol. Chem., lvii, p. 161, 1908.

a Klercker: Zeitschr. f. k&n. Med., lxviii, p. 22, 1909. 3 Ewing and Wolf: Arch. of Int. Med., iv, p. 330, 1909. 4 Shaffer and Coleman: ibid., iv, p. 538, 1909. 5 Wolf and I,ambert : ibid., v, p. 406, 1910.

489

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490 Effect of Fever on Creatinine Elimination

the dat’a on this point can hardly be regarded as conclusive, owing to the unreliability of the methods available.

Since Folin6 with his calorimetric method first demonstra.ted the absolute constancy in the elimination of creatinine by normal individuals under a variety of dietary conditions, this nitrogenous urinary constituent, which stands next to urea in point of quantit,p, has been a subject of study at the hands of numerous investigators. X lowered creatinine output has been observed to be associat’ed with a variety of diseases,? but the only condition which has been found to be accompanied by an immediate change in the elimination of creatjnine is fever; and here the excretion of this constituent is increased, the amount of the increase apparently bearing a close relationship to the rise in body t,emperature. van Hoogenhuyze and Verploegh8 claim to have observed a slightly increased elimination of creatinine after stimulation with syrup of cola and strych- nine, and a slight decrease after potassium bromide and absolute rest. The changes they observed were very slight and in no w\-ay comparable to the greatly increased elimination during fever. In view of the lack of knowledge with regard to the origin of creatinine, the increased excretion brought about by fever is of particular interest.

This rise in creatinine elimination during fever appears to have been first observed by Leathesg after the production of a hyper- pyrexia in normal subjects by the use of antityphoid vaccine. He found that the curve of the creatinine elimination followed both the temperature and the total nitrogen, but that the percentage of creatinine nitrogen in terms of total nitrogen fell somewhat below the normal percent,age with a marked increase in the eliminat,ion of total nitrogen, though the absolute amount of the creatinine excretion was increased about 25 per cent at the highest point. Subsequently, van Hoogenhuyze and Verploegh’o noted that the maximum creatinine excretion appeared at the same time or n-it,hin a few hours of the highest temperature. The observations of I<lercke+ on the elimination of creatinine and creatine in febrile

6 Folin: Amer. Jown. of Physiol., xiii, p. 66, 1905. i Cf. Mgers: Amer. Joztm. of Med. Sci., cxxxix, p. 256, 1910. 8 Loc. cil. n Leathcs: Jown. 0s Physiol., xxxv, p. 205, 1907.

10 Lot. cil. ‘1 Lot. cii.


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V. C. Myers and G. 0. Volovic 49’

diseases, but more especially the contributions of Ewing and TVolf12 and Shaffer and Coleman13 on protein metabolism during typhoid fever, and Wolf and Lambert”” on protein metabolism in pneumonia, have greatly amplified our knowledge on this subject. The increased excretion of creatinine during fever has likewise been noted by XIanuchin,15 though the’deduct.ions he drams would hardly appear in accord with other ohservat.ions.

Not only has an increased excretion of creatinine been observed during the active stages of fever, but a decrease in its elimination during convalescence. It has furt’her been noted that sooner or later during the course of a fever creatine appears in the urine, and its elimination in increased quantities seems of grave diagnost’ic importance. Thiswas st,rikingly shown in the series of fatal pneu- monias reported by Wolf and Lambert. In general, a parallel between the febrile temperature, total nitrogen, urea and creatinine has been observed. Shaffer and Coleman found that the increased excretion of creatinine in fevers was hardly in proport’ion to t,he amount of body protein catabolized, their highest increase in the creatinine excretion being calculated as about 20 per cent. The destruction of body proteins during fever, though perhaps more severe, is quite comparable t’o that occurrirrg during fasting, and Mendel and Rose,16 and Myers and FineI have observed that the total creatinine nitrogen (from both creatinine and creatine) forms a uniform proportion of the total nitrogen in starving rabbits.

In producing this increased metabolism in fever, as shown by t,he increased excretion of nitrogenous waste pr0duct.s and also by the increased elimination of carbon dioxide, several factors play a part, viz., t,he hyperthermia per se, the accompanying inanition, and the toxic agent causing the fever.

That pyrexia, prbducecl by artificially raising the body temperature with a hot bath, or otherwise, mill raise the level of body metabolism has been demonstrated. The carbon-dioxide elimination has been observed to be increased from 30 to 40 per cent’ under these conditions, and somen-hat similar figures have been obtained

I5 Manuchin: Russlci Wrntsclz, is, pp. 13: 5.5, 89, 1910. lfi Mcndel and Rose: this Jowrd, x, p. 213, 1911. I7 ;\lyers and Oine: unpublished data.


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for the nitrogen elimination. Linser and Schmid18 have pointed out that in man it is not until the body temperature is increased above 39°C. t.hat there is an increase in protein metabolism. From this I<rehllg concludes that in infective fevers with a temperature under 49°C. t,he additional protein metabolism must be of toxic origin.

