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Determination of sodium24 “Space” in infants,children, and adults
D E T E R M I N A T I O N O F SODIUM 24 " S P A C E " C H I L D R E N , AND A D U L T S *
IN INFANTS,
ANNE PERLEY, M.A., GILBERT B. FORBES, M.D., AND MIRIAM M. PENNOYER, M.D.** ST. LOUIS, MO. INTRODUCTION
T U D I E S of the a p p a r e n t volume of distribution of radioactive sodium 24 in man (sodium " s p a c e " ) have been made by a n u m b e r of investigators. Kaltreider, Meneely, Alien, and Bale 1 in 1941 r e p o r t e d observations on the fluid available for the distribution of Na 24 over periods of 3, 6, 9, and 12 hours, and applied eertain corrections to the 6-, 9-, and 12h o u r values for exchange of Na 24 with excess sodium in the skeleton. Sulfocyanate space was d e t e r m i n e d simultaneously. Moore * in 1946 rep o r t e d measurement of the various fluid c o m p a r t m e n t s in m a n by the isotopic method, giving a singie value for radio-sodium volume in an adult. The period allowed for distribution was not stated. F l e x n e r and associates ~ measured sodium space in three n e w b o r n infants 21/2 to 3 hours a f t e r injection of N a f t Changes in thiocyanate and sodium spaces during growth were r e p o r t e d b y Fellers, Barnett, Hare, and McNamara 4 in 1949. T h e y observed the sodium spaces occupied between 2 ~ and 4 hours a f t e r injection of the Na 24 in t h i r t y - t w o infants and children and in five adults.
S
In this paper we are r e p o r t i n g estimations of the fluid t h r o u g h which Na 24 is r a p i d l y distributed (sodium " s p a c e " ) in nineteen adult males and thirty-seven infants and children, and have e x t e n d e d the observations to smaller p r e m a t u r e infants t h a n those hitherto reported. The measurements were made f r o m la~ to 4 8 9 hours a f t e r intravenous injection of the Na 24. METHODS
Most of the infants studied were healthy n e w b o r n babies in the St. Louis M a t e r n i t y Hospital. The remaining infants and the older child r e n were patients o n the wards of the St. Louis Children's Hospital and were free from cardiac, renal, or allergic diseases. Their general nutritional and physical condition was good. None of them was receiving fluid therapy. The adult subjects ineluded medical students and members of the resident house staff. T h e y were all in good health. Radioactive Na 24, half-life 14.8 hours, was p r e p a r e d in the Washington University cyclotron b y deuteron b o m b a r d m e n t of metallic sodium; in our l a b o r a t o r y the material was conv e r t e d to the chloride, and sufficient w a t e r was added to r e n d e r the solu-. tion isotonic. I t was then autoclaved and diluted with sterile saline to the p r o p e r activity. The material was injected intravenously, using the method described b y B a r n e t t and Fellers ~
F r o m the D e p a r t m e n t of Pediatrics, W a s h i n g t o n U n i v e r s i t y School o f M e d i c i n e ; t h e St. L o u i s C h i l d r e n ' s H o s p i t a l , a n d t h e St. L o u i s Maternity Hospital. T h e cooperation of the Cyclotron Group a t W a s h i n g t o n U n i v e r s i t y is g r a t e f u l l y a c k n o w l edged. 9T h i s w o r k w a s c a r r i e d o u t u n d e r g r a n t s from the Children's Research Foundation and the United States Atomic Energy Commission. 9*Fellow of the A m e r i c a n College of P h y sicians d u r i n g the period of this study. 299
300
THE JOURNAL OF PEDIATRICS TABLE
SUBJECT Fo. He. B. He. A. Da. Do. Pe. MeCr. We. Tr. Fr, Be. AI. Is. Tit. Mi. Ca. G1. Br. Ad. B1. Ma. Bo. t{a. Pa. Lu. Sp. Av. E.H. R.S. G.J. S.P. S. McF. E.R. B.T. C.M. L. ~ e K .
SEX M F F M F F M F M M F F M F F M M M M IK IV[ IVi M F F F M M iV[ F M M M F IV[
I.
~ODIUIVf ~ ~ SPACE t J I N
AGE 22 da. 7 da. 7 da. 16 da. 15 da. 15 da. 15 da. 4 da. 21 da. 4 da. 5 da. 6 da. 5 da. 7 da. 8 da. 1 da. 4 da. 3 da. 3 da. 3 da. 7 da. 6 da. 2 da. 3 da. 16 hr. 13 wk. 6 da. 8 da. 10 wk. 10 wk. 14 too. 13 too. 22 me. 3 yr. 3} yr: 10 yr. 14 yr.
for the q u a n t i t a t i v e a d m i n i s t r a t i o n of small volumes of fluid. The volume of Na 24 solution injected was usually 1.0 c.c., r a r e l y 2.0 c.c., and the volume of wash solution was 3 c.c. The quant i t y of Na 2~ given to these subjects r a n g e d f r o m 1 to 11/2 microcuries per k i l o g r a m of b o d y w e i g h t ; this a m o u n t has been c o m p u t e d to deliver a total dose of f r o m 0.11 to 0.17 r o e n t g e n s equivalent physical in the adult2 Venous blood samples were drawn, at the times to be stated, f r o m a vein other t h a n the one used for the injection. The s e r u m was s e p a r a t e d f r o m the clot within one hour a f t e r collec-
INFANTS
WEIGHT (Ka.) 1.70 1.87 1.87 1.98 2.04 2.12 2.33 2.34 2.42 2.43 ~.48 2.52 2.57 2.57 2.61 2.89 3.02 3,02 3.06 3.17 3.18 3.23 3.25 3.35 3.37 3.65 3.78 4.57 4.86 6.00 6.96 9.45 11.6 15.4 18.4 23.9 56,8
AND
CHILDREN
TIZfE A F T E g INJECTION
2 3 3 2 3 2 2 3 ~ 3 3 2 3 1 2 1 1 4 4 4 3 3 2 3 1 2 2 2 2 2 3 2 2 2 1 2 2
hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr.
50 0 26 14 9 51 49 20 0 23 28 38 31 50 48 40 58 17 25 29 18 19 10 35 44 6 39 13 15 10 17 59 58 19 48 26 44
rain. rain. rain. rain. rain. rain. min. mln. min. min. rain. min. rain. min. mln. rnin. 'min. mln. mira min. mill. rain. rain. rain. rain. rain. rain. rain. rain. rain. min. rain. rain. rain. rain. rain. mln.
NA g~SPACE ' ' PER CENT BODY WT. 51.5 43.2 44.8 39.3 48.7 49.9 43.7 49.8 36.5 33.2 38.0 39.6 33.8 41.3 38.5 35.5 33.2 34.6 39.6 39.2 31.1 34.4 34.0 28.2 32.8 40.0 35.6 33.4 43.4 32.5 35.2 27.9 23.2 33.8 31.4 31.3 28.9
tion. One cubic centimeter amounts of serum, usually in duplicate, were t r a n s f e r r e d to m e t a l planchets, "~ 33 ram. in d i a m e t e r containing a drop of " a c i d o l a t e " to facilitate spreading, and the samples were dried in the oven at 70 ~ to 80 ~ C. Suitable allquots of the Na 24 solutions were prep a r e d in the same w a y in duplicate or triplicate. Urine samples were prep a r e d similarly. An end window Geiger tube with autoscaler was used in m e a s u r i n g the activity. The counting periods for most of the serum *In t he e a r l i e r studies, w a t c h g l a s s e s or porcelai n c a ps ul e s w e r e used for m o u n t i n g the samples.
PERLEY
ET A L . :
DETERNHNATION
TABLE I I .
SUBJECT H . M. ( 1 )
H. M. (2) W.D. I).B. W.G. B.H. M.C. R.B. R.B. J . Me. S.S.
L.I(. R.M. R.G. V.T. A.R. J.R. P.J. A. H. E.C.
AGE (YR.) 29 29 28 22 25 25 23 24 28 24 25 27 23 24 34 26 29 24 28 23
SODIUIV[ ~~SPACE' ' IN ADULT I~[ALES
WEIGHT (KG.) 58.3 60.6 66.2 67.3 68.1 71.8 71.8 73.5 73.9 73.9 74.1 74.4 75.6 75.4 75.4 77.6 77.8 84.8 91.6 100.0
TI1Vs AFTER INJECTION 3 h r . 11 r a i n . 3 h r . 40 r a i n . 3 hr. 0 rain. 3 hr. 2 rain. 2 h r . 52 r a i n . 3 h r . 36 r a i n . 3 h r . 15 m i r a 3 h r . 41 r a i n . 3 h r . 17 m i n . 3 h r . 30 m i n . 3 h r . 30 r a i n . 3 hr. 0 min. 3 h r . 43 r a i n . 2 h r . 45 r a i n . 3 h r . 30 m l n . 3 hr. 0 rain. 3 hr. 0 mira 3 hr. 44 min. 3 h r . 16 r a i n . 3 h r . 46 r a i n .
Average TABLE I I I .
301
OF S O D I U M 24 " S P A C E ~'
PEg CENT ADMINISTERED NA24 EXCRETED DUllING DISTRIBUTION PERIOD 1.1 2.3 1.2 0.3 0.3 0.2 1.2 1.3 1.3 1.6 0.4 1.0 1.8 0.8 1.3 2.1 1.2 0.6 0.9 1.7 1.1
NA ~~SPACE ' ~ PER CENT BODY "WT. 19.7 27.4 26:4 27.1 35.8 21.5 24.] 20.6 26.1 25.8 28.6 25.4 27.4 30.5 20.8 27.6 24.4 20.2 23.5 20.8 25.2
SUMMARY OF SODIU1V[ ~' SPACE' ~ IN INFANTS, @HILDRENt AND .~.DULTS
RANGE OF WEIGIIT (KG.) 1.70- 1 . 9 8 2.04- 2.48 2.52- 2 . 8 9 3.02- 3 . 7 8 4.57- 6.96 9.45- 18.4 23.9 - 56.8 58.3 - 1 0 0 . 0
NO. SUBJEGTN 4 7 5 11 4 4 2 19
samples were of such length t h a t the statistical v a r i a t i o n due to r a n d o m fluctuations of r a d i o a c t i v e emission was +3 per cent or less ( s t a n d a r d deviation). The volmne of distribution of Na 24 at a n y given time was c o m p u t e d by dividing the q u a n t i t y of the Na 2~ injected ( c o r r e c t e d for u r i n a r y loss d u r i n g the period of equilibration in the ease of adults) by the q u a n t i t y in 1.0 e.c. of serum. Correction was not m a d e for the D o n n a n effect, for the w a t e r content of the serum, or for the volume of fluid injected when the N a ~4 w a s given.
RAlXrGE OF NA ~' SPACE ~~ 9PEg CENT OF BODY WT. 39.8-51.5 33.2-49.9 33.8-41.3 28.2-40.0 32.5-43.4 23.2-33.8 28.9~31.3 19.7-35.8
1ViEAN 44.8 42.8 37.7 34.8 36.1 29.1 30.1 25.2
RESULTS
The values for sodium " s p a c e " in thirty-seven infants and children ranging in age f r o m 16 hours to 14 years are given in Table I. T h e y varied f r o m 23.2 to 51.7 per cent of body weight. The results of %wenty determinations on nineteen adult males f r o m 22 to 34 y e a r s of age are to be f o u n d in Table II. The sodium " s p a c e " r a n g e d f r o m 19.7 to 3518 per cent of the b o d y Weight and averaged 25.2 per cent., A s u m m a r y of the values for the different weight ranges is given in Table I I I . The values f o r sodium " s p a c e " for all the
302
THE
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OF PEDIATRICS
VALUES FOR SODIUM "SPACE" IN INFANTS CHILDREN AND ADULTS
9 infants and children X odults
~= 40
~o
9
9
Xx 9
x =
x
-= x
9
x x=
x x
I0
* K)
t 20
l 30
t 40
! 50
| 60
l 70
! 80
Weight in KilOgram= :Fig,
VALUES
FOR SODIUM
"SPACE"
IN
1.
PREMATURE
AND
FULL-TERM
NEWBORNS
50
00 c
o9 =.
"8
~o qb e
30
20
10
i
l
i
I
!
1.0
2.0
3,O
4.0
5.0
Weight
in K i l o g r o m s
Fig.
2.
!
so
f IOO
PERLEY
ET
AL. :
DETERMINATION
subjects listed in Tables I and II are plotted in Fig. 1. Fig. 2 shows the values for only the newborn infants, including both fu]Lterm and premature infants. In the small weight range covered here, striking differences are to be seen in the sodium " s p a c e . " The highest values with respect to weight occur in the very small infants. 50
OF S O D I U M 2~ " S P A C E '~
303
cellular fluid. During the period of time which must be allowed for the distribution of sodium 2~ through the extracellular fluid, there is probably some passage of sodium into nonextracellular compartments, particularly intracellular fluid and bone2, 7 On the other hand, sodium is distributed less rapidly through spinal fluid than through other portions of
CHANGES IN APPARENT VOLUME OF DtSTRIBUT[ON OF SODIUM24 FOLLOWING (NTRAVENOUS INJECTION
9 children x adults
4C
g 7,
I I
f 2
I
i
i
|
3
4
5
6
Hours otter Injection
Fig.
DISCUSSION
i n determining sodium " s p a c e " by the procedure which we have described we have measured the volume of fluid in the body with which sodium exchanges readily, that is, int o which and out of which sodium passes rapidly. This determination, however, does not necessarily afford a measure of the volume of extra-
3.
the extracellular compartment, about 12 hours being required for equilibrium to be established between serum and spinal fluid as observed by Kaltreider and collaborators. 1 These authors also postulate that sodium may penetrate comparatively slowly into the extracellu]ar spaces of central nervous system tissue. Manery and Bale also are of this opinion/
~0~
THE JOURNAL OF PEDIATRICS
The periods allowed for the distribution of Na ~4 in the observations made by other workers have already been mentioned. I n our studies on infants and children, the time allowed r a n g e d ' f r o m 1 hour 40 minutes to 41/2 hours, l~ig. 3 gives the a p p a r e n t volume of distribution of Na 24, eomp u t e d as per cent of body weight, plotted against time in a n u m b e r of subjects from whom two or more blood samples were eolleeted a f t e r the injection of Na 2~. It m a y be seen that in the infants observed, d u r i n g the period between 1 and 13~ hours after the injection, there is a sharp rise in the a p p a r e n t volume of distribution, but between the latter time and 41/2 hours the curves flatten, and the change in the a p p a r e n t volmne is slight, indicating t h a t the end of the rapid phase of mixing has been reaehed. In f o u r eases the a p p a r e n t volume increased 0.5 per cent, 1.5 per cent, 0.3 per cent, and 9.1 per eent, respectively, d u r i n g this time; in a fifth the value decreased 1 per eent. We conclude, therefore, t h a t in infants and children the volume of fluid with which sodium exchanges readily m a y be a p p r o x i m a t e d at any time between 1 hour 40 minutes and 4 8 9 hours, a f t e r the Na 2~ has been injeeted intravenously. In the adults r e p o r t e d in Tabl~ II, the period allowed for equilibration was between 2 ~ and 3 ~ hours. In Fig. 3 are plotted the a p p a r e n t volumes of d i s t r i b u t i o n against time in six subjects on whom more t h a n one blood sample was drawn between 1 hour 52 minutes and 3 hours a f t e r the injection. The increases ill a p p a r e n t volume amounted to 4.5 per cent, 5.4 per cent, 11 per cent, 2 per cent, 5 per cent, and 2.4 per cent, respee-
tively. In this period of time the app a r e n t volume of distribution of Na 24 is increasing v e r y little and, therefore, would serve to estimate the volume of fluid available for distribution of readily exchangeable sodium. In the adult subjects, the excretion of Na 24 during the period allowed for distribution was measured, and the values m a y be seen in Table II. The loss a f t e r injection, d u r i n g periods of from 23~ to 3 ~ hours, r a n g e d from 0.3 to 2.3 per cent of the a m o u n t given and averaged 1.2 per cent. In eomp u t i n g the sodium "space" in adults, a correction was made for this loss in each instance, but it is a p p a r e n t that the results are not significantly affeeted. In the infants and children studied, estimation of and correction for the u r i n a r y loss was not made since collection of urine over these short periods was not feasible. Other methods which have been used in an a t t e m p t to measure extracellular fluid in man also have certain disadvantages as pointed out by Kaltreider and associates. 1 Sucrose, while having the a d v a n t a g e of ~eing a nonelectrolyte, is u n s a t i s f a c t o r y beeause it is quite r a p i d l y excreted. The same objection applies to sulfate. Thioeyanate, while r a p i d l y distributed and slowly excreted, diffuses into the red blood cells and into the eells of certain glandular organs~ Nevertheless, measurements of the sodium " s p a c e " and thioeyanate space provide useful relative values. Our finding t h a t the sodium " s p a c e " computed as per cent of body weight is considerably higher in young" infants t h a n in older children and adMts confirms the observations of Fellers and co-workers2 F r o m Table I it is a p p a r e n t that the
PERLEY ET AL. : DETERMINATION OF SODIU1V[24 "SPACE ~'
average, sodium " s p a c e " in eleven p r e m a t u r e newborn infants is higher t h a n in the sixteen full-term newborn infants, being 43.5 per cent of the body weight in the f o r m e r group and 35.3 per cent in the latter. Harrison, Darrow, and Yannet, s using the chloride analyses of Iob and Swanson, 9 have computed "extracellular f l u i d " contents of fetuses and obtained a value of 62 per cent of body weight on a 5-month fetus with values decreasing to 43 per cent of b o d y w e i g h t on one which was practically full term. Our observations on children from 1 to 14 years of age are too few to bear analysis, but the s o d i u m "spaces" are appreciably lower t h a n those of y o u n g infants, averaging 30.2 per cent. Fellers and collaborators 4 observed a period of relative constancy between early i n f a n c y and adolescence with a small decline during adolescence. Our sodium "spaces" on adults v a r y widely as do those of K a l t r e i d e r and associates, ~ but the average of 25.2 per cent of body weight compares well with their mean of 24.8 per cent and with t h a t of 27.1 per cent r e p o r t e d b y Fellers and coworkers 4 and the single value of 26.5 per cent obtained b y Moore2 SUMMARY AND CONCLUSIONS
1. The volume of fluid t h r o u g h which radioactive sodium 24 is rapidly distributed (sodium " s p a c e " ) has been measured in thirty-seven infants and children and in nineteen adult males. 2. The period allowed for distribution of Na sA r a n g e d from 13/~ to 41/2 hours.
305
3. ]n eleven p r e m a t u r e infants the sodium " s p a c e " a v e r a g e d 43.5 per cent of body weight, and in 16 fullt e r m n e w b o r n infants 35.2 per cent. In seven children from 1 to 14 years of age, the values a v e r a g e d 30.2 per cent, and in nineteen adult mafes 25.2 per cent. 4. Although the sodium " s p a c e " computed as per cent of body weight varied considerably i n given weight ranges, the data indicate t h a t the volrune of fluid occupied by sodium in relation to b o d y weight declines as growth proceeds. REFERENCES 1. Kaltreider, 1~. L., Meneely, G. R., Allen, J. R., and Bale, W. F. : Determination of the Volume of Extraccllular Fluid of the Body With Radioactive Sodium, J. Exper. ~ e d . 74: 569, 1941. 2. Moore, D. F.: D e t e r m i n a t i o n of Total Body W a t e r and Solids W i t h Isotopes, Science 104: 157, 1946. ' 3. Flexner, L. B., Wilde, W. S., Proctor, N. K., Cowie, D. B., Vosburgh, G. J., and Heilman, L. M.: Estimation of Extracellular and Total Body W a t e r in the Newborn Human Infant With l~adioactive Sodium and Deuterium Oxide, J. PEDIAT. 30: 413~ 1947. 4. Fellers, F. X., Barnett, H. L., Hare, X., and ~ c N a m a r a , H.: Changes in Thiocyanate and Sodinm2~ Spaces During Growth, Pediatrics 3: 622, 1949. 5. B a r n e t t , H. L., and Fellers, F. X.: A Simple Q u a n t i t a t i v e Method for I n t r a venous I n j e c t i o n of Small Volumes of Fluid, Science 106: 401, 1947. 6. ]~[arineltl, L. D., Quimby, F. H., and Hine, G . J . : Dosage D e t e r m i n a t i o n W i t h Radioactive Isotopes. II. P r a c t i c a l Consideration in Therapy a n d Protection, Am. J. Roentgenol. 59: 260, 1948. 7. Manery, J. F., and Bate, W. F.: The P e n e t r a t i o n of ]~adioactive Sodium and Phosphorus Into t h e Extra- and Intracellular Phases of Tissues, Am. J. Physiol. 132: 215, 1941. 8. Harrison, I-I] E., Barrow, D. C., and Yannet, H.: The Total Electrolyte Content of Animals and Its Probable Relation to Distribution of Body Water~ J. Biol. Chem. 113: 515, 1936. 9. Iob, V., and Swanson, W. W.: Mineral Growth of Human Fetus, Am. J. Dis. Child. 47: 302, 1934.
IN INFANTS,
ANNE PERLEY, M.A., GILBERT B. FORBES, M.D., AND MIRIAM M. PENNOYER, M.D.** ST. LOUIS, MO. INTRODUCTION
T U D I E S of the a p p a r e n t volume of distribution of radioactive sodium 24 in man (sodium " s p a c e " ) have been made by a n u m b e r of investigators. Kaltreider, Meneely, Alien, and Bale 1 in 1941 r e p o r t e d observations on the fluid available for the distribution of Na 24 over periods of 3, 6, 9, and 12 hours, and applied eertain corrections to the 6-, 9-, and 12h o u r values for exchange of Na 24 with excess sodium in the skeleton. Sulfocyanate space was d e t e r m i n e d simultaneously. Moore * in 1946 rep o r t e d measurement of the various fluid c o m p a r t m e n t s in m a n by the isotopic method, giving a singie value for radio-sodium volume in an adult. The period allowed for distribution was not stated. F l e x n e r and associates ~ measured sodium space in three n e w b o r n infants 21/2 to 3 hours a f t e r injection of N a f t Changes in thiocyanate and sodium spaces during growth were r e p o r t e d b y Fellers, Barnett, Hare, and McNamara 4 in 1949. T h e y observed the sodium spaces occupied between 2 ~ and 4 hours a f t e r injection of the Na 24 in t h i r t y - t w o infants and children and in five adults.
S
In this paper we are r e p o r t i n g estimations of the fluid t h r o u g h which Na 24 is r a p i d l y distributed (sodium " s p a c e " ) in nineteen adult males and thirty-seven infants and children, and have e x t e n d e d the observations to smaller p r e m a t u r e infants t h a n those hitherto reported. The measurements were made f r o m la~ to 4 8 9 hours a f t e r intravenous injection of the Na 24. METHODS
Most of the infants studied were healthy n e w b o r n babies in the St. Louis M a t e r n i t y Hospital. The remaining infants and the older child r e n were patients o n the wards of the St. Louis Children's Hospital and were free from cardiac, renal, or allergic diseases. Their general nutritional and physical condition was good. None of them was receiving fluid therapy. The adult subjects ineluded medical students and members of the resident house staff. T h e y were all in good health. Radioactive Na 24, half-life 14.8 hours, was p r e p a r e d in the Washington University cyclotron b y deuteron b o m b a r d m e n t of metallic sodium; in our l a b o r a t o r y the material was conv e r t e d to the chloride, and sufficient w a t e r was added to r e n d e r the solu-. tion isotonic. I t was then autoclaved and diluted with sterile saline to the p r o p e r activity. The material was injected intravenously, using the method described b y B a r n e t t and Fellers ~
F r o m the D e p a r t m e n t of Pediatrics, W a s h i n g t o n U n i v e r s i t y School o f M e d i c i n e ; t h e St. L o u i s C h i l d r e n ' s H o s p i t a l , a n d t h e St. L o u i s Maternity Hospital. T h e cooperation of the Cyclotron Group a t W a s h i n g t o n U n i v e r s i t y is g r a t e f u l l y a c k n o w l edged. 9T h i s w o r k w a s c a r r i e d o u t u n d e r g r a n t s from the Children's Research Foundation and the United States Atomic Energy Commission. 9*Fellow of the A m e r i c a n College of P h y sicians d u r i n g the period of this study. 299
300
THE JOURNAL OF PEDIATRICS TABLE
SUBJECT Fo. He. B. He. A. Da. Do. Pe. MeCr. We. Tr. Fr, Be. AI. Is. Tit. Mi. Ca. G1. Br. Ad. B1. Ma. Bo. t{a. Pa. Lu. Sp. Av. E.H. R.S. G.J. S.P. S. McF. E.R. B.T. C.M. L. ~ e K .
SEX M F F M F F M F M M F F M F F M M M M IK IV[ IVi M F F F M M iV[ F M M M F IV[
I.
~ODIUIVf ~ ~ SPACE t J I N
AGE 22 da. 7 da. 7 da. 16 da. 15 da. 15 da. 15 da. 4 da. 21 da. 4 da. 5 da. 6 da. 5 da. 7 da. 8 da. 1 da. 4 da. 3 da. 3 da. 3 da. 7 da. 6 da. 2 da. 3 da. 16 hr. 13 wk. 6 da. 8 da. 10 wk. 10 wk. 14 too. 13 too. 22 me. 3 yr. 3} yr: 10 yr. 14 yr.
for the q u a n t i t a t i v e a d m i n i s t r a t i o n of small volumes of fluid. The volume of Na 24 solution injected was usually 1.0 c.c., r a r e l y 2.0 c.c., and the volume of wash solution was 3 c.c. The quant i t y of Na 2~ given to these subjects r a n g e d f r o m 1 to 11/2 microcuries per k i l o g r a m of b o d y w e i g h t ; this a m o u n t has been c o m p u t e d to deliver a total dose of f r o m 0.11 to 0.17 r o e n t g e n s equivalent physical in the adult2 Venous blood samples were drawn, at the times to be stated, f r o m a vein other t h a n the one used for the injection. The s e r u m was s e p a r a t e d f r o m the clot within one hour a f t e r collec-
INFANTS
WEIGHT (Ka.) 1.70 1.87 1.87 1.98 2.04 2.12 2.33 2.34 2.42 2.43 ~.48 2.52 2.57 2.57 2.61 2.89 3.02 3,02 3.06 3.17 3.18 3.23 3.25 3.35 3.37 3.65 3.78 4.57 4.86 6.00 6.96 9.45 11.6 15.4 18.4 23.9 56,8
AND
CHILDREN
TIZfE A F T E g INJECTION
2 3 3 2 3 2 2 3 ~ 3 3 2 3 1 2 1 1 4 4 4 3 3 2 3 1 2 2 2 2 2 3 2 2 2 1 2 2
hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr.
50 0 26 14 9 51 49 20 0 23 28 38 31 50 48 40 58 17 25 29 18 19 10 35 44 6 39 13 15 10 17 59 58 19 48 26 44
rain. rain. rain. rain. rain. rain. min. mln. min. min. rain. min. rain. min. mln. rnin. 'min. mln. mira min. mill. rain. rain. rain. rain. rain. rain. rain. rain. rain. min. rain. rain. rain. rain. rain. mln.
NA g~SPACE ' ' PER CENT BODY WT. 51.5 43.2 44.8 39.3 48.7 49.9 43.7 49.8 36.5 33.2 38.0 39.6 33.8 41.3 38.5 35.5 33.2 34.6 39.6 39.2 31.1 34.4 34.0 28.2 32.8 40.0 35.6 33.4 43.4 32.5 35.2 27.9 23.2 33.8 31.4 31.3 28.9
tion. One cubic centimeter amounts of serum, usually in duplicate, were t r a n s f e r r e d to m e t a l planchets, "~ 33 ram. in d i a m e t e r containing a drop of " a c i d o l a t e " to facilitate spreading, and the samples were dried in the oven at 70 ~ to 80 ~ C. Suitable allquots of the Na 24 solutions were prep a r e d in the same w a y in duplicate or triplicate. Urine samples were prep a r e d similarly. An end window Geiger tube with autoscaler was used in m e a s u r i n g the activity. The counting periods for most of the serum *In t he e a r l i e r studies, w a t c h g l a s s e s or porcelai n c a ps ul e s w e r e used for m o u n t i n g the samples.
PERLEY
ET A L . :
DETERNHNATION
TABLE I I .
SUBJECT H . M. ( 1 )
H. M. (2) W.D. I).B. W.G. B.H. M.C. R.B. R.B. J . Me. S.S.
L.I(. R.M. R.G. V.T. A.R. J.R. P.J. A. H. E.C.
AGE (YR.) 29 29 28 22 25 25 23 24 28 24 25 27 23 24 34 26 29 24 28 23
SODIUIV[ ~~SPACE' ' IN ADULT I~[ALES
WEIGHT (KG.) 58.3 60.6 66.2 67.3 68.1 71.8 71.8 73.5 73.9 73.9 74.1 74.4 75.6 75.4 75.4 77.6 77.8 84.8 91.6 100.0
TI1Vs AFTER INJECTION 3 h r . 11 r a i n . 3 h r . 40 r a i n . 3 hr. 0 rain. 3 hr. 2 rain. 2 h r . 52 r a i n . 3 h r . 36 r a i n . 3 h r . 15 m i r a 3 h r . 41 r a i n . 3 h r . 17 m i n . 3 h r . 30 m i n . 3 h r . 30 r a i n . 3 hr. 0 min. 3 h r . 43 r a i n . 2 h r . 45 r a i n . 3 h r . 30 m l n . 3 hr. 0 rain. 3 hr. 0 mira 3 hr. 44 min. 3 h r . 16 r a i n . 3 h r . 46 r a i n .
Average TABLE I I I .
301
OF S O D I U M 24 " S P A C E ~'
PEg CENT ADMINISTERED NA24 EXCRETED DUllING DISTRIBUTION PERIOD 1.1 2.3 1.2 0.3 0.3 0.2 1.2 1.3 1.3 1.6 0.4 1.0 1.8 0.8 1.3 2.1 1.2 0.6 0.9 1.7 1.1
NA ~~SPACE ' ~ PER CENT BODY "WT. 19.7 27.4 26:4 27.1 35.8 21.5 24.] 20.6 26.1 25.8 28.6 25.4 27.4 30.5 20.8 27.6 24.4 20.2 23.5 20.8 25.2
SUMMARY OF SODIU1V[ ~' SPACE' ~ IN INFANTS, @HILDRENt AND .~.DULTS
RANGE OF WEIGIIT (KG.) 1.70- 1 . 9 8 2.04- 2.48 2.52- 2 . 8 9 3.02- 3 . 7 8 4.57- 6.96 9.45- 18.4 23.9 - 56.8 58.3 - 1 0 0 . 0
NO. SUBJEGTN 4 7 5 11 4 4 2 19
samples were of such length t h a t the statistical v a r i a t i o n due to r a n d o m fluctuations of r a d i o a c t i v e emission was +3 per cent or less ( s t a n d a r d deviation). The volmne of distribution of Na 24 at a n y given time was c o m p u t e d by dividing the q u a n t i t y of the Na 2~ injected ( c o r r e c t e d for u r i n a r y loss d u r i n g the period of equilibration in the ease of adults) by the q u a n t i t y in 1.0 e.c. of serum. Correction was not m a d e for the D o n n a n effect, for the w a t e r content of the serum, or for the volume of fluid injected when the N a ~4 w a s given.
RAlXrGE OF NA ~' SPACE ~~ 9PEg CENT OF BODY WT. 39.8-51.5 33.2-49.9 33.8-41.3 28.2-40.0 32.5-43.4 23.2-33.8 28.9~31.3 19.7-35.8
1ViEAN 44.8 42.8 37.7 34.8 36.1 29.1 30.1 25.2
RESULTS
The values for sodium " s p a c e " in thirty-seven infants and children ranging in age f r o m 16 hours to 14 years are given in Table I. T h e y varied f r o m 23.2 to 51.7 per cent of body weight. The results of %wenty determinations on nineteen adult males f r o m 22 to 34 y e a r s of age are to be f o u n d in Table II. The sodium " s p a c e " r a n g e d f r o m 19.7 to 3518 per cent of the b o d y Weight and averaged 25.2 per cent., A s u m m a r y of the values for the different weight ranges is given in Table I I I . The values f o r sodium " s p a c e " for all the
302
THE
JOURNAL
OF PEDIATRICS
VALUES FOR SODIUM "SPACE" IN INFANTS CHILDREN AND ADULTS
9 infants and children X odults
~= 40
~o
9
9
Xx 9
x =
x
-= x
9
x x=
x x
I0
* K)
t 20
l 30
t 40
! 50
| 60
l 70
! 80
Weight in KilOgram= :Fig,
VALUES
FOR SODIUM
"SPACE"
IN
1.
PREMATURE
AND
FULL-TERM
NEWBORNS
50
00 c
o9 =.
"8
~o qb e
30
20
10
i
l
i
I
!
1.0
2.0
3,O
4.0
5.0
Weight
in K i l o g r o m s
Fig.
2.
!
so
f IOO
PERLEY
ET
AL. :
DETERMINATION
subjects listed in Tables I and II are plotted in Fig. 1. Fig. 2 shows the values for only the newborn infants, including both fu]Lterm and premature infants. In the small weight range covered here, striking differences are to be seen in the sodium " s p a c e . " The highest values with respect to weight occur in the very small infants. 50
OF S O D I U M 2~ " S P A C E '~
303
cellular fluid. During the period of time which must be allowed for the distribution of sodium 2~ through the extracellular fluid, there is probably some passage of sodium into nonextracellular compartments, particularly intracellular fluid and bone2, 7 On the other hand, sodium is distributed less rapidly through spinal fluid than through other portions of
CHANGES IN APPARENT VOLUME OF DtSTRIBUT[ON OF SODIUM24 FOLLOWING (NTRAVENOUS INJECTION
9 children x adults
4C
g 7,
I I
f 2
I
i
i
|
3
4
5
6
Hours otter Injection
Fig.
DISCUSSION
i n determining sodium " s p a c e " by the procedure which we have described we have measured the volume of fluid in the body with which sodium exchanges readily, that is, int o which and out of which sodium passes rapidly. This determination, however, does not necessarily afford a measure of the volume of extra-
3.
the extracellular compartment, about 12 hours being required for equilibrium to be established between serum and spinal fluid as observed by Kaltreider and collaborators. 1 These authors also postulate that sodium may penetrate comparatively slowly into the extracellu]ar spaces of central nervous system tissue. Manery and Bale also are of this opinion/
~0~
THE JOURNAL OF PEDIATRICS
The periods allowed for the distribution of Na ~4 in the observations made by other workers have already been mentioned. I n our studies on infants and children, the time allowed r a n g e d ' f r o m 1 hour 40 minutes to 41/2 hours, l~ig. 3 gives the a p p a r e n t volume of distribution of Na 24, eomp u t e d as per cent of body weight, plotted against time in a n u m b e r of subjects from whom two or more blood samples were eolleeted a f t e r the injection of Na 2~. It m a y be seen that in the infants observed, d u r i n g the period between 1 and 13~ hours after the injection, there is a sharp rise in the a p p a r e n t volume of distribution, but between the latter time and 41/2 hours the curves flatten, and the change in the a p p a r e n t volmne is slight, indicating t h a t the end of the rapid phase of mixing has been reaehed. In f o u r eases the a p p a r e n t volume increased 0.5 per cent, 1.5 per cent, 0.3 per cent, and 9.1 per eent, respectively, d u r i n g this time; in a fifth the value decreased 1 per eent. We conclude, therefore, t h a t in infants and children the volume of fluid with which sodium exchanges readily m a y be a p p r o x i m a t e d at any time between 1 hour 40 minutes and 4 8 9 hours, a f t e r the Na 2~ has been injeeted intravenously. In the adults r e p o r t e d in Tabl~ II, the period allowed for equilibration was between 2 ~ and 3 ~ hours. In Fig. 3 are plotted the a p p a r e n t volumes of d i s t r i b u t i o n against time in six subjects on whom more t h a n one blood sample was drawn between 1 hour 52 minutes and 3 hours a f t e r the injection. The increases ill a p p a r e n t volume amounted to 4.5 per cent, 5.4 per cent, 11 per cent, 2 per cent, 5 per cent, and 2.4 per cent, respee-
tively. In this period of time the app a r e n t volume of distribution of Na 24 is increasing v e r y little and, therefore, would serve to estimate the volume of fluid available for distribution of readily exchangeable sodium. In the adult subjects, the excretion of Na 24 during the period allowed for distribution was measured, and the values m a y be seen in Table II. The loss a f t e r injection, d u r i n g periods of from 23~ to 3 ~ hours, r a n g e d from 0.3 to 2.3 per cent of the a m o u n t given and averaged 1.2 per cent. In eomp u t i n g the sodium "space" in adults, a correction was made for this loss in each instance, but it is a p p a r e n t that the results are not significantly affeeted. In the infants and children studied, estimation of and correction for the u r i n a r y loss was not made since collection of urine over these short periods was not feasible. Other methods which have been used in an a t t e m p t to measure extracellular fluid in man also have certain disadvantages as pointed out by Kaltreider and associates. 1 Sucrose, while having the a d v a n t a g e of ~eing a nonelectrolyte, is u n s a t i s f a c t o r y beeause it is quite r a p i d l y excreted. The same objection applies to sulfate. Thioeyanate, while r a p i d l y distributed and slowly excreted, diffuses into the red blood cells and into the eells of certain glandular organs~ Nevertheless, measurements of the sodium " s p a c e " and thioeyanate space provide useful relative values. Our finding t h a t the sodium " s p a c e " computed as per cent of body weight is considerably higher in young" infants t h a n in older children and adMts confirms the observations of Fellers and co-workers2 F r o m Table I it is a p p a r e n t that the
PERLEY ET AL. : DETERMINATION OF SODIU1V[24 "SPACE ~'
average, sodium " s p a c e " in eleven p r e m a t u r e newborn infants is higher t h a n in the sixteen full-term newborn infants, being 43.5 per cent of the body weight in the f o r m e r group and 35.3 per cent in the latter. Harrison, Darrow, and Yannet, s using the chloride analyses of Iob and Swanson, 9 have computed "extracellular f l u i d " contents of fetuses and obtained a value of 62 per cent of body weight on a 5-month fetus with values decreasing to 43 per cent of b o d y w e i g h t on one which was practically full term. Our observations on children from 1 to 14 years of age are too few to bear analysis, but the s o d i u m "spaces" are appreciably lower t h a n those of y o u n g infants, averaging 30.2 per cent. Fellers and collaborators 4 observed a period of relative constancy between early i n f a n c y and adolescence with a small decline during adolescence. Our sodium "spaces" on adults v a r y widely as do those of K a l t r e i d e r and associates, ~ but the average of 25.2 per cent of body weight compares well with their mean of 24.8 per cent and with t h a t of 27.1 per cent r e p o r t e d b y Fellers and coworkers 4 and the single value of 26.5 per cent obtained b y Moore2 SUMMARY AND CONCLUSIONS
1. The volume of fluid t h r o u g h which radioactive sodium 24 is rapidly distributed (sodium " s p a c e " ) has been measured in thirty-seven infants and children and in nineteen adult males. 2. The period allowed for distribution of Na sA r a n g e d from 13/~ to 41/2 hours.
305
3. ]n eleven p r e m a t u r e infants the sodium " s p a c e " a v e r a g e d 43.5 per cent of body weight, and in 16 fullt e r m n e w b o r n infants 35.2 per cent. In seven children from 1 to 14 years of age, the values a v e r a g e d 30.2 per cent, and in nineteen adult mafes 25.2 per cent. 4. Although the sodium " s p a c e " computed as per cent of body weight varied considerably i n given weight ranges, the data indicate t h a t the volrune of fluid occupied by sodium in relation to b o d y weight declines as growth proceeds. REFERENCES 1. Kaltreider, 1~. L., Meneely, G. R., Allen, J. R., and Bale, W. F. : Determination of the Volume of Extraccllular Fluid of the Body With Radioactive Sodium, J. Exper. ~ e d . 74: 569, 1941. 2. Moore, D. F.: D e t e r m i n a t i o n of Total Body W a t e r and Solids W i t h Isotopes, Science 104: 157, 1946. ' 3. Flexner, L. B., Wilde, W. S., Proctor, N. K., Cowie, D. B., Vosburgh, G. J., and Heilman, L. M.: Estimation of Extracellular and Total Body W a t e r in the Newborn Human Infant With l~adioactive Sodium and Deuterium Oxide, J. PEDIAT. 30: 413~ 1947. 4. Fellers, F. X., Barnett, H. L., Hare, X., and ~ c N a m a r a , H.: Changes in Thiocyanate and Sodinm2~ Spaces During Growth, Pediatrics 3: 622, 1949. 5. B a r n e t t , H. L., and Fellers, F. X.: A Simple Q u a n t i t a t i v e Method for I n t r a venous I n j e c t i o n of Small Volumes of Fluid, Science 106: 401, 1947. 6. ]~[arineltl, L. D., Quimby, F. H., and Hine, G . J . : Dosage D e t e r m i n a t i o n W i t h Radioactive Isotopes. II. P r a c t i c a l Consideration in Therapy a n d Protection, Am. J. Roentgenol. 59: 260, 1948. 7. Manery, J. F., and Bate, W. F.: The P e n e t r a t i o n of ]~adioactive Sodium and Phosphorus Into t h e Extra- and Intracellular Phases of Tissues, Am. J. Physiol. 132: 215, 1941. 8. Harrison, I-I] E., Barrow, D. C., and Yannet, H.: The Total Electrolyte Content of Animals and Its Probable Relation to Distribution of Body Water~ J. Biol. Chem. 113: 515, 1936. 9. Iob, V., and Swanson, W. W.: Mineral Growth of Human Fetus, Am. J. Dis. Child. 47: 302, 1934.