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Studies of amino acid administration
STUDIES OF AMINO ACID ADMINISTRATION I . U T I L I Z A T I O N OF A N ]~NZYIVIATIC D I G E S T OF C A S E I N
ALEXIS F. I-IART~ANN, ~V[.D., CORNELIUS S. MEEKEa, M.D., ANNE M. PEaLEY, AND HELEN G. McGINNIs ST. LouIs, Mo.
1912 and 1916 several reports appeared in the literature B ETWEEN concerning the utilization of amino acids prepared by digestion of caseinY, 2, 3, ~ Recently, due to the development by the Mead Johnson LaboratoriesL, 5~ of a particularly promising casein digest which became available for study, observations concerning its utilization in human beings when administered by both parentera] and oral routes have been reported by Elman, 6 Carbould, 7 Fetzer, 8 Shohl, 9 Farr, ~~ ~0~ Altshuler,~ and their co-workers. Still more recently, studies concerning the possible value o~ such amino acid mixtures in promoting regeneration of plasma protein and in correcting hypoproteinemia have been made by 1V[adden,~2' ~ Ho]man, ~ and Elman, ~ and their co-workers and by us (unpublished data). The work to be reported here was undertaken during the summer and fall of 1940 as part o~ a broad study o~ parenteral feeding. Its chief purpose was investigation of the possibilities of parenteral administration of the digest and comparison o~ its Utilization when given enterally and parenterally. M E T H O D OF S T U D Y
Nitrogen balance studies were made with the casein digest "~ given in the following ways: (1) as a supplement to the diet; (2) as a replacement of meat, milk, and eggs in the diet; and (3) as the only appreciable source o~ nitrogen, given either enterally, intravenously, or by combined enteral and intravenous routes. Selected children who were in the hospital for long periods were used for the study. During the periods of observation they were allowed about the ward when their condition permitted. Special nurses trained for the work cared for them and prepared the diets. Nitrogen balance studies were made in three-day periods. Usually, except when continuous balances were run, the patients received the particular diets for a period of from two to five days before the balances opened. F r o m t h e D e p a r t m e n t of P e d i a t r i c s , W a s h i n g t o n U n i v e r s i t y School of Medicine, a n d 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 . * T h i s c a s e i n d i g e s t f u r n i s h e d u s a s L a b o r a t o r y P r o d u c t s 92-Z a n d 92-403, n o w g i v e n t h e t r a d e n a m e " A r n i g e n , " w a s m a d e t h r o u g h t h e h y d r o l y t i c a c t i o n of t h e e n z y m e s of p o r k p a n c r e a s on c a s e i n . D u r i n g h y d r o l y s i s , t h e p r o t e i n of t h e p a n c r e a s is also dig e s t e d , so t h a t 85 p e r c e n t of t h e n i t r o g e n in t h e f i n a l p r o d u c t c o m e s f r o m c a s e i n a n d 15 p e r c e n t f r o m t h e p a n c r e a s . T h e d r y m a t e r i a l c o n t a i n s a p p r o x i m a t e l y 12 p e r c e n t t o t a l n i t r o g e n a n d 7.4 p e r c e n t a m i n o n i t r o g e n . I t is s t a t e d ( p e r s o n a l c o m m u n i c a t i o n ) t h a t g u i n e a Digs c a n n o t be s e n s i t i z e d to it a n d t h a t it is p y r o g e n - f r e e . 3O8
t I A R , T M A N N ]ST AL. :
S T U D I E S OF A1YillqO, ACID, ADI~/III~ISTR~iTIO,I~
PgEPARATION
309
OF DIETS
The patients were placed on diets which were estimated to be adequate for total metabolic requirements. In some instances it was possible to keep the total calories and the carbohydrate to fat ratios reasonably constant; in others this was not accomplished. Essential vitamins were supplied in the form of commercial preparations. The carbohydrate, fat, and caloric contents of the diets were estimated from the tables of McCance and Widdowson. 16 The nitrogen content of all food fed was determined directly by analysis of duplicate weighed samples which were made into a homogeneous mixture in sulfuric acid by use of a mechanical stirrer.
In certain diets the " n i t r o g e n - f r e e " component was concocted from foods containing only traces of nitrogen, as indicated by the tables, and was then checked by actual analysis. Olive o~1 and butter were used for fat. Cane sugar, dextrose, lemon juice, and peache% pears, and apples were sometimes included for carbohydrate. The casein digest was incorporated into the diet in various ways, according to the preferences of the individnal subjects. This was accomplished by making up pastes, solutions, or mixtures with other food ingredients and then seasoning with flavorings and condiments. Despite these measures, the combinations sometimes proved distasteful and nauseating; vomiting, however, was exceedingly rare. With some of the diets containing the casein digesi which were almost completely without residue, constipation occurred and was remedied with mineral oil. On the other hand, with these same diets diarrhea occasionally occurred and was corrected with paregoric. The casein digest for intravenous administration was prepared as a 5 per c e n t solution in freshly distilled water and was then passed with sterile technique in rapid succession through a Seitz, then a Berkefeld filter to remove pyrogens and bacteria. Usually merthiolate was added in final dilution of 1:20,000 to inhibit growth of molds. The solutions for use were diluted so that the final concentration of casein digest was 1 per cent or 2~ per cent with 5 or 10 per cent dextrose. The pH of the 5 per cent solution was usually 4.9. No neutralization was attempted. Intravenous administration was frequently accompanied by nausea, but vomiting usually did not occur if the stomach was empty at the time the injection was started. One I3-year-old girl (A. R.) suffered violent chills followed by sharp rises in temperature when 21~ and I per cent solutions were administered intravenously on two different days. The same lot of material caused no reaction in three other children to whom it was given. Repeated injections of either 21/2 or I per cent solutions sometimes caused phlebitis and thrombosis of veins. Frequently, administration by the continuous drip method resulted in marked edema of the extremity used when the injection lasted as long as two or three days.
310
THE JOURNAL OF PEDIATRICS COLLECTION OF URINE AND STOOLS
The stools were marked with carmine, and the urine and stools were collected separately. When infants were studied, they were placed on padded canvas metabolism frames. Preservation of urine was accomplished by the addition of 5 c.c. of concentrated sulfuric acid. Stools were placed in sulfuric acid and, before analysis, were made into a homogeneous mixture by the use of an electric stirrer. Vomitus was treated in a similar fashion and its nitrogen content determined and subtracted from the nitrogen intake. CHEMICAL
ANALYSIS
The total nitrogen of the food, urine, and stools was determined by macro-Kjeldahl analysis, using the Arnold Gunning technique with 30 per cent hydrogen peroxide as an extra oxidizing agent. 17 Urine protein nitrogen was estimated by difference after the nonprotein nitrogen had been determined on a tungstic acid filtrate. The chemical analyses were made chiefly by two of us (C. M. and tI. G. M.) and nearly all of the determinations were run in triplicate. CASE I~EPORTS CASE 1.--A. J., a 2-yenr-old colored boy with a lye stricture of the esophagus, was admitted to the hospital for dilatations. I-Its nutrition had been well maintained by gastrostomy tube feeding. The total serum protein was 7.08 Gm. per 100 c.c. and the albumin, 4.19 Gm. During the first period, on a diet containing 0.44 Gm. nitrogen (2.7 Gm. protein) per kilogram of body weight derived largely f r o m dairy products, the pas was in positive ~itrogen balance and retained 0.15 Gm. nitrogen per kilogram per day (Table I ) . V(hen the protein of this diet was replaced by an amount of casein digest which provided 0.52 Gm. nitrogen per kilogram of body weight, the nitrogen retention was approximately the same, 0.17 Gin. per kilogram. During the third period the nitrogen intake was 0.48 Gm. per kilogram and again was derived largely from casein digest, but one-half was given enterally and one-half intravenously. On the second day the intra.venous injection was accompanied by a chill, and the p a t i e n t ' s temperature rose to 38.8 ~. I n the fourth period no casein digest was given enterally, but the intravenous injection was continued. The total nitrogen intake was only 0.27 Gm. per kilogram per day, 73 per cent of it being derived from casein digest. On these two ,days the fever was again high, reaching 40 ~ and 40.3 ~, respectively, and for this reason the injections were discontinued. St will be noted from Table I t h a t in the period when casein digest was given both enterally and intravenously the nitrogen retention was less t h a n half of t h a t in the preceding period. I t is possible that. the reduced retention may have been associated with the fever which occurred on the second day, for on this day the urinary nitrogen was considerably increased. I n the fourth period the shift to a negative balance was not unexpected, for the nitrogen intake h a d been reduced by almost 50 per cent without a n adjustment period having been allowed, and, i n addition, the fever was high. I t cannot be said whether the balance would have become positive i f the intravenous administration of the indicated amount of casein digest could have been continued without reaction. I n the fifth period, when the same amount of casein digest t h a t had been given by vein was given enterally, there was slight nitrogen retention.
Average
10/28/40 12.7 10/29/40 10/30/40 Average *Small a m o u n t of u r i n e
Average
lO/27/4o
10/26/40
12.7
12.7
10/24/40
lO/25/4o
11.8
13.1
(KG.)
WEIGHT
10/21/40 10/22/40 10/23/40 Average
Average
lO/16/4o
10/14/40 10/15/40
BATE
BODY
CASE I
1,380 1,380 1,380 1,380 lost.
1,416 1,416 1,416
1,380 !,380 1,380
1,354 1,354 1,354 1,354
1,340 1,340 1,340 1,340
24 HR.
181 181 181 181
181 181 181
170 170 170
170 170 170 170
170 170 170 170
24 Ha.)
67 67 67 67
67 67 67
58 58 58
58 58 58 58
58 58 58 58
FAT (GM. PER 24 ~R.)
CHO
(G~. PER
0.70 0.70 0.70 0.70
0.74 0.74 0.74
0.82 0.82 0.82
0.69 0.69 0.69 0.69
5.45 5.63 5.92 5.66
FOOD
FOOD I N T A K E
AGE, 2 llrEARS
PER
J.