In infect’ive fevers, whether in man or animals, it has often been noted that the rise in nitrogenous metabolism is greater than should be observed if due entirely t.o the pyrexia and accompanying inanition. This added excess in the nitrogen elimination has been explained as toxic in origin. Ewing and Wolf in their study of protein metabolism in typhoid fever observed that the highest excretion of nitrogen in proport.ion to body weight occurred in the so- called toxic cases and that, alt.hough t,his was generally coincident with a high temperature, the total nitrogen appeared to be less affected by the fever than by the intoxication. Some of the most widely quot’ed experiments on fever are those by MayzO performed on rabbits inoculated probably with the same organism as in our experiments. The inoculations were made during a period of starvation, and on the second day after inoculation the output of nitrogen exceeded the normal by 28.4 to 51.9 per cent. The rise in nitrogen elimination is quite comparable to that observed in our experiments below except that here the animals were not starving and the fever appeared several days later. These figures probably represent, in a general way the increase in nitrogenous metabolism which may be observed in febrile conditions in man. The particular advantage of such experiments, as those of May on animals, is the fact that one has a fairly adequate control period which cannot be so readily obtained in similar diseases in man.

One ot.her phase of the quest,ion, which is of the utmost practical importance in the treatment of fever in man, especially typhoid fever as shown by Shaffer and Coleman, is the diet. The lower specific dynamic action of carbohydrate in comparison to protein and the protective action of carbohydrate on protein is well known. Xay called attention, in his experiments in 1894, to the protective action of carbohydrate on body protein. By the use of diets high

I8 Linser and Schmid: Deufsch. 3nA .f. klirc. died., Ixxix, p. 514, 1904. I9 Krehl: Clinical Pathology, Amer. Edit. by Hewlett, 1907, p. 406. *O Mt~v: Zeifsckr. j”. Bid., xxx, p. 1, 1894.


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V. C. Myers and G. 0. Volovic 493

in caloric value and rich in carbohydrate, Shaffer and Coleman”’ have shown it possible to retard and even prevent the febrile loss of body protein nitrogen in subjects of typhoid fever. This is of particular interest in this connection in view of the inhibitory influence of carbohydrate upon the excretion of creatine by starving animals.

EXPERIMENTAL PART.

Nine experiments are reported on rabbits inoculated with Bacillus suipesticuP and three experiment,s upon animals whose temperature was raised artificially. The routine procedures in the first series of experiments consisted in determinations of total nitrogen, urea, ammonia, creatinine, creatine, chlorides, phosphates, potassium, and the routine clinical examination of the urine, together with morning and evening temperature observations during the fever period, and a previous control period of four or more days. In the last three experiments determinations of total nitrogen, creatinine, creatine and chlorides were made.

The analytical methods employed were: Kjeldahl method for total nitrogen, Benedict method for urea,23 Folin methods for ammonia and creatinine,24 Benedict-Myers modification of the Folin method for creatine,25 T,‘olhard-Harvey26 method for chlorides, titration with uranium nitrate for phosphates and Drushel’s method for potassium.27

The rabbits were all healthy animals, females being usetl because it is somewhat easier to compress the bladder. Prior to beginning t,he experiment, the animals were .placed upon a uniform carrot diet for a period of several days. During the experiment the blatl- der was squeezed out at a definite time each morning, the animal weighed, and then given its daily ration which was ordinarily con- sumed during the day in the control period. After inoculation or placing in an incubator the appetite of the animals declined, ohvi-

11 Lot cit.; also Coleman: +A~~zer. Jown. ojdled. Sci., &iii, p. i7, 1912. ?? A preliminary report of these experiments was made at the 1911 Meeting

of the Society of Biological Chemists, cf. Proceedings: this Jowrd, xi, p. xxi, 1912.

23 Benedict: this Journnl, viii, p. 405, 1910. u Folin: Amer. Joum. (1,~” I’/~~~siol., xiii, p. 43, 1905. ?j Benedict and Myers: ibid., xviii, p. 397, 1907. p’i Harvey: flrch. 01 Inl. Med., vi, p. 12, 1910. Li Drushel: Amer. Jown. oy’ Sci., xxvi, 11, 5.53, 19OS: also AIgers: this Jour-

rlnl, vi, 11. 122, 1909.


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ously introducing an important factor into the figures for the nitrogen elimination. However, starving animals would have been less satisfactory, for several reasons, the most important of which is the elimination of creatine which develops very quickly in the rabbit during inanition.

The 350400 grams of carrots (contain 0.6-0.7 gram N) would appear t,o furnish a fairly adequate dietary for the rabbit, generally close to 100 calories per kilogram, with 10 per cent in the form of protein. The rabbit with its large skin area should require a com- paratively high caloric intake, but this would appear to have been well supplied. Owing to the exhaustion of the old carrot supply (July 1911), rabbits 0, P and Q were fed 300 graps of new roots and 200 grams of the green “tops,” thus making the 500 grams recorded in the tables. No detailed protocols, aside from the tabu- lated results of the urine analyses, appear to be necessary.

The first series of experiments was carried out at the Bender Laboratory at the suggestion of Dr. Ordway with the idea that some correlation might be observed between our chemical findings and the histological data obtained in independent experiments on the same animals by Ordway, Kel- lert and Huested.?* We were able to detect little relationship between the lesions observed in the various organs and the composition of the urine. Our chemical data were found to be chiefly of interest from the standpoint of creatinine, and on this account figures for the potassium, chlorides, phosphates and likewise ammonia have not been included.

Below is given, however, a brief summary of the results obtained for the elimination of these constituents. Data on the excretion of potassium mere obtained in the first seven experiments. The excretion appeared to follow closely in all cases t)he food intake, although this was rather high to have allowed the demonstration of changes due to fever or accompanying conditions. In general, with the development of fever, there was an increase in Ohe chloride elimination, followed by a very decided decrease not accounted for by the decreased intake. This is believed to have been due to a decreased kidney (tubular) permeability. The phosphate elimination showed an increase during the fever period in certain of the experiments, while in others there was little change.

The figures for ammonia are also not recorded, for the reason t.hat with one possible exception, Rabbit M, no indication was observed of an increased excretion of ammonia. Normally, the rabbit eliminates practically no ammonia, as might be expected from the nature of its dietary. Though the reaction of the urine was frequently observed to be acid at the height of the fever, sufficient time hardly elapsed to have caused a very great deple- tion of the supply of basic elements in the body.

25 Ordway, Kellert and Hueatcd: J~UVL oj Merl. ks., xxviii, 1,. 41, 1913.


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kvns.

1.40 1.39 1.43 1.36 1.40

1.40 1.36 1.36 1.34 1.24 1.28 1.29 1.32 1.26

LRRO’I DIET

‘rams

350 350 350 350 350

pm. a.m.

“C. “C. cc.

38.3 36.7 235 39.5 37.8 250 37.8 36.1 275 37.2 38.1 250 38.7 38.6 240

1.014; 16.1 1.016’ 15.3

247 1.015 17.2

37.8 38.5

40.6 40.1 39.8 39.2 40.8 35.3 39.5

37.8 38.3 40.1 40.1 40.3 40.0 38.6 38.6 38.7 40.0 39.3

240 1.021 22.6 260 1.020 19.6 250 18.1 200 1.014 21.5

75 1.024 22.2 60 1.028 20.7

120 1.020 18.4 175 1.025 16.7 235 1.014 18.2 200’ 1.020 16.4 200 1.016 17.4

TABLE II. Rub, bii I c.

“C. “C.

37.5 37.5 37.8 38.3 39.1

37.8 37.8 38.8 38.4

cc.

218 275 275 260 220

-.- 246

mgms.

1.017 25.8 1.019 25.8 1.019 25.8 1.020’ 18.4 1.022 28.2

350 350 350 350 300

1.018 25.4

38.6 38.5 38.2 39.6 40.6

280 39.9 90 41.0 80 40.6

38.6 40.5 40.3 38.3

300 1.016 32.6 250 1.0201 25.4 350 1 33.2 275 1.018, 22.3 235 1.0121 37.5

50 60

1.030; 21.8 1.035 39.4

50 1.0361 29.1

DATE 1911

February and March 20 21 22 23 24

Average 15-24..

25 26 27 28

1 2 3 4 5

-L I

I- --

6 : 1.24 7 ~ 1.25

350 350 350 200 180

70 160 280 300 300 300

--

0 0

0 0 0 0 0 0 0

2.1 2.1

0 0.5

i

February and March 20 21 22 23 24

1.75 1.76 1.72 1.77 1.75

grams

350 350 350 350

_ 350

n

Average E-24..

25 26 27 2s

1 2 3 4

.~~

1.65 1.66 1.67 1.70 1.65 1.52 1.47 1.47

i

0 0 0 0 0 0 0

5.6 I

R&bit A inoculated subcukmeously on February 24 with 0.5 cc. of a 24-hour bouillon culture of Bacillus suipesticus. Pulse on February 21, 180; on February 28, 280. Animal recovered.

Rabbit C inoculated subcutaneously on February 24 with 0.5 cc. of a 24- hour bouillon culture of BaciZZ~s szaipesliczcs.


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DATE

1011

p.

m.

June

kg

ms.

gm

ms

“C.

1 1.7

0 35

0 39

.8 2

1.71

350

39.5

3 1.6

9 35

0 40

.2 4

1.70

350

39.7

Aver

. 1-4

1.67

1.68

1.64

1.52

1.47

343

347

200 0

H,O,

16

cc.

40.9

41.0

42.0

41.7

40.0

I- a.m

.

“C.

39.5

39.2

40.1

39.7

40.3

41.4

41.8

41.1

39.1

TABL

E 11

1.

Rabb

it N.

250

1.01

3

230

~ 1.

015

250

1.01

8 15

2 1.

017

70

1.01

5 33

1

1.01

5

~ I~

--.

~.-L

- .._

~ cc

.

’ gr

a?n.

s

260

1.01

8 1

0.70

250

1.01

3 0.5

5 26

0 1.

010

0.50

230

1.01

5 ~

0.42

0.53

0.35

I- I -- 66

0.63

0.48

76

0.72

0.61

84

0.69

0.62

90

0.83

0.70

84

0.25

0.24

96

gram

s pe

r ce

nt

0.45

60

0.33

60

0.30

60

0.32

76

UREA

N

i- I ~,

CREA

T-

ININ

E N

mgm

s.

25.1

25.1

25.8

/ 25

.8 ~---

I-

25.5

-Ti

i- 31

.7 I

34.7

1 35

.4 17

.2 ~

CREA

T-

IiwNE

N

per

cent

3.6

4.6

5.1

6.0

5.0

~___

5.0

4.4

5.0

4.2

6.9

:REAT

INE N

mgm

s.

0 0 0 0 0 0 0 0 0 5.4

Rabb

it H

inocu

lated

su

bcuta

neou

sly

on

June

4

at 12

.30

p.m.

with

0.5

cc

. of

24-h

our

bouil

lon

cultu

re

of Ba

cillus

su

ipes-

1’1’~~

~s.

Urine

str

ongly

ac

id on

las

t tw

o da

ys,

and

on

last

day

conta

ined

album

in,

a few

pu

s ce

lls

and

many

hy

aline

ca

sts.

Rabb

it die

d at

10

a.m.

on

June

9.


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TABL

E IV

.

Rabb

it I.

UR

EA

N

UR

El

N

per

c.9 70

84

77

86

CRBA

T-

9”

CREg

rNE

c 9 pe

r ce

nt pe

r cent

mg

ms.

mgm

s. 5:

3.

0 3.

0 0 0

cd

3.5

3.5

0 0 CD

2.8

2.8

0 0 z

3.3

3.3

0 0 P g

mgm

s.

27.8

27

.8

25.8

26

.1

26.9

-I p.

m.

gram

s

350

350

350

350

“C.

39.2

39.2

39.5

39

.1

-~

a.m

. ~-

“C

.

38.9

39.0

39.2

39.1

cc.

230

275

230

265

250

350

39.8

39

.9

237

350

39.5

40

.0

185

350

39.8

40

.1

265

0 41

.7

40.7

30

0 LO

, 24

cc.

40

.3

37.6

96

TOTA

L N

gram

s

0.92

0.78

0.

91

0.79

0.85

0.94

0.

56

0.70

1.

04

0.88

L at --

8P.

GR.

1.01

6 1.

017

1.01

7 1.

017

1.01

7

1.01

7 1.

020

1.01

5 1.

013

1.01

2

gram

s

0.64

0.

66

0.70

0.

68

0.67

80

3.

1 ?

-.___

3.

2 4.

0 P

4.6

3.3

c 4.

1 0

0 3.

3 0

F 3.

4 0

1 -. 0

0.73

77

30

.1

0.42

75

25

.8

0.57

80

29

.1

0.77

74

34

.7

0.63

71

30

.1

1.96

2.

05

2.05

1.

83

1.70

Rabb

it I

inocu

lated

su

bcuta

neou

sly

on

June

4

at 12

.30

p.m.

with

0.5

cc

. of

a 24

-hou

r bo

uillon

cu

lture

of

Bacil

lus

suipe

s- tic

ue.

Urine

fai

ntly

acid

on

last

day,

and

on

the

last

two

days

co

ntaine

d alb

umin.

An

imal

died

at 2

p.m.

on

June

9

with

co

nvuls

ions;

was

foun

d to

be p

regn

ant.

s v


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TABL

E V.

Rabb

it K.

9er c

e

82

93

90

90

86

DATE

1911

gram

s

1.05

0.75

0.94

0.84

0.85

UREA

N CR

EATI

NE

N 2 R

ngm

s.

0 10

.3 -

8P.

GR.

p.m.

-I-

"C.

40.2

40.0

40.0

a.m.

CREA

T-

ININ

E N

39.8

“C.

cc.

40.0

315

39.9

315

40.0

320

40.0

282

39.8

310

1.01

7 1.

015

1.015

. 1.

017

1.01

5

gram

s

0.85

0.70

0.85

0.74

0.73

1 m

gms.

pe

r ce

nt

28.8

2.7

32.4

4.3

32.4

3.4

30.5

3.6

28.9

3.4

308

1.01

6 0.8

9 0.7

8 87

30

.6

40.2

40.2

300

1.01

5 0.9

4 0.7

8 83

31

.9 41

.0 39

.8 28

5 1.

015

1.03

0.89

86

30.1

40.0

40.8

295

1.01

4 0.8

6 0.7

5 89

30

.5 40

.7 41

.4 27

5 1.

015

0.87

0.74

85

30.8

42.7

39.9

158

1.01

9 1.3

3 1.0

9 80

38

.3

3.4

3.3

3.0

3.5

3.5

3.0

June

an

d Ju

ly kg

ms.

22

1.84

23

1.84

24

1.84

25

1.85

26

1.84

gram

s

400

400

400

400

400

400

400

400

400

150

ELO,

25

cc

.

2.1

r 7.4

2

10.0

CD

CL

6.8

6.8

E E 6.9

6.9

n n

0 0 ; ;

0 0 CL

CL

e. e.

1.9

1.9

=r =r 2.6

2.6

k’ k’

4.6

4.6

M M =: ti Ra

bbit

K ino

culat

ed

in the

us

ual

way

at 5.3

0 p.m

. on

Ju

ne

26;

preg

nant

and

abor

ted

on J

uly

1; die

d at

9.45

gm.

on

July2

. L*

Th

e fac

t tha

t cre

atine

wa

s ex

creted

du

ring

the

contr

ol pe

riod

finds

pr

obab

le ex

plana

tion

in the

fac

t tha

t the

an

imal

was

2 pr

egna

nt.

This

migh

t als

o be

a

poss

ible

expla

natio

n of

the

excre

tion

of cre

atine

by

the

pr

eviou

s an

imal

after

ino

culat

ion,

but

prev

ious

to the

ou

tset

of the

fev

er.?”

g s

Aver

age

22-2

6..

. . .

27

1.84

28

1.86

29

1.85

30

1.84

1 1.6

6

I

w Cf

. Me

llanb

y: Pr

oc.

Roy.

Sot.,

B,

lxx

xvi,

p. 88

, 19

13.


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TABL

E VI

.

Rabb

it M.

DATE

19

11

June

an

d Ju

ly 22

23

24

25

26

Aver

age

22-2

6.

27

28

29

30 1

- I

I BO

DY

1 C*

RBOT

W

EIGH

T 1

DIET

~~~~

~ I-

kgm

s. I

gram

s

1.85

i 40

0 1.8

2 1

400

1.85

400

1.84

I 40

0 1.8

2 j

400

-/

1.82

400

1.80

, 39

0 1.8

4 1

380

1.79

1 0

1.61

I O

i

p.m

.

“C.

39.7

39.7

40.0

39.5

39.6

I- I-

40.0

40.0

40.9

42.0

39.5

a.m

.

“C.

cc.

39.6

315

39.7

280

39.6

I ;;;

39.5

320

-I- 30

2 -,--

40

.1 I

307

40.0

, 25

3 41

.5 30

7 40

.8 1

167 25

1.01

5 1.

015

1.01

5 1.

015

1.01

5

gram

s

0.51

0.55

0.52

0.57

0.53

1.01

5 0.5

3 __

_~

1.01

7 0.5

0 1.

014

0.64

1.01

4 0.6

0 1.

013

/ 0.9

1 ac

id 1

--

UREA

UR

EA

N N

/

-I- gr

ams

per

cent

0.49

96

0.46

1 83

0.4

4 84

0.4

5 /

80

0.45

85

0.46

87

0.44

88

0.52

81

0.49

81

0.79

87

0.34

CRE‘

W-

ININ

E N

mgm

s.

25.4

24.2

24.0

24.5

24.8

24.6

26.7

26.3

29.7

32.4 5.6

CR

ILW

- I

NE

-%

per

cent

5.0

4.4

4.6

4.3

4.7

4.6

5.3

4.1

4.9

3.5

CR

EATI

NE

c N

9 m

gms.

0

ZA

w 0

rD

0 tf

0 0 E CL

0 0

0 P

0 0 c 0

0 5

2 c w.

0

Rabb

it M

inocu

lated

in

the

usua

l wa

y at

5.30

p.nr.

on

June

26

; sm

all

amou

nt

of alb

umin

detec

ted

in the

ur

ine

on

June

29

; ur

ine

on

morn

ing

of las

t tw

o da

ys

obse

rved

to be

ac

id;

rabb

it die

d in

conv

ulsion

s at,

3 p

.m.

on

June

30


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July 16

17

18

19

20

~.

.____

Av

er.

9-20

.

?sgm

s.

1.95

1.94

1.95

1.95

1.95

21

1.95

22

1.95

23

1.97

24

1.95

25

1.92

26

1.81

27

3.75

--

CARR

OT

TEM

PER*

*URE

DI

ET

p.m

. a.

m.

__-

grm

s “C

. “C

.

500

40.0

39.5

500

40.0

39.8

500

39.8

39.3

500

39.6

39.5

500

39.9

39.6

____

--

_-

--

cc.

365

1.01

9 33

5 1.

024

300

1.02

1 36

7 1.

018

330

1.02

2

328

1.02

1

330

1.02

1 30

6 1.

022

208

1.02

1 32

0 1.

019

140

1.01

9 19

0 1.

014

50

1.02

8

gram

s gr

ams

per

cm:

?n~r

n.?.

0.87

0.66

76

26.8

1.13

0.88

78

31.0

0.83

0.62

74

31.0

0.86

0.69

80

31.3

0.97

0.68

70

30.1

- I’ ,- per

cent

311

2.7

3.7

3.7

3.1

0.85

0.64

76

-___

78

77

76

69

73

90

90

29.2

____

500

40.0

40.3

500

39.7

39.7

500

’ 40

.8 ‘40

.7

500

41.4

41.1

refus

ed

42.2

41.1

food

but

41.5

40.9

drank

41

.1 40

.7 Hz

0

1.05

0.82

0.96

0.74

0.90

0.68

0.96

0.66

0.94

0.79

1.65

1.49

1.28

1.10

28.9

30.1

31.0

36.3

38.3

47.9

33.4

3.4

~__ 2.7

3.0

3.4

3.8

4.0

22

9 ’ 2

%

1 L

~_

__-.

Rabb

it 0

rece

ived

5 cc

. of

a bo

uillon

cu

lture

of

Bacil

lus

suipe

~licu

s by

mo

uth

at 5

p.m.

July

12 o

n an

em

pty

stoma

ch

but

no

infec

tion

appa

rentl

y en

sued

. At

5.3

0 p.m

. on

Ju

ly 20

,0.2

cc.

of a

24-h

our

bouil

lon

cultu

re

was

given

su

bcutk

eous

ly.

Anim

al die

d at

12.3

0 p.m

. Ju

ly 27

.

TABL

E VI

I..

Rabb

it 0.

TOTb

L N UR

Eh N

ux**

N

CRlb

T-

nmo3

N ,


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TABL

E VI

II.

Rabb

it P.

I T&

AL

. N

&A N

gra?

n*

0.68

0.86

0.75

0.92

-~ gr

ams

0.57

0.59

0.61

0.68

mpn

s.

35.1

35.1

35.1

35.1

DATE

BO

DY

CAR

RO

T 19

11

WEI

OH

T D

lET

8P.

OR.

IIRE.

N p.

m.

*An.

_-

Ju

ly kg

ms.

pr

nms

“C.

‘C.

ce.

per

cent

pe

r ce

nt 9

2.56

500

39.5

39.5

305

1.02

1 88

5.2

10

2.3

4 50

0 40

.0 23

5 1.

026

69

4.1

11

2.37

500

41.1

39.2

305

1.02

0 81

4.7

12

2.3

8 50

0 40

.0 39

.6 26

5 1.

025

74

3.8

Aver

age

g-12

.. 28

2 1.

023

76

__-

13

2.36

’ 50

0 46

.2 40

.3 30

0 1.

023

77

14

2.40

500

39.7

39.2

325

1.02

4 74

15

2.3

6 50

0 39

.7 40

.6 30

6 1.

019

75

16

2.32

300

41.9

41.9

325

1.01

9 77

17

2.2

2 10

0 41

.9 41

.7 10

7 1.

020

77

18

2.17

0 41

.3 i

29

77

----.

Rabb

it P

rece

ived

0.2

cc.

of the

us

ual

cultu

re

subc

utane

ously

at

5 p.m

. Ju

ly 12

and

die

d du

ring

the

night

of

July

17.

0.80

0.61

55.1

0.85

0.83

0.59

1.05

1.07

0.26

0.65

0.61

0.44

0.81

0.82

0.20

35.1

35.1

27.0

39.7

40.5

16.7

4.4

0 Q

~___

4.1

0 4.2

0

4.6

0 3.8

0

3.8

0 6.4

0

-


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DmTE

19

11

July 17

18

19

20

Aver

age

9-29

21

22

23

24

25

26

27

28

29

--

--

-

_-

--

-

303

1.02

0 ~~

325

1.02

1 22

6 1.

025

296

1.02

4 32

0 1.

019

285

1.02

0 17

2 1.

022

75

1.02

7 10

0 1.

040

85

1.02

6

0.56

0.38

_-

--

68

1.57

1.61

1.62

1.57

1.61

1.53

1.54

1.56

1.50

500

500

500

500

300

360

215

225 70

40.0

49.1

40.0

41.2

49.7

42.1

41.4

41.6

41.1

49.2

40.1

40.0

40.9

41.7

41.4

41.1

49.6

38.6

--

0.61

0.44

72

0.59

0.45

76

0.84

0.64

76

0.62

0.48

77

0.71

0.53

75

0.91

0.77

85

0:89

0.74

83

0.92

0.74

80

1.50

1.25

83

- da

ys

8-14

’

19.5

3.5

17.6

2.9

17.6

3.0

20.2

2.4

21.3

3.4

21.7

3.1

26.4

2.9

25.1

2.8

25.1

2.7

26.3

11.8

- Ra

bbit

Q re

ceive

d 5

cc.

of the

us

ual

bouil

lon

cultu

re

by

mout

h at

5 p.m

. Ju

ly 12

on

an

empty

sto

mach

, bu

t no

inf

ectio

n fo

llowe

d.

On

July

21 t

he

anim

al wa

s giv

en

a su

bcuta

neou

s inj

ectio

n of

0.2

cc.

of the

cu

lture

. Ra

bbit.

died

July

29.

BOD

Y W

EIO

ET

kps.

1.63

1.60

1.59

1.59

gmm

.9

509

500

500

560

-

TABL

E IX

.

Rabb

it Q.

cc.

265

1.03

0 34

3 1.

018

342

1.01

9 33

0 1.

029

- -_

‘Y

gram

a

0.76

0.46

0.65

0.54

- UR

EI

N

gram

s

0.51

0.32

0.50

0.41

__-

URE.

4 N

per

cent

67

70

77

76

nt


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V. C. Myers and G. 0. Volovic

c T

--

--

P ’

p.m. a.m.

July and kgms. August 31 1.87 1 1.74 2 1.57 3 1.70 4 1.65 5 1.62

Average 31-5. . .

!lmms “C. “C.

309 39.8 39.0 309 39.5 39.3 350 39.6 39.1 350 39.9 39.0 350 39.3 39.5 350 39.6 39.5

6 1.64 250 40.9 41.1 7 1.56 120 41.0 41.7 8 1.41 110 41.7 43.6 9 1.42 240 39.0 39.1

10 1.52 350 39.2 39.5 11 1.58 350 39.3 39.6

7

v -

-

T

CB&.vr ININE

N --

wmza mgms per cant

236 268 230 242 300 225

_- 250

-- 85 40 30 73

183 305

1.017 0.67 1.017 0.84 1.018 0.68 1.018 0.64 1.016 0.68 1.017 0.74 ____ 1.017 0.71

22.0 3.3 27.0 3.2 23.0 3.4 24.7 3.9 27.4 3.7 27.4 4.0

-- 24.6 3.5

1.023 0.41 23.8 5.8 1.027 0.82 30.6 3.7 1.030 0.99 32.1 3.2 1.031 1.07 28.7 2.7 1.018 0.72 21.2 2.9 1.016 0.70 20.8 3.0

- Rabbit 45 was placed in the incubator on the morning of Augur 3t 5 and

kept there continuously for three days, except for about one hour each morning. During the incubator period the animal drank a smal1 amount of water. The first day, after being removed from the incubator the rabbit appeared sick, but was apparently normal on the following day.

TABLE X.

Rabbit &5.30

503

80 In this last series of experiments we were assisted by Mr. Adolph Bern- hard.


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TABLE XI.. Rabbit 47.

mpms. per cent 20.3 7.5 19.6 5.9 16.0 6.5 18.4 4.2 19.2 5.8

18.7 5.5

23.2 7.0 25.9 4.2 26.9 3.7 21.5 2.6 20.1 4.6

DATE BODY CARROT TEMPERATTUBE

1913 WEIGHT DIET p.m. a.m.

~--- January kgms. grams ‘C. “C.

16 1.58 320 39.4 39.0 17 1.59 340 39.6 39.0 18 1.59 325 39.5 39.0 19 1.56 350 39.7 38.7 20 1.60 350 38.7 39.0

-a--- Average 16-20.

-__-__ 21 1.48 110 41.2 40.6 22 1.35 35 40.2 41.7 23 1.33 0 41.6 41.4 24 1.46 200 39.4 38.0 2.5 1.56 310 38.0 39.1

___- cc. pnmn8

225. 1.012 0.27 235 1.012 0.33 270 1.010’ 0.31 268 1.013 0.44 200 1.010 0.33

-_____ 240 1.011 0.34

-~- 58 1.018 0.33 28 1.028 0.62 25 1.028 0.73 40 1.030 0.82

140 1.020 0.44

Rabbit 47 was placed in the incubator at 2 p.m. on January 20 and kept there continuously, except for the time necessary to take temperatures, etc., until 9 a.m. on the 23rd. On the last two of these three days the reaction of the urine was observed to be acid.

TABLE XII. Rabbit 49.

350 80 50

350 350

---

kgm.

1.36 1.32 1.32 1.34 1.42

1.39 1.26 1.29 1.36 1.45

cc.

290 315 230 245 180

.- 252

.- 220 30 35

295 109

m!lm

18.4 21.1 18.3 20.0 16.4

-i(

-,- .li

--

per cent

15.3 11.1 8.0 7.1 7.5

9.0

21 .i 6.1 18.8 8.5 24.1 3: 3 21.4 3.6 15.0 7.9

I” DATTE 1913

January 16 17 18 19 20

Average 16-20

21 22 23 24 25

“C.

39.7 39.7 40.0 39.7 38.1

42.0 40.7 41.5 38.9 39.1

.-

39.1 42.1 41.5 39.0 39.1

Rabbit 49 was placed in the incubator at 2 p.m. on January 23. The temperature at 8.45 p.m. wss found to be 42.1”C., and it was thought best to remove the animal to the room. The next morning (22nd) the rabbit was again placed in the incubator and kept there for the two followingdays.


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V. C. Myers and G. 0. Volovic

Discussion.

The results of the foregoing experiments can most advantage- ously be discussed together. The parallel between the body temperature and the total nitrogen, urea, and creatinine is quite strik- ing, though in considerable measure probably due to the shortness of the fever, generally five to eight days. In all cases ,the highest elimination of nitrogen has been found to coincide with the highest temperature. The relation between the total nitrogen and urea, as shown by the percentage of urea nitrogen, does not markedly differ from the normal. In general, during the fever p&iod there was a slight increase in the per cent of urea nitrogen. At the height of the fever this was sometimes accompanied by a still further increase, and in other cases by a decrease.

The relation between the body temperature and the amount of the creatinine elimination is most interesting. As soon as the body temperature rises noticeably above the normal level, there is an accompanying increase in the excretion of creatinine, and with a decline in the febrile temperature there is an immediate fall. Though, in general, the creatinine follows the increased total nitrogen excretion, there is a very noticeable lag at the height of the fever, the average figures disclosing a fall of from 3.8 per cent to 3.3 per cent in terms of total nitrogen. The maximum temperature, about 42”C., was found to be accompanied by the highest creatinine elimination, the percentage increase over the control elimination averaging 36 per cent-64 per cent in one case-as recorded in Table XIII.

Creatine was generally found to be eliminated after the crisis of t,he disease. This was also the case in one other experiment not reported, Rabbit L. The recent experiments of Myers and Fine31 on starving rabbits make it evident that the creatine of the urine, at least in that condition, has the origin generally assumed, viz., from the setting free of creatine in the absorption of muscle tissue. Though creatine may be an index as to the amount of a certain kind of abnormal catabolism, the creatine itself bears no uniform relation to the endogenous total nitrogen excretion.

To secure further light on the factors causing the increased elimination of creatinine during fever, three animals were placed in a

3L Myers and Fine: Proc. Sot. Exp. Biol. and Med., x, p. 12, IWZ.


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large incubator at about 38.5”C. As is well known, the rabbit is easily susceptible to external changes in temperature and in this way a typical hyperthermia was easily produced with maximum temperatures varying between 41.7“ and 43.3”C.

As is shown in Tables X, XI and XII, the rise in temperature here was likewise found to be accompanied by an increased elimination of creatinine, the maximum output being noted on the day of the highest temperature. The increased excretion was of the same intensity as that observed in the previous series of experiments. It is of interest to note that here no creatine was found to appear in the urine, possibly indicating that there was no abnormal destruction of muscle tissue. Inasmuch as no creatine was found no tabulation was made. The maximum total nitrogen excretion in this series did not appear at the time of the highest temperature, but on the day following. The coincidence in the previous series finds probable explanation in the fact that the highest temperature and the highest total nitrogen just preceded the premortal fall.

TABLE XIII.

EXPERIMENT

_.- - -

A C H I K iv 0

i

grams

0.53 0.83 0.85 1.04 0.89 1.33 0.53 0.91 0.85 1.65 0.80 1.07 0.56 1.50

-7

?ngms. Wm.

17.2 22.2 25.4 39.4 25.5 35.4 26.9 34.7 30.6 38.3 24.6 32.4 29.2 47.9 35.1 40.5 19.5 26.4

Average increased excretion of creatinine . . . . . . . . . . . . . . . . .

45 0.71 1.07 24.6 32.1 47 0.34 0.82 18.7 26.9 49 0.21 0.72 18.8 24.1

Averageincreaaed excretion ofcreatinine................. .I -

- INCRE**ED

CBENTTININE BXCBETION DUE

TO FEYER -

per cent

29 55 39 29 25 32 64 15 35

~.

36

31 44 28

34


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In the above table are summarized the more important data in connection with the excretion of creatinine. Percentage figures for the increased excretion of total nitrogen during the height of the fever are not given owing to the fact that it appeared impossible to compute reliable figures. During the control period a number of the animals showed a plus nitrogen balance, with nitrogen in- takes varying between 0.6 and 0.7 gram. F,urthermore, during the fever period, they were burning increased amounts of their own tissue due in part to the decreased food intake. However, it appears that there was a greater increase in the excretion of nitrogen during pyrexia in the first series of experiments than in the second.

CONCLUSIONS.

The excretion of creatinine closely follows the rise in temperature during fever, whether the hyperthermia is of infective origin or artificially induced. The highest continued temperature (about 42°C.) has been found to be accompanied by the highest creatinine elimination.

In nine experiments on rabbits inoculated with Bacillus suipesticus, the percentage increase at the height of the fever over the control elimination averaged 36 per cent. In three experiments, where hyperthermia was artificially induced, the average increase was 34 per cent. This is believed to show that the increased elimination of creatinine is due entirely to the hyperthermia.

The view is expressed that the increased creatinine elimination during fever still represents the normal endogenous metabolism, which is proceeding here at an abnormal intensity due to the high temperature. It is possible that this is in accord with the law of the increased velocity of chemical reactions at increased temperatures.

It is suggested that the amount of the increased creatinine excretion may be of value in indicating the increase in nitrogenous metabolism due to simple pyrexia. The increased excretion of nitrogen in physiological fever corresponds very well with the increased excretion of creatinine (35 per cent), but in toxic fevers the excretion of nitrogen may be much greater.

In the series of toxic fevers, creatine was generally found to be excreted, and when present was observed, as a rule, following the


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crisis of the fever. In the series of physiological fevers an elimination of creatine was not detected. It is reasonable to believe that creatine is excreted during fever, because the protein is drawn upon to supply unusual demands (e.g., to supply energy in the absenc’e of carbohydrate), and in this abnormal catabolism, creatine is set free more rapidly than the body can oxidize it.

In fever, creatinine, though increased, still appears to indicate the amount of a certain type of normal endogenous metabolism, while creatine possibly indicates the amount of abnormal endogenous metabolism.


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Victor C. Myers and G. O. VolovicELIMINATION OF CREATININE

THE INFLUENCE OF FEVER ON THE

1913, 14:489-508.J. Biol. Chem.

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THE INFLUENCE OF FEVER ON THE ELIMINATION OF