CALORIES
t.
2.70 2.70 2.70 2.70
2.70 2.70 2.70
5.40 5.40 5.40 5.40
ALLY
ENTER-
2.70 2.70 2.70
2.70 2.70 2.70
I.V.
CASEIN DIGEST
NITROGEN (GM.)
0.27
0.27
0.48
0.52
0.44
TOTAL PER KG.
STRICTURE OF ESOPHAGUS
TABLE I
4.00 2.51 2.38 2.97
4.46 4.12 4.29
4.18 5.59 4.88
3.84 *3.88 (+) 4.06 3.93(+)
0.15
0.21
0.54
0.21
0.58
(G~.)
2.66 3.32 3.41 3.13
FECES
(am)
+0.28
-1.06
+0.80
+1.95+
+1.95
,
+0.02
-0.08
+0.06
+0.17+
+0.15
G:~. PER KG. PER 24 HR.
BALANCE GM. PER 24 HR.
NITROGEN
URINE
EXCR~ETION
GASTROSTOI~IY FEEDINGS
i--a i--a
>
9
5~
5o-
..
>
Z Z
312
THE
JOURNAL
Interpret~tion.--When t h e
OF
PEDIATRICS
u s u a l f o o d p r o t e i n was r e p l a c e d b y casein
digest, t h e p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n b a l a n c e a n d t h e a m o u n t of n i t r o g e n r e t a i n e d was u n c h a n g e d . W h e n p a r t of the casein digest was g i v e n e n t e r a l l y a n d p a r t i n t r a v e n o u s l y , chills a n d f e v e r r e s u l t e d , m a k i n g difficult i n t e r p r e t a t i o n of this p a r t of t h e data. CASE 2.--O. S., also a 2-year-old colored boy with a lye stricture of the esophagus, was in the hospital for dilatations. He, too, was fed through a gastrostomy tube. He was otherwise normal physically. The serum protein was 7.29 Gin. per 100 e.e., and the albumin, 4.14. During the period when a diet containing 0.47 Grn. of nitrogen per kilogram of body weight per day, largely in the form of milk and eggs, was given, and during the period when casein digest in approximately the same amount replaced the usual food protein, the nitrogen retentions were nearly identical, 0.16 and 0.15 Gin. per kilogram per day, respectively (Table I I ) . During the third period in which the quantity of casein .digest given was unchanged but one-half was administered enterMly and one-half intravenously, the nitrogen retention again was ahnost the same. This period lasted only two days, because on the second day the child had fever, and it was thought, owing to recent exposure, that he might be developing chicken pox. On Oct. 12, four days later, typical lesions were noted. During the last period, when the child was recovering from chicken pox, the nitrogen intake, which consisted of casein digest given enterally, was approximately one-half of that previously given, a~d the nitrogen retention also was about half that noted during the first two periods.
Interpretatiou.--When t h e u s u a l d i e t a r y n i t r o g e n was r e p l a c e d b y n i t r o g e n of e n z y m a t i c casein digest, w h i c h was g i v e n e i t h e r e n t e r a l l y or b y c o m b i n e d e n t e r a l a n d i n t r a v e n o u s r o u t es, the p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n balance. CasE 3.--C. E., a 5-year-old white boy, was admitted to the hospital for tonsillectomy because of recurrent tonsillitis and chronic malnutrition. Except for large infected tonsils, malnutrition, and a mild degree of anemia, he was quite well. During the first balance period he received each day a total of 103 calories per kilograms of body weight and 0.01 Gin. of nitrogen per kilogram, which was derived from the usual foe.d protein. During this time the nitrogen retention averaged 0.03 Gin. per kilogram per day (Table I I I ) . In the next period the nitrogen intake was 0.76 Gin. per kilogram, 68 per cent o~ which was derived from casein digest and the remainder from fruits and vegetable protein; and the nitrogen retention again was positive, averaging 0.09 Gin. per kilogram per day.
Interpreta,fion.--When . a n i m a l p r o t e i n in t h e d i e t of a m a l n o u r i s h e d c h i l d was r e p l a c e d b y casein digest, t h e n i t r o g e n b a l a n c e r e m a i n e d positive, s u g g e s t i n g t h a t t h e n i t r o g e n of t h e casein digest was well u t i l i z e d . CASE 4.--0. A., a 21~-year-old white boy, was convalescing from acrodynia which had led to a severe degree of malnutrition. The patient, however, was not anemic and the serum total protein on one occasion was 7.07 Gin. per 100 c.c, with 5A8 Gm. of albumin. For a period of two weeks after a~dmission the patient was offered the regular ward diet and ate very poorly. During the first nitrogen balance period, which was not preceded by a period of weighed diet, the caloric value of the food offered
Average
10/16/40
10/!5/40
lO/14/4o
Average
lO/ 8/40
1 0 / 7/40
Average
10/ 1/40 10/ 2/40
9/30/40
9/28/40 Average
9/26/40 9/27/40
DATE
:(K~.) GT
CASE 2
184 184 184 184
150 150 150 150
1,272 1,272 1,272 1,272
1,282 1,282 1,282 1,282
1,278 1,278 1,278 1,278
160 160 160 160
150 150 150
24 ~R.)
24 ~B.
1,282 1,282 1,282
CHO (G~.PEE
CALOKIES PER
0. S.
24
62 62 62 62
58 58 58
58 58 58 58
44 44 44 44
HR.)
FAT (GM. PER
0.88 0.88 0.88 0.88
0.78 0.78 0.78
0.79 0.79 0.79 0.79
5.56 5.38 5.48
FOOD
FOOD INTAKE
AGE, 2 YEARS
2.4 2.4 2.4 2.4
2.4 2.4 2.4
4.8 4.8 4.8 4.8
ENTERALLY
CASEIN
2.54 2.54 2.54
I.V.
DIGEST
NITROGEN ((HV[,)
0.25
0.48
0.47
0.47
TOTAL PER KG.
STRICTURE OF E S O P H A G U S
T A B L E II
2.19 1.66 1.76 1.87
0.34
0.37
0.46
3.14 3.13 3.31 3.19 4.14 3.17 3.65
0.67
(GM.)
2.75 3.14 3.06 2.98
FECES
(Gin)
+1.07
+1.72
+1.84
+1.83
+0.08
+0.14
+0.15
+0.16
24 ~R.
KG, PER
Gh~. PER
BALANCE GM. PER 2 4 HR.
NITROGEN
VBINE
EXCRETION
~ASTROSTOMY ~ E E D I N G S
e,.,o
> r
2~Y
>
Z 9
O
5~
5~
>
Average
8/21/4o 8/22/40
8/20/40
8/16/40 Average
8/15/40
8/14/40
s/ 8/4o
DATE
15.0
14.5
(XO.)
WEIGHT
BODY
CASE
3
1,518 1,518 1,518 1,518
197 197 197 197
178 178 178 178
24 HR.)
24 Hm
1,490 1,490 1,490 1,490
CHO (O~[. F E E
CALORIES PER
C. E.
FAT
42 42 42 42
62 62 62 62
(GM. PER 24 HR.)
FOOD
3.68 3.97 3.45 3.70
8.29 8.84 9.22 8.78
FOOD
I
III
7.8 7.8 7.8 7.8
CASEIN DIGEST EN'TERALLY I.V.
(~.)
0.76
0.61
TOTAL P E E KG.
9.68 8.36 7.70 8.65
7.48 7.14 7.46 7.39
(G~.)
URINE
1.40
0.99
(G~.)
+1.45
+O.4O
24 ~m
+0.09
+0.03
24 ~R.
KG. PER
G~. PER
BALANCE G~f- PER
NITROGEN
FEC~ES
EXCRETION
~Y~ALNUTRITION ASSOCIATED WITH C~RONIC INFECTION
NITROGEN
TABLE
INTAKE
AGE~ 5 YEARS
r~
o
Z >
O
r
HARTiY[AI'qN E,T AL. :
STUDIES OF AI~INO ACID AD:~cIINISTRATIO,N
315
averaged 172 calories per kilogram per day, with 0.65 Gin. of nitrogen per kilogram derived from the usual foods. The ,diet was not well taken, however, and each day the nitrogen content of the uneaten portion was determined by analysis; the actual nitrogen intake averaged 0.48 Gm. per kilogram per day, a n d the retention in this period was 0.:11 Gm. per kilogram per day. I n the second period casein digest was added to the diet so t h a t the average nitrogen intake was 0.89 Gm. per kilogram per ,day, with approximately one-third of it derived from the casein digest, and the total caloric intake was 157 calories per kilogram. The nitrogen retention was essentially the same. CASE 5.--A. l~., a 12-year-old white girl, was admitted to the hospital on May 6, 1940, because of intractable diarrhea which was found to be due to ulcerative colitis of undetermined origin. She had had the disease for nine months prior to hospitalization and had lost 15 pounds. Physical examination revealed slight enla~'gement of the liver a~d the proetoscopic finding of a hyperemic rectal mucosa studded with occasional small ulcers.
The urine was not abnormal. The blood count revealed a slight anemia and a leuceeytosis, the white blood cells numbering from :1:1,000 to 19,000. The serum total protein was 6.68 @m. per :100 c.e. Stool cultures were negative for organisms of the typhoid and dysentery groups, and examination for parasites also was negative. The patient was given a low residue, high caloric diet with added commercial vitamin preparations. On May 29 treatment with neoprontosil was started, on J u n e 7 addition of casein digest to the ,diet was begun, and on J u n e 24 kaopectate was added. Preceding and during the first nitrogen balance period, the patient received each day approximately 96 calories per kilogram of body weight~ with 0.69 Gin. of nitrogen per kilogram, 42 per cent of which was derived from casein digest (80 Gm. of casein digest per day). I n addition she was given each day neoprontosil, 6 Gin. ; thiamine chloride, 1.5 mg. ; nicotinic acid, 200 rag. ; K i n n e y ' s yeast extract, 8 e.c. ; o]eum pereomorph, 45 drops; kaopectate, 90 c.c. ; a n d ascorbie acid, :100 rag. The nitrogen balance was markedly positive, the retention averaging 0.15 Gm. per kilogram per day. The child's general conditon became considerably improved; and between July 5 and July 23 the number of stools decreased from three to five a day to one or two. The casein ,digest was then withdrawn a n d the patient was given a diet containing 0.59 Gin. of nitrogen per kilogram per day, derived from low residue foods. The nitrogen retention was 0.08 Gin. per kilogram per day, and the stool nitrogen did not change appreciably. The patient continued to do well a n d returned home on August 4 on a low residue diet without added casein digest. She re-entered the hospital two months later in a n acute exacerbation. I t seemed advisable to rest the gastrointestinal tract completely, and intravenous feeding with casein digest and glucose was undertaken. On two successive days a f t e r having received intravenously some of the same lot of solution used in several other patients without reactions, the child developed chills and fever, which rose to 40 ~ C., and she appeared very much prostrated. No f u r t h e r attempts were n~ade to continue casein digest feeding by vein.
Interpretation.--After s e v e r a l w e e k s o n a l o w r e s i d u e d i e t i n w h i c h the nitrogen intake was derived chiefly from dairy products and casein digest, the patient who was suffering from chronic ulcerative colitis showed considerable clinical improvement. The nitrogen balance was markedly positive.
7.2
7.7
9/18/40 9/19/40 9/20/40 Average
(XG.)
9/ 4/40 9/ 5/40 9/ 6/40 Average
DATE
BODY WEIGHT
24 ~m.)
24 HR.
24 HR.)
FAT ( G ~ . PEI~
O . .~s
99 99 99 99
(Taken) 172 172 172 ]72
(Offered) 1,238 ],238 1,238 1,238
(Taken) 1,206 1,206 I~206 i 1,206
(Taken) 37 37 37 37
74 74 74 74
(Of(Offered) fered)
CHO (GI~. P E R
CALORIES PER
CASE 4
TABLE IV
4151 4.78 4.43
(Tfg)
(Of(Taken) fered) 4.57 3.53 4.87 2.63 4.87 [ 4.09 4.71 3.42
FOOD
FOOD INTAKE
(a~I.)
(Taken) 2.4 2.4 2.4 2.4
0.65
(Offered)
! - -
I i
i
0.89
(Taken)
0.48
(Taken)
TOTAL PER KG.
4.75 4.16 6.66 5.19
0.74
0.42
(G~.)
2.07 1.88 2.50 2.]8
FECES
>m
+0.90
+0.82
24 ~
HR.
+0.12
+0.11
24
PER KG. PER GBI.
BALANCE ~f. PI
NITROGEN
7RIN
EXCRETION
SEVERE MALNUTRITION ( A c R O D Y N I A )
CASEIN DIGEST ENI.V. TERALLY
~ITROGEN
AGe, 2 89 YEARS
b..a
7/26/40 7/27/40 7/28/40 A~erage
7/17/40 Average
7/16/40
7/15/40
DATE
33.6
31.3
BODY ~u (XG.)
127 127 127 ]27
173 173 173 173
2,989 2,989 2,989 2,989
2,898 2,898 2,898 2,898 190 190 190 190
207 207 207 207
24 HI~.)
2r ~R.)
PER
24 ~ .
19.96 19.78 ]9.86 ]9.87
11.9 12.0 12.18 12.03
FOOD
FOOD INTAKE
AGE, 12 YEARS
FAT (G~i. F E E
A. ~.
OHO (GI~r PER
CALORIES
CASE 5
9.6 9.6 9.6 9.6
ENTERALLY I.V.
NITROOEN ( ~ . )
0.59
0.69
PER KO.
TOTAL
CHRONIC D I A R R H E A
TABLE V
13.96 15.]1 15.70 ]4.93
14.43 14.48 ]4.61 14.51
URINE (G~.)
2.36
2.30
+2.58
+4.82
+0.08
+0.15
24 HR.
KG. P E K
GIrl. PER
BALANCE G~[. PER 24 HR.
NIT}COGEN
FECES (G~-)
EXCRETION
ULCERATIVE COLITIS
C~
O
9
5~
5~
Z
318
THE JOURNAL OF PEDIATRICS
CASE 6.--1~. H., a 6-year-old white girl, entered the hospital on April 14, 1940, with generalized edema, suffering from chronic glomerulonephritis. Five days after entry she ,developed a type u pneumoeoceus peritonitis which was treated successf u l l y with snlfathiazole. I n May she had a n erysipeloid skin infection which also was treated successfully with the same drug. On severM occasions during July and August she developed a mild rhinitis. The urine on admission contained large amounts of protein; the quantity, however, gradually decreased but with considerable fluctuation from about 12 Gin. per 24 hours to only a trace by qualitative test. Microscopic examination revealed increased numbers of red blood cells, white and epithelial cells, and occasional casts. There was never any appreciable anemia. The blood pressure usually was only slightly elevated and on just one occasion the systolic pressure was noted to be as high as 140 ram. I-Ig. The blood urea clearance was 155 per cent of the normal. The serum total protein until July remained around 4 Gin. per 100 e.c., and the albumin usually was below 1.5 Gin. With gradual recovery from the nephritis and concomitant with the addition o2 casein digest to the diet, the total serum protein during the course of three months gradually rose to 6.49 Gin. per 100 e.c., with 3.75 Gin. albumin. During the first balance periad the diet contained the usual food proteins with 0.40 Gin. nitrogen per kilogram of body weight per day, and the nitrogen retention was 0.02 Gm. per kilogram per day (Table u I n the second period, when casein digest was substituted for the animal protein a n d comprised about two-thirds of the nitrogen intake with the calories increased about 20 per cent, the nitrogen retained was 0.05 Gin. per kilogram, with, however, some increase in stool nitrogen. I n the t h i r d period the total caloric intake was a g a i n increased and the nitrogen intake was 0.47 Gin. per kilogram and was .derived from the usual food. The nitrogen content of the stools decreased considerably, a n d the retention rose to 0.14 Gm. per kilogram per day. I n the fourth period casein digest again replaced the animal protein in the diet but this time constituted slightly less t h a n one-half of the nitrogen intake. AgMn the stool nitrogen increased but the nitrogen retention was almost the same.
Interpretation.--When casein digest was substituted for animal protein in the diet, the patient continued to ha~e a positive nitrogen balance; there occurred, however, some increase in the stool nitrogen. CASE 7.--L. B., a 5-year-old colored boy, re-entered the hospital on Sept. 11, 1940, with marked nephrotic edema and a n erysipelo~d infection of the left knee. He was treated with sulfathiazole, and the infection subsided within a few days. During the time that he was in the hospital and while the nitrogen balance studies were being carried out, the amount of edema varied considerably and occasionally he became edema-free. On admission there was marked proteinuria an~d during the period of hospitalization the excretion of protein ranged from less t h a n 1 Gin. per twenty-four hours to 6 Gin. On microscopic examination of the urine, the number of red blood cells did not appear to be inareased. There was only a slight degree of anemia. The serum t o t a l protein values ranged f r o m 3.08 to 4.77 Gin. per 100 c.c., the albumin from 0.90 to 2.10 Gm., and the nonprotein nitrogen from 20 to 29 rag. per 100 c.c. Seven nitrogen balance periods were carried out. During the first, the calorie intake was 78 calories per kilogram of ideal body weight (18.6 kg.), with 0.40 Gin. nitrogen per kilogram derived from ordinary f0ads (Table V I I ) . The nitrogen retention averaged 0.06 Gin. per kilogram per day. I n the second period casein digest replaced the usual food protein; the nitrogen intake, being unchanged with the calories, increased to 86 per kilogram. The nitrogen retention was approximately
9/ 2/40 9/ 3/40 9/ 4/40 Average
8/23/40 Average
8/22/40
8/21/4o
8 / 6/40 8 / 7/40 Average
S/ 5/40
8/ 2/40 Average
8/ 1/4o
7/31/40
D~TE
17.2 17.1 17.2
16.6 16.5 16.6
16.3 16.5 16.3
16.0 16.7 16.2
BoDY WEIG T (KG.)
R.H.
TABLE V I AGE, 6 YEAES
1,617 1,617 1,617
1,642 1,642 1,642
1,312 1,312 1,312
1,077 1,077 1,077 1,077
2O2 202 202 202
198 198 198 198
123 123 123 123
83 83 83 83
65 65 65 65
73 73 73 73
7O 7O 7O 7O
65 65 65 65
4.35 4.65 3.64 4.22
8.23 7.86 7.54 7.88
1.81 2.34 1.93 2.03
6.49 6.31 6.53 6.44
3.6 3.6 3.6 3.6
4.2 4.2 4.2 4.2
TERALLY
0.46
0.47
0.39
0.40
4.40 5.26 4.734.79
5.59 5.04 5.54 5.32
4.61 3.81 4.44 4.28
3.80 4.88 4.70 4.46
4.78 4.79 4.75 4.77
4.50 3.54 3.98 4.00
5.13 4.50 4.29 4.64
.60 .38 .03 .33
.61 .25 .79 .55
.11 .27 .46 .28
.39 1.03 1.15 .86
(G~.)
(aM.)
(G~.) 5.52 5.53 5.44 5.50
PROTEIN
N.P.N.
j
0.90
0.27
1.08
0.69
FECES (GM.)
NITROGEN
TOTAL
URINE
EXCRETION
I%]-EPHROTIC STAGE OF GLOMERULONEPHRITIS
FOOD I NT'-A-KE NITROGEN (aM.) CALORIES oso I PAT CASEIN DIGEST PER (GM. FER I (GM. PER TOTAL FOOD EN24 ~R. 24 I-IR.) 1 24 HE.) PEI~ KG. LV.
CASE 6
+2.13
+2.29
+0.87
+0.26
24 HR.
GM. P E R
+0.12
+0.14
+0.05
+0.02
24 ~ a .
KG. PER
GM. P E R
BALANCE
17.1 17,4 17.7 17.4
19.5 19.1 19.1 19.4
20.1 20.2 20.0 20.1
20.1 20.0 20.2 20.1
D%TE
9/25/40 9/26/40 9/27/40 Average
9/30/40 10/ ]/40 1 0 / 2/40 Average
10/7/40 1 0 / 8/40 1 0 / 9/40 Average
10/14/40 10/15/40 10/16/40 Average
1,835 1,835 1,835 1,835
1,835 1,835 1,835 1,835
1~595 1,595 1,595 1,595
1,449 1,449 1,449 1,449
24 ~R.
PEI~
CALORIES
10/21/40 18.2 1,835 10/22/40 .18.2 1,835 10/23/40 18.0 1,835 Average 18.1 1,835 *Small amount of urine lost.
(KG.)
BODY ~EIGttT
~R~)
170 170 170 170
170 170 170 170
170 170 170 170
170 ]70 170 170
163 163 163 163
24
(GM* PER
CI~O
L. ]~.
AGE, 5 Y E A R S
75 75 75 75
75 75 75 75
75 75 75 75
75 75 75 75
68 68 68 68
0.78 0.78 0.78 0.78
0.78 0.78 0.78 0.78
0.78" 0.78 0.78 0.78
0.78 0.78 0.78 0.78
7.42 7.49 7.29 7.40
14.16 14.16 14.16 14.16
13.38 13.38 13.38 13.38
]3.60 13.60 13.60 13.60
6.40 6.40 6.40 6.40
0.80
0.76
0.77
0.39
0.40
FOOD INTAKE NITROGEN (GM.) FAT CASEIN DIGEST TOTAL (GI~. P E R FOOD ENTERPER 24 RR.) ALLY LV. KG.
CASE 7
TABLE V I I
11.27 "9.81+ 11.25 10.79+
11.95 9.85 10.40 10.73
9.60
I0.01
8.21 10.57
4.57 4.75 4.85 4.76
6.06 5.87 5.94 5.95
TOTAL (G~.)
10.70 9.30+ 10.58 10.19+
9.10 9.63 9.98 9.57
7.70 9.49 8.90 8.70
4.50 4.40 4.47 4.46
4.75 5.43 5.39 5.19
0.57 0.51+ 0.67 0.60+
2.85 0.22 0.42 1.16
0.51 1.08 1.11 0.90
0.07 0.35 0.38 0.30
1.31 0.44 0.55 0.76
1.24
1.30
1.16
1.06
0.42
NITROGEN EXCF~ETION URINE FECES N.P.N. PROTEIN (G~.) (G~L) (e~.)
NEPttROSIS
+2.91+
+2.13
+3.62
+1.36
+1.03
24 HR.
G~[. PER
+0.16+
+0.11
+0.19
+0.07
+0.06
KG. PER 24 Rm
G~[. pER
BALANCE
9/ 9/40 9/10/40 9/11/40 Average
DATE
14.7 15.2 15.6 15.2
(~:G.)
BODY "WEIGtIT
8
l~. B.
1,719 1,719 1,719 1,719
137 137 137 137
85 85 85 85
9.13 9.88 10.77 9.93
FOOD
(GIVe.)
4.80 4.80 4.80 4.80
I
CASEIN DIGEST ENTERI.V. ALLY
NITROGEN
AGE, 21/.2 YEARS FOOD INTAKE
FAT CALORIES cI~IO PER J (a~. PER ( G ~ . P E R 24 H m ) 24 HR. 24 HR.)
CASE
TABLE VIII
0.97
TOTAL PER KG.
I
9.74 10.66 11.40 10.60
(G~.)
TOTAL 8.23 8.48 9.62 8.78
(a~.
1.51 2.18 1.78 1.82
(O~i.)
1.69
N~TEOGEN EXCRETION URINE FECES N . P . i N PROTEIN (a~.)
~TEPHROTIC STAGE OF GL0~fERULONEFHROSIS
+2.44
24 HR.
GM. PER
+0.16
GI~I. PER KG. PER 24 H~.
BALANCE
>
b~
Q >
k2
0
U~
u~
>
Z Z
322
THE JOURNAL OF PEDIATRICS
the same with an increase in the stool nitrogen. The data on the third period in which casein digest was given by both oral and intravenous routes is not included because on more than one occasion vomiting occurred. During the last three balance studies the caloric intake was approximately 99 calories per kilogram, with an average of 0.78 Gin. nitrogen per kilogram, which was derived very largely from casein digest given orally. In these three periods the nitrogen balances were markedly positive, ranging from 0.11 te 0.19 Gin. per kilogram per day. It is of interest
to note that between October 5 and October 24, while casein digest was the only appreciable source of nitrogen in the diet, the patient's serum total protein rose from 3.08 Gin. per 100 c.c. to 4.77 Gin., and the albumin from 1.03 to 2.10 Gin.
Interp~vtatio~.--When casein d i g e s t r e p l a c e d t h e u s u a l f o o d p r o t e i n , t h e p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n b a l a n c e w i t h an i n c r e a s e in stool n i t r o g e n . W h e n t h e q u a n t i t y of c a s e i n d i g e s t t a k e n was i n c r e a s e d b y 100 p e r cent, t h e n i t r o g e n r e t e n t i o n i n c r e a s e d a p p r e c i a b l y . CASE 8.--1% B., a 21~-year-old white boy, was in the hospital for over a year with the nephrotic type of glomerular nephritis. During this period he suffered from repeated episodes of infection and on several occasions was treated with one of the sulfonamides. During the entire period in the hospital, there was marked proteinuria which, at times, amounted to as much as 14 Gm. per day. Microscopic examination o f the urine usually revealed occasional red blood cells and varying numbers of casts, quite frequently fatty in nature. The serum albumin was greatly reduced during the entire perio.d of observation. On discharge from the hospital the total serum protein was 3.80 Gin. per 100 c.c., the albumin, 0.92, and the nonprotein nitrogen, 33 mg. per cent. Casein digest (10 to 40 @m. per day) was added to the patient's diet during nearly all of the seven-week period preceding the nitrogen balance study. The protein intake varied considerably; occasionally, it was very low but more often was between 0.3 and 0.6 Gin. of nitrogen per kilogram per day. Because of more or less persistent nausea with occasional vomiting, only one balance period was obtaine.d. During this period the nitrogen intake averaged 0.97 Gin. per kilogram per day, approximately one-third of it being derived from casein digest. The patient was in marked positive nitrogen balance, retaining 0.16 Gin. per kilogram per day (Table VrII). This retention occurred while his urinary protein nitrogen averaged 0.12 Gm. per kilogram per day. The patient returned home still with active nephritis and has continued to receive 40 Gin. of casein digest per day added to his regular ~]iet. At the time of this writing, June 1, 1941, he continues to have intense proteinuria and usually has considerable edema. SUMMARY AND CONCLUSIONS I n e i g h t c h i l d r e n t h e u t i l i z a t i o n of a n e n z y m a t i c casein digest, A m i g e n , was s t u d i e d w h e n g i v e n in one or m o r e of t h e f o l l o w i n g w a y s : (1) as a s u p p l e m e n t to an o r d i n a r y d i e t ; (2) as a r e p l a c e m e n t of m eat , milk, a n d eggs~ in th e d ie t; a n d (3) as t h e o n l y a p p r e c i a b l e source of n i t r o g e n , g i v e n e i t h e r e n t e r a l l y , i n t r a v e n o u s l y , or b y t h e c o m b i n e d e n t e r a l a n d i n t r a v e n o u s routes. C o n c l u s i o n s w e r e as f o l l o w s : 1. I t was easily possible to i n c r e a s e a n o r d i n a r y n i t r o g e n i n t a k e of 0.4 t o 0.6 Gin. p e r k i l o g r a m of b o d y w e i g h t b y 50 p e r cent or m o r e w h e n casein d i g e s t was g i v e n as a s u p p l e m e n t to t h e r e g u l a r diet.
~ART]KANN E,T AL,. :
STUDIES OF A]V[IN0. ACID ADfC[INISTt~ATION
323
2. When casein digest was given enterally as a substitute for meat, milk, and eggs, positive nitrogen balances were maintained at essentially unchanged levels. 3. When almost the entire food nitrogen was replaced by an equal amount of casein digest nitrogen administered enterally, nitrogen retention as observed in single three-day balance periods was essentially unaffected. When the casein digest intake was approximately doubled, nitrogen retention doubled or tripled. In one patient when casein digest was the only appreciable source of nitrogen and half was given enterally and half intravenously, the nitrogen retention equaled that observed when the entire amount of casein digest was given enterally as: well as that when the nitrogen intake was derived from meat, milk, and eggs. In another patient in a similar study less nitrogen was retained when half of the casein digest was given entera]ly and half intravenously than when it was all given enterally or when meat, milk, and eggs were the chief sources of nitrogen. Because of the occurrence of reactions, a such as vomiting, chills, and fever, or phlebitis with edema, or because of unrelated intercurrent infections, attempts to obtain nitrogen balance data were unsuccessful when casein digest as the only appreciable source of nitrogen was given entirely by the intravenous route. REFERENCES 1. 2. 3. 4. 5.
Buglia, G.: Ztsehr. f. Biol. 58: 162, ]912. I-Ienriques, V., and Andersen, A. C.: Ztschr. f. physiol. Chem. 88: 357, 1913. Van Slyke, D. D., and Meyer, G . M . : g. Biol. Chem. 16: 197, 1913. 0shorn, T. B., and Mendel, L . B . : J. Biol. Chem. 26: 1, 1916. Mueller, A. J., ]~en~nerer, K. S., Cox, W. M., Jr., and Barnes, S. T. : J. Biol. Chem. 134: 573, 1940. 5u. Cox, W. M., and Mueller, A . J . : Proc. Soc. Exper. Biol. & Me d. 42: 658, 1939. 6. Elman, R., and Weiner, D. 0.: J . A . M . A . 112: 796, 1939. 7. Carbotfl~d, I., Clark, 1~. It., and McKechnie, 1%. E. : Am. J. Digest. Dis. 6: 185, 1939. 8. Fetzer, L. W.: Dallas M. 5. 25: 75, 1939. 9. Shohl, A. T., Butler, A. M., Blaekfan, K. D., and MacTachlan, E. : J. PEDIA~. 15: 469, 1939. ]0. F a r r , L. E., and MacFadyen, E. D.: Proc. Soe. Exper. Biol. & Med. 42: 444, ]939. 10a. F a r r , L. E. : J. PEDI/~T. 16: 679, 1940. 11. Altshuler, S. S., Hensel, H. M., Sayhum, M. : Am. J. M. Se. 200: 239, 1940. 12. Madden, S. C., Noehren, W. A., Waraich, G. S., and Whipple, G. If. : J. Exper. Med. 69: 721, 1939. 13. l~adden, S. C., Finch, C. A., Swalbach, W. G., and Whipple, G. It.: 5. Exper. 1Y[ed. 71: 283, ]940. 14. Holman, I~. L., and Mebane, 5. G. : 5. E x p e l Med. 71: 299, 1940. 15. Elman, R.: Proc. Soc. Exper. Biol. & Med. 43: ]4, 1940. ]6. l~cCanee, tr A., and Widdowson, E. M. : The Chemical Composition of Foo.ds, London, ]940, His M a j e s t y ' s Stationery Office. 17. Peters, 5. D., and Van Slyke, D. D. : Quantitative Clinical Chemistry, Baltimore, 1932, Williams and Wilkins Co., vol. 2, p. 518. *During the past year ~ much improved solution of Amigen has been furnished us by Mead Johnson & Co., and its use in concentrations of from 3 to 10 per cent is rarely followed by even mild reactions. In a later communication we intend to discuss the many" clinical uses for intravenously administered solutions of Amigen.
324
THE JOURNAL OF PEDIATRICS
ADDITIONAL PAPERS WHICH HAVE APPEARED SINCE THE COMPLETION OF OUR STUDY 1. 2. 3. 4. 5. 6. 7.
Shoht, A. T., and Blaekfan, I(. D.: J. N u t r i t i o n 20: 305, 1940. Elman, Robert: Ann. Surg. 112: 594, 1940. F a r r , I~. E., Emerson, K.~ Jr., and Fntcher, P. It.: J. PE~)IA~:. 17: 595, 1940. Farr, :L. E.: Connecticut M. J. 5: 24, 1941. Zetzel, L., and :Banks, B. M.: Am. J. Digest. Dis. 8: 2], 194I. Hill, Louis W e b b : J . A . M . A . 116: 2135, 1941. Madden, S. C., Turner, A. P., Ir A. P., and Whipple, G . H . : J. Exper. Med. 73: 571~ 1941. 8. Editorial: J. A. 1VI. t . 116: 838, 1941. 9. Cox, Warren M., Jr., Mueller, Arthur J., and Fiekas, Dallas: Personal communicatmu.
ALEXIS F. I-IART~ANN, ~V[.D., CORNELIUS S. MEEKEa, M.D., ANNE M. PEaLEY, AND HELEN G. McGINNIs ST. LouIs, Mo.
1912 and 1916 several reports appeared in the literature B ETWEEN concerning the utilization of amino acids prepared by digestion of caseinY, 2, 3, ~ Recently, due to the development by the Mead Johnson LaboratoriesL, 5~ of a particularly promising casein digest which became available for study, observations concerning its utilization in human beings when administered by both parentera] and oral routes have been reported by Elman, 6 Carbould, 7 Fetzer, 8 Shohl, 9 Farr, ~~ ~0~ Altshuler,~ and their co-workers. Still more recently, studies concerning the possible value o~ such amino acid mixtures in promoting regeneration of plasma protein and in correcting hypoproteinemia have been made by 1V[adden,~2' ~ Ho]man, ~ and Elman, ~ and their co-workers and by us (unpublished data). The work to be reported here was undertaken during the summer and fall of 1940 as part o~ a broad study o~ parenteral feeding. Its chief purpose was investigation of the possibilities of parenteral administration of the digest and comparison o~ its Utilization when given enterally and parenterally. M E T H O D OF S T U D Y
Nitrogen balance studies were made with the casein digest "~ given in the following ways: (1) as a supplement to the diet; (2) as a replacement of meat, milk, and eggs in the diet; and (3) as the only appreciable source o~ nitrogen, given either enterally, intravenously, or by combined enteral and intravenous routes. Selected children who were in the hospital for long periods were used for the study. During the periods of observation they were allowed about the ward when their condition permitted. Special nurses trained for the work cared for them and prepared the diets. Nitrogen balance studies were made in three-day periods. Usually, except when continuous balances were run, the patients received the particular diets for a period of from two to five days before the balances opened. F r o m t h e D e p a r t m e n t of P e d i a t r i c s , W a s h i n g t o n U n i v e r s i t y School of Medicine, a n d 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 . * T h i s c a s e i n d i g e s t f u r n i s h e d u s a s L a b o r a t o r y P r o d u c t s 92-Z a n d 92-403, n o w g i v e n t h e t r a d e n a m e " A r n i g e n , " w a s m a d e t h r o u g h t h e h y d r o l y t i c a c t i o n of t h e e n z y m e s of p o r k p a n c r e a s on c a s e i n . D u r i n g h y d r o l y s i s , t h e p r o t e i n of t h e p a n c r e a s is also dig e s t e d , so t h a t 85 p e r c e n t of t h e n i t r o g e n in t h e f i n a l p r o d u c t c o m e s f r o m c a s e i n a n d 15 p e r c e n t f r o m t h e p a n c r e a s . T h e d r y m a t e r i a l c o n t a i n s a p p r o x i m a t e l y 12 p e r c e n t t o t a l n i t r o g e n a n d 7.4 p e r c e n t a m i n o n i t r o g e n . I t is s t a t e d ( p e r s o n a l c o m m u n i c a t i o n ) t h a t g u i n e a Digs c a n n o t be s e n s i t i z e d to it a n d t h a t it is p y r o g e n - f r e e . 3O8
t I A R , T M A N N ]ST AL. :
S T U D I E S OF A1YillqO, ACID, ADI~/III~ISTR~iTIO,I~
PgEPARATION
309
OF DIETS
The patients were placed on diets which were estimated to be adequate for total metabolic requirements. In some instances it was possible to keep the total calories and the carbohydrate to fat ratios reasonably constant; in others this was not accomplished. Essential vitamins were supplied in the form of commercial preparations. The carbohydrate, fat, and caloric contents of the diets were estimated from the tables of McCance and Widdowson. 16 The nitrogen content of all food fed was determined directly by analysis of duplicate weighed samples which were made into a homogeneous mixture in sulfuric acid by use of a mechanical stirrer.
In certain diets the " n i t r o g e n - f r e e " component was concocted from foods containing only traces of nitrogen, as indicated by the tables, and was then checked by actual analysis. Olive o~1 and butter were used for fat. Cane sugar, dextrose, lemon juice, and peache% pears, and apples were sometimes included for carbohydrate. The casein digest was incorporated into the diet in various ways, according to the preferences of the individnal subjects. This was accomplished by making up pastes, solutions, or mixtures with other food ingredients and then seasoning with flavorings and condiments. Despite these measures, the combinations sometimes proved distasteful and nauseating; vomiting, however, was exceedingly rare. With some of the diets containing the casein digesi which were almost completely without residue, constipation occurred and was remedied with mineral oil. On the other hand, with these same diets diarrhea occasionally occurred and was corrected with paregoric. The casein digest for intravenous administration was prepared as a 5 per c e n t solution in freshly distilled water and was then passed with sterile technique in rapid succession through a Seitz, then a Berkefeld filter to remove pyrogens and bacteria. Usually merthiolate was added in final dilution of 1:20,000 to inhibit growth of molds. The solutions for use were diluted so that the final concentration of casein digest was 1 per cent or 2~ per cent with 5 or 10 per cent dextrose. The pH of the 5 per cent solution was usually 4.9. No neutralization was attempted. Intravenous administration was frequently accompanied by nausea, but vomiting usually did not occur if the stomach was empty at the time the injection was started. One I3-year-old girl (A. R.) suffered violent chills followed by sharp rises in temperature when 21~ and I per cent solutions were administered intravenously on two different days. The same lot of material caused no reaction in three other children to whom it was given. Repeated injections of either 21/2 or I per cent solutions sometimes caused phlebitis and thrombosis of veins. Frequently, administration by the continuous drip method resulted in marked edema of the extremity used when the injection lasted as long as two or three days.
310
THE JOURNAL OF PEDIATRICS COLLECTION OF URINE AND STOOLS
The stools were marked with carmine, and the urine and stools were collected separately. When infants were studied, they were placed on padded canvas metabolism frames. Preservation of urine was accomplished by the addition of 5 c.c. of concentrated sulfuric acid. Stools were placed in sulfuric acid and, before analysis, were made into a homogeneous mixture by the use of an electric stirrer. Vomitus was treated in a similar fashion and its nitrogen content determined and subtracted from the nitrogen intake. CHEMICAL
ANALYSIS
The total nitrogen of the food, urine, and stools was determined by macro-Kjeldahl analysis, using the Arnold Gunning technique with 30 per cent hydrogen peroxide as an extra oxidizing agent. 17 Urine protein nitrogen was estimated by difference after the nonprotein nitrogen had been determined on a tungstic acid filtrate. The chemical analyses were made chiefly by two of us (C. M. and tI. G. M.) and nearly all of the determinations were run in triplicate. CASE I~EPORTS CASE 1.--A. J., a 2-yenr-old colored boy with a lye stricture of the esophagus, was admitted to the hospital for dilatations. I-Its nutrition had been well maintained by gastrostomy tube feeding. The total serum protein was 7.08 Gm. per 100 c.c. and the albumin, 4.19 Gm. During the first period, on a diet containing 0.44 Gm. nitrogen (2.7 Gm. protein) per kilogram of body weight derived largely f r o m dairy products, the pas was in positive ~itrogen balance and retained 0.15 Gm. nitrogen per kilogram per day (Table I ) . V(hen the protein of this diet was replaced by an amount of casein digest which provided 0.52 Gm. nitrogen per kilogram of body weight, the nitrogen retention was approximately the same, 0.17 Gin. per kilogram. During the third period the nitrogen intake was 0.48 Gm. per kilogram and again was derived largely from casein digest, but one-half was given enterally and one-half intravenously. On the second day the intra.venous injection was accompanied by a chill, and the p a t i e n t ' s temperature rose to 38.8 ~. I n the fourth period no casein digest was given enterally, but the intravenous injection was continued. The total nitrogen intake was only 0.27 Gm. per kilogram per day, 73 per cent of it being derived from casein digest. On these two ,days the fever was again high, reaching 40 ~ and 40.3 ~, respectively, and for this reason the injections were discontinued. St will be noted from Table I t h a t in the period when casein digest was given both enterally and intravenously the nitrogen retention was less t h a n half of t h a t in the preceding period. I t is possible that. the reduced retention may have been associated with the fever which occurred on the second day, for on this day the urinary nitrogen was considerably increased. I n the fourth period the shift to a negative balance was not unexpected, for the nitrogen intake h a d been reduced by almost 50 per cent without a n adjustment period having been allowed, and, i n addition, the fever was high. I t cannot be said whether the balance would have become positive i f the intravenous administration of the indicated amount of casein digest could have been continued without reaction. I n the fifth period, when the same amount of casein digest t h a t had been given by vein was given enterally, there was slight nitrogen retention.
Average
10/28/40 12.7 10/29/40 10/30/40 Average *Small a m o u n t of u r i n e
Average
lO/27/4o
10/26/40
12.7
12.7
10/24/40
lO/25/4o
11.8
13.1
(KG.)
WEIGHT
10/21/40 10/22/40 10/23/40 Average
Average
lO/16/4o
10/14/40 10/15/40
BATE
BODY
CASE I
1,380 1,380 1,380 1,380 lost.
1,416 1,416 1,416
1,380 !,380 1,380
1,354 1,354 1,354 1,354
1,340 1,340 1,340 1,340
24 HR.
181 181 181 181
181 181 181
170 170 170
170 170 170 170
170 170 170 170
24 Ha.)
67 67 67 67
67 67 67
58 58 58
58 58 58 58
58 58 58 58
FAT (GM. PER 24 ~R.)
CHO
(G~. PER
0.70 0.70 0.70 0.70
0.74 0.74 0.74
0.82 0.82 0.82
0.69 0.69 0.69 0.69
5.45 5.63 5.92 5.66
FOOD
FOOD I N T A K E
AGE, 2 llrEARS
PER
J.
CALORIES
t.
2.70 2.70 2.70 2.70
2.70 2.70 2.70
5.40 5.40 5.40 5.40
ALLY
ENTER-
2.70 2.70 2.70
2.70 2.70 2.70
I.V.
CASEIN DIGEST
NITROGEN (GM.)
0.27
0.27
0.48
0.52
0.44
TOTAL PER KG.
STRICTURE OF ESOPHAGUS
TABLE I
4.00 2.51 2.38 2.97
4.46 4.12 4.29
4.18 5.59 4.88
3.84 *3.88 (+) 4.06 3.93(+)
0.15
0.21
0.54
0.21
0.58
(G~.)
2.66 3.32 3.41 3.13
FECES
(am)
+0.28
-1.06
+0.80
+1.95+
+1.95
,
+0.02
-0.08
+0.06
+0.17+
+0.15
G:~. PER KG. PER 24 HR.
BALANCE GM. PER 24 HR.
NITROGEN
URINE
EXCR~ETION
GASTROSTOI~IY FEEDINGS
i--a i--a
>
9
5~
5o-
..
>
Z Z
312
THE
JOURNAL
Interpret~tion.--When t h e
OF
PEDIATRICS
u s u a l f o o d p r o t e i n was r e p l a c e d b y casein
digest, t h e p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n b a l a n c e a n d t h e a m o u n t of n i t r o g e n r e t a i n e d was u n c h a n g e d . W h e n p a r t of the casein digest was g i v e n e n t e r a l l y a n d p a r t i n t r a v e n o u s l y , chills a n d f e v e r r e s u l t e d , m a k i n g difficult i n t e r p r e t a t i o n of this p a r t of t h e data. CASE 2.--O. S., also a 2-year-old colored boy with a lye stricture of the esophagus, was in the hospital for dilatations. He, too, was fed through a gastrostomy tube. He was otherwise normal physically. The serum protein was 7.29 Gin. per 100 e.e., and the albumin, 4.14. During the period when a diet containing 0.47 Grn. of nitrogen per kilogram of body weight per day, largely in the form of milk and eggs, was given, and during the period when casein digest in approximately the same amount replaced the usual food protein, the nitrogen retentions were nearly identical, 0.16 and 0.15 Gin. per kilogram per day, respectively (Table I I ) . During the third period in which the quantity of casein .digest given was unchanged but one-half was administered enterMly and one-half intravenously, the nitrogen retention again was ahnost the same. This period lasted only two days, because on the second day the child had fever, and it was thought, owing to recent exposure, that he might be developing chicken pox. On Oct. 12, four days later, typical lesions were noted. During the last period, when the child was recovering from chicken pox, the nitrogen intake, which consisted of casein digest given enterally, was approximately one-half of that previously given, a~d the nitrogen retention also was about half that noted during the first two periods.
Interpretatiou.--When t h e u s u a l d i e t a r y n i t r o g e n was r e p l a c e d b y n i t r o g e n of e n z y m a t i c casein digest, w h i c h was g i v e n e i t h e r e n t e r a l l y or b y c o m b i n e d e n t e r a l a n d i n t r a v e n o u s r o u t es, the p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n balance. CasE 3.--C. E., a 5-year-old white boy, was admitted to the hospital for tonsillectomy because of recurrent tonsillitis and chronic malnutrition. Except for large infected tonsils, malnutrition, and a mild degree of anemia, he was quite well. During the first balance period he received each day a total of 103 calories per kilograms of body weight and 0.01 Gin. of nitrogen per kilogram, which was derived from the usual foe.d protein. During this time the nitrogen retention averaged 0.03 Gin. per kilogram per day (Table I I I ) . In the next period the nitrogen intake was 0.76 Gin. per kilogram, 68 per cent o~ which was derived from casein digest and the remainder from fruits and vegetable protein; and the nitrogen retention again was positive, averaging 0.09 Gin. per kilogram per day.
Interpreta,fion.--When . a n i m a l p r o t e i n in t h e d i e t of a m a l n o u r i s h e d c h i l d was r e p l a c e d b y casein digest, t h e n i t r o g e n b a l a n c e r e m a i n e d positive, s u g g e s t i n g t h a t t h e n i t r o g e n of t h e casein digest was well u t i l i z e d . CASE 4.--0. A., a 21~-year-old white boy, was convalescing from acrodynia which had led to a severe degree of malnutrition. The patient, however, was not anemic and the serum total protein on one occasion was 7.07 Gin. per 100 c.c, with 5A8 Gm. of albumin. For a period of two weeks after a~dmission the patient was offered the regular ward diet and ate very poorly. During the first nitrogen balance period, which was not preceded by a period of weighed diet, the caloric value of the food offered
Average
10/16/40
10/!5/40
lO/14/4o
Average
lO/ 8/40
1 0 / 7/40
Average
10/ 1/40 10/ 2/40
9/30/40
9/28/40 Average
9/26/40 9/27/40
DATE
:(K~.) GT
CASE 2
184 184 184 184
150 150 150 150
1,272 1,272 1,272 1,272
1,282 1,282 1,282 1,282
1,278 1,278 1,278 1,278
160 160 160 160
150 150 150
24 ~R.)
24 ~B.
1,282 1,282 1,282
CHO (G~.PEE
CALOKIES PER
0. S.
24
62 62 62 62
58 58 58
58 58 58 58
44 44 44 44
HR.)
FAT (GM. PER
0.88 0.88 0.88 0.88
0.78 0.78 0.78
0.79 0.79 0.79 0.79
5.56 5.38 5.48
FOOD
FOOD INTAKE
AGE, 2 YEARS
2.4 2.4 2.4 2.4
2.4 2.4 2.4
4.8 4.8 4.8 4.8
ENTERALLY
CASEIN
2.54 2.54 2.54
I.V.
DIGEST
NITROGEN ((HV[,)
0.25
0.48
0.47
0.47
TOTAL PER KG.
STRICTURE OF E S O P H A G U S
T A B L E II
2.19 1.66 1.76 1.87
0.34
0.37
0.46
3.14 3.13 3.31 3.19 4.14 3.17 3.65
0.67
(GM.)
2.75 3.14 3.06 2.98
FECES
(Gin)
+1.07
+1.72
+1.84
+1.83
+0.08
+0.14
+0.15
+0.16
24 ~R.
KG, PER
Gh~. PER
BALANCE GM. PER 2 4 HR.
NITROGEN
VBINE
EXCRETION
~ASTROSTOMY ~ E E D I N G S
e,.,o
> r
2~Y
>
Z 9
O
5~
5~
>
Average
8/21/4o 8/22/40
8/20/40
8/16/40 Average
8/15/40
8/14/40
s/ 8/4o
DATE
15.0
14.5
(XO.)
WEIGHT
BODY
CASE
3
1,518 1,518 1,518 1,518
197 197 197 197
178 178 178 178
24 HR.)
24 Hm
1,490 1,490 1,490 1,490
CHO (O~[. F E E
CALORIES PER
C. E.
FAT
42 42 42 42
62 62 62 62
(GM. PER 24 HR.)
FOOD
3.68 3.97 3.45 3.70
8.29 8.84 9.22 8.78
FOOD
I
III
7.8 7.8 7.8 7.8
CASEIN DIGEST EN'TERALLY I.V.
(~.)
0.76
0.61
TOTAL P E E KG.
9.68 8.36 7.70 8.65
7.48 7.14 7.46 7.39
(G~.)
URINE
1.40
0.99
(G~.)
+1.45
+O.4O
24 ~m
+0.09
+0.03
24 ~R.
KG. PER
G~. PER
BALANCE G~f- PER
NITROGEN
FEC~ES
EXCRETION
~Y~ALNUTRITION ASSOCIATED WITH C~RONIC INFECTION
NITROGEN
TABLE
INTAKE
AGE~ 5 YEARS
r~
o
Z >
O
r
HARTiY[AI'qN E,T AL. :
STUDIES OF AI~INO ACID AD:~cIINISTRATIO,N
315
averaged 172 calories per kilogram per day, with 0.65 Gin. of nitrogen per kilogram derived from the usual foods. The ,diet was not well taken, however, and each day the nitrogen content of the uneaten portion was determined by analysis; the actual nitrogen intake averaged 0.48 Gm. per kilogram per day, a n d the retention in this period was 0.:11 Gm. per kilogram per day. I n the second period casein digest was added to the diet so t h a t the average nitrogen intake was 0.89 Gm. per kilogram per ,day, with approximately one-third of it derived from the casein digest, and the total caloric intake was 157 calories per kilogram. The nitrogen retention was essentially the same. CASE 5.--A. l~., a 12-year-old white girl, was admitted to the hospital on May 6, 1940, because of intractable diarrhea which was found to be due to ulcerative colitis of undetermined origin. She had had the disease for nine months prior to hospitalization and had lost 15 pounds. Physical examination revealed slight enla~'gement of the liver a~d the proetoscopic finding of a hyperemic rectal mucosa studded with occasional small ulcers.
The urine was not abnormal. The blood count revealed a slight anemia and a leuceeytosis, the white blood cells numbering from :1:1,000 to 19,000. The serum total protein was 6.68 @m. per :100 c.e. Stool cultures were negative for organisms of the typhoid and dysentery groups, and examination for parasites also was negative. The patient was given a low residue, high caloric diet with added commercial vitamin preparations. On May 29 treatment with neoprontosil was started, on J u n e 7 addition of casein digest to the ,diet was begun, and on J u n e 24 kaopectate was added. Preceding and during the first nitrogen balance period, the patient received each day approximately 96 calories per kilogram of body weight~ with 0.69 Gin. of nitrogen per kilogram, 42 per cent of which was derived from casein digest (80 Gm. of casein digest per day). I n addition she was given each day neoprontosil, 6 Gin. ; thiamine chloride, 1.5 mg. ; nicotinic acid, 200 rag. ; K i n n e y ' s yeast extract, 8 e.c. ; o]eum pereomorph, 45 drops; kaopectate, 90 c.c. ; a n d ascorbie acid, :100 rag. The nitrogen balance was markedly positive, the retention averaging 0.15 Gm. per kilogram per day. The child's general conditon became considerably improved; and between July 5 and July 23 the number of stools decreased from three to five a day to one or two. The casein ,digest was then withdrawn a n d the patient was given a diet containing 0.59 Gin. of nitrogen per kilogram per day, derived from low residue foods. The nitrogen retention was 0.08 Gin. per kilogram per day, and the stool nitrogen did not change appreciably. The patient continued to do well a n d returned home on August 4 on a low residue diet without added casein digest. She re-entered the hospital two months later in a n acute exacerbation. I t seemed advisable to rest the gastrointestinal tract completely, and intravenous feeding with casein digest and glucose was undertaken. On two successive days a f t e r having received intravenously some of the same lot of solution used in several other patients without reactions, the child developed chills and fever, which rose to 40 ~ C., and she appeared very much prostrated. No f u r t h e r attempts were n~ade to continue casein digest feeding by vein.
Interpretation.--After s e v e r a l w e e k s o n a l o w r e s i d u e d i e t i n w h i c h the nitrogen intake was derived chiefly from dairy products and casein digest, the patient who was suffering from chronic ulcerative colitis showed considerable clinical improvement. The nitrogen balance was markedly positive.
7.2
7.7
9/18/40 9/19/40 9/20/40 Average
(XG.)
9/ 4/40 9/ 5/40 9/ 6/40 Average
DATE
BODY WEIGHT
24 ~m.)
24 HR.
24 HR.)
FAT ( G ~ . PEI~
O . .~s
99 99 99 99
(Taken) 172 172 172 ]72
(Offered) 1,238 ],238 1,238 1,238
(Taken) 1,206 1,206 I~206 i 1,206
(Taken) 37 37 37 37
74 74 74 74
(Of(Offered) fered)
CHO (GI~. P E R
CALORIES PER
CASE 4
TABLE IV
4151 4.78 4.43
(Tfg)
(Of(Taken) fered) 4.57 3.53 4.87 2.63 4.87 [ 4.09 4.71 3.42
FOOD
FOOD INTAKE
(a~I.)
(Taken) 2.4 2.4 2.4 2.4
0.65
(Offered)
! - -
I i
i
0.89
(Taken)
0.48
(Taken)
TOTAL PER KG.
4.75 4.16 6.66 5.19
0.74
0.42
(G~.)
2.07 1.88 2.50 2.]8
FECES
>m
+0.90
+0.82
24 ~
HR.
+0.12
+0.11
24
PER KG. PER GBI.
BALANCE ~f. PI
NITROGEN
7RIN
EXCRETION
SEVERE MALNUTRITION ( A c R O D Y N I A )
CASEIN DIGEST ENI.V. TERALLY
~ITROGEN
AGe, 2 89 YEARS
b..a
7/26/40 7/27/40 7/28/40 A~erage
7/17/40 Average
7/16/40
7/15/40
DATE
33.6
31.3
BODY ~u (XG.)
127 127 127 ]27
173 173 173 173
2,989 2,989 2,989 2,989
2,898 2,898 2,898 2,898 190 190 190 190
207 207 207 207
24 HI~.)
2r ~R.)
PER
24 ~ .
19.96 19.78 ]9.86 ]9.87
11.9 12.0 12.18 12.03
FOOD
FOOD INTAKE
AGE, 12 YEARS
FAT (G~i. F E E
A. ~.
OHO (GI~r PER
CALORIES
CASE 5
9.6 9.6 9.6 9.6
ENTERALLY I.V.
NITROOEN ( ~ . )
0.59
0.69
PER KO.
TOTAL
CHRONIC D I A R R H E A
TABLE V
13.96 15.]1 15.70 ]4.93
14.43 14.48 ]4.61 14.51
URINE (G~.)
2.36
2.30
+2.58
+4.82
+0.08
+0.15
24 HR.
KG. P E K
GIrl. PER
BALANCE G~[. PER 24 HR.
NIT}COGEN
FECES (G~-)
EXCRETION
ULCERATIVE COLITIS
C~
O
9
5~
5~
Z
318
THE JOURNAL OF PEDIATRICS
CASE 6.--1~. H., a 6-year-old white girl, entered the hospital on April 14, 1940, with generalized edema, suffering from chronic glomerulonephritis. Five days after entry she ,developed a type u pneumoeoceus peritonitis which was treated successf u l l y with snlfathiazole. I n May she had a n erysipeloid skin infection which also was treated successfully with the same drug. On severM occasions during July and August she developed a mild rhinitis. The urine on admission contained large amounts of protein; the quantity, however, gradually decreased but with considerable fluctuation from about 12 Gin. per 24 hours to only a trace by qualitative test. Microscopic examination revealed increased numbers of red blood cells, white and epithelial cells, and occasional casts. There was never any appreciable anemia. The blood pressure usually was only slightly elevated and on just one occasion the systolic pressure was noted to be as high as 140 ram. I-Ig. The blood urea clearance was 155 per cent of the normal. The serum total protein until July remained around 4 Gin. per 100 e.c., and the albumin usually was below 1.5 Gin. With gradual recovery from the nephritis and concomitant with the addition o2 casein digest to the diet, the total serum protein during the course of three months gradually rose to 6.49 Gin. per 100 e.c., with 3.75 Gin. albumin. During the first balance periad the diet contained the usual food proteins with 0.40 Gin. nitrogen per kilogram of body weight per day, and the nitrogen retention was 0.02 Gm. per kilogram per day (Table u I n the second period, when casein digest was substituted for the animal protein a n d comprised about two-thirds of the nitrogen intake with the calories increased about 20 per cent, the nitrogen retained was 0.05 Gin. per kilogram, with, however, some increase in stool nitrogen. I n the t h i r d period the total caloric intake was a g a i n increased and the nitrogen intake was 0.47 Gin. per kilogram and was .derived from the usual food. The nitrogen content of the stools decreased considerably, a n d the retention rose to 0.14 Gm. per kilogram per day. I n the fourth period casein digest again replaced the animal protein in the diet but this time constituted slightly less t h a n one-half of the nitrogen intake. AgMn the stool nitrogen increased but the nitrogen retention was almost the same.
Interpretation.--When casein digest was substituted for animal protein in the diet, the patient continued to ha~e a positive nitrogen balance; there occurred, however, some increase in the stool nitrogen. CASE 7.--L. B., a 5-year-old colored boy, re-entered the hospital on Sept. 11, 1940, with marked nephrotic edema and a n erysipelo~d infection of the left knee. He was treated with sulfathiazole, and the infection subsided within a few days. During the time that he was in the hospital and while the nitrogen balance studies were being carried out, the amount of edema varied considerably and occasionally he became edema-free. On admission there was marked proteinuria an~d during the period of hospitalization the excretion of protein ranged from less t h a n 1 Gin. per twenty-four hours to 6 Gin. On microscopic examination of the urine, the number of red blood cells did not appear to be inareased. There was only a slight degree of anemia. The serum t o t a l protein values ranged f r o m 3.08 to 4.77 Gin. per 100 c.c., the albumin from 0.90 to 2.10 Gm., and the nonprotein nitrogen from 20 to 29 rag. per 100 c.c. Seven nitrogen balance periods were carried out. During the first, the calorie intake was 78 calories per kilogram of ideal body weight (18.6 kg.), with 0.40 Gin. nitrogen per kilogram derived from ordinary f0ads (Table V I I ) . The nitrogen retention averaged 0.06 Gin. per kilogram per day. I n the second period casein digest replaced the usual food protein; the nitrogen intake, being unchanged with the calories, increased to 86 per kilogram. The nitrogen retention was approximately
9/ 2/40 9/ 3/40 9/ 4/40 Average
8/23/40 Average
8/22/40
8/21/4o
8 / 6/40 8 / 7/40 Average
S/ 5/40
8/ 2/40 Average
8/ 1/4o
7/31/40
D~TE
17.2 17.1 17.2
16.6 16.5 16.6
16.3 16.5 16.3
16.0 16.7 16.2
BoDY WEIG T (KG.)
R.H.
TABLE V I AGE, 6 YEAES
1,617 1,617 1,617
1,642 1,642 1,642
1,312 1,312 1,312
1,077 1,077 1,077 1,077
2O2 202 202 202
198 198 198 198
123 123 123 123
83 83 83 83
65 65 65 65
73 73 73 73
7O 7O 7O 7O
65 65 65 65
4.35 4.65 3.64 4.22
8.23 7.86 7.54 7.88
1.81 2.34 1.93 2.03
6.49 6.31 6.53 6.44
3.6 3.6 3.6 3.6
4.2 4.2 4.2 4.2
TERALLY
0.46
0.47
0.39
0.40
4.40 5.26 4.734.79
5.59 5.04 5.54 5.32
4.61 3.81 4.44 4.28
3.80 4.88 4.70 4.46
4.78 4.79 4.75 4.77
4.50 3.54 3.98 4.00
5.13 4.50 4.29 4.64
.60 .38 .03 .33
.61 .25 .79 .55
.11 .27 .46 .28
.39 1.03 1.15 .86
(G~.)
(aM.)
(G~.) 5.52 5.53 5.44 5.50
PROTEIN
N.P.N.
j
0.90
0.27
1.08
0.69
FECES (GM.)
NITROGEN
TOTAL
URINE
EXCRETION
I%]-EPHROTIC STAGE OF GLOMERULONEPHRITIS
FOOD I NT'-A-KE NITROGEN (aM.) CALORIES oso I PAT CASEIN DIGEST PER (GM. FER I (GM. PER TOTAL FOOD EN24 ~R. 24 I-IR.) 1 24 HE.) PEI~ KG. LV.
CASE 6
+2.13
+2.29
+0.87
+0.26
24 HR.
GM. P E R
+0.12
+0.14
+0.05
+0.02
24 ~ a .
KG. PER
GM. P E R
BALANCE
17.1 17,4 17.7 17.4
19.5 19.1 19.1 19.4
20.1 20.2 20.0 20.1
20.1 20.0 20.2 20.1
D%TE
9/25/40 9/26/40 9/27/40 Average
9/30/40 10/ ]/40 1 0 / 2/40 Average
10/7/40 1 0 / 8/40 1 0 / 9/40 Average
10/14/40 10/15/40 10/16/40 Average
1,835 1,835 1,835 1,835
1,835 1,835 1,835 1,835
1~595 1,595 1,595 1,595
1,449 1,449 1,449 1,449
24 ~R.
PEI~
CALORIES
10/21/40 18.2 1,835 10/22/40 .18.2 1,835 10/23/40 18.0 1,835 Average 18.1 1,835 *Small amount of urine lost.
(KG.)
BODY ~EIGttT
~R~)
170 170 170 170
170 170 170 170
170 170 170 170
170 ]70 170 170
163 163 163 163
24
(GM* PER
CI~O
L. ]~.
AGE, 5 Y E A R S
75 75 75 75
75 75 75 75
75 75 75 75
75 75 75 75
68 68 68 68
0.78 0.78 0.78 0.78
0.78 0.78 0.78 0.78
0.78" 0.78 0.78 0.78
0.78 0.78 0.78 0.78
7.42 7.49 7.29 7.40
14.16 14.16 14.16 14.16
13.38 13.38 13.38 13.38
]3.60 13.60 13.60 13.60
6.40 6.40 6.40 6.40
0.80
0.76
0.77
0.39
0.40
FOOD INTAKE NITROGEN (GM.) FAT CASEIN DIGEST TOTAL (GI~. P E R FOOD ENTERPER 24 RR.) ALLY LV. KG.
CASE 7
TABLE V I I
11.27 "9.81+ 11.25 10.79+
11.95 9.85 10.40 10.73
9.60
I0.01
8.21 10.57
4.57 4.75 4.85 4.76
6.06 5.87 5.94 5.95
TOTAL (G~.)
10.70 9.30+ 10.58 10.19+
9.10 9.63 9.98 9.57
7.70 9.49 8.90 8.70
4.50 4.40 4.47 4.46
4.75 5.43 5.39 5.19
0.57 0.51+ 0.67 0.60+
2.85 0.22 0.42 1.16
0.51 1.08 1.11 0.90
0.07 0.35 0.38 0.30
1.31 0.44 0.55 0.76
1.24
1.30
1.16
1.06
0.42
NITROGEN EXCF~ETION URINE FECES N.P.N. PROTEIN (G~.) (G~L) (e~.)
NEPttROSIS
+2.91+
+2.13
+3.62
+1.36
+1.03
24 HR.
G~[. PER
+0.16+
+0.11
+0.19
+0.07
+0.06
KG. PER 24 Rm
G~[. pER
BALANCE
9/ 9/40 9/10/40 9/11/40 Average
DATE
14.7 15.2 15.6 15.2
(~:G.)
BODY "WEIGtIT
8
l~. B.
1,719 1,719 1,719 1,719
137 137 137 137
85 85 85 85
9.13 9.88 10.77 9.93
FOOD
(GIVe.)
4.80 4.80 4.80 4.80
I
CASEIN DIGEST ENTERI.V. ALLY
NITROGEN
AGE, 21/.2 YEARS FOOD INTAKE
FAT CALORIES cI~IO PER J (a~. PER ( G ~ . P E R 24 H m ) 24 HR. 24 HR.)
CASE
TABLE VIII
0.97
TOTAL PER KG.
I
9.74 10.66 11.40 10.60
(G~.)
TOTAL 8.23 8.48 9.62 8.78
(a~.
1.51 2.18 1.78 1.82
(O~i.)
1.69
N~TEOGEN EXCRETION URINE FECES N . P . i N PROTEIN (a~.)
~TEPHROTIC STAGE OF GL0~fERULONEFHROSIS
+2.44
24 HR.
GM. PER
+0.16
GI~I. PER KG. PER 24 H~.
BALANCE
>
b~
Q >
k2
0
U~
u~
>
Z Z
322
THE JOURNAL OF PEDIATRICS
the same with an increase in the stool nitrogen. The data on the third period in which casein digest was given by both oral and intravenous routes is not included because on more than one occasion vomiting occurred. During the last three balance studies the caloric intake was approximately 99 calories per kilogram, with an average of 0.78 Gin. nitrogen per kilogram, which was derived very largely from casein digest given orally. In these three periods the nitrogen balances were markedly positive, ranging from 0.11 te 0.19 Gin. per kilogram per day. It is of interest
to note that between October 5 and October 24, while casein digest was the only appreciable source of nitrogen in the diet, the patient's serum total protein rose from 3.08 Gin. per 100 c.c. to 4.77 Gin., and the albumin from 1.03 to 2.10 Gin.
Interp~vtatio~.--When casein d i g e s t r e p l a c e d t h e u s u a l f o o d p r o t e i n , t h e p a t i e n t r e m a i n e d in p o s i t i v e n i t r o g e n b a l a n c e w i t h an i n c r e a s e in stool n i t r o g e n . W h e n t h e q u a n t i t y of c a s e i n d i g e s t t a k e n was i n c r e a s e d b y 100 p e r cent, t h e n i t r o g e n r e t e n t i o n i n c r e a s e d a p p r e c i a b l y . CASE 8.--1% B., a 21~-year-old white boy, was in the hospital for over a year with the nephrotic type of glomerular nephritis. During this period he suffered from repeated episodes of infection and on several occasions was treated with one of the sulfonamides. During the entire period in the hospital, there was marked proteinuria which, at times, amounted to as much as 14 Gm. per day. Microscopic examination o f the urine usually revealed occasional red blood cells and varying numbers of casts, quite frequently fatty in nature. The serum albumin was greatly reduced during the entire perio.d of observation. On discharge from the hospital the total serum protein was 3.80 Gin. per 100 c.c., the albumin, 0.92, and the nonprotein nitrogen, 33 mg. per cent. Casein digest (10 to 40 @m. per day) was added to the patient's diet during nearly all of the seven-week period preceding the nitrogen balance study. The protein intake varied considerably; occasionally, it was very low but more often was between 0.3 and 0.6 Gin. of nitrogen per kilogram per day. Because of more or less persistent nausea with occasional vomiting, only one balance period was obtaine.d. During this period the nitrogen intake averaged 0.97 Gin. per kilogram per day, approximately one-third of it being derived from casein digest. The patient was in marked positive nitrogen balance, retaining 0.16 Gin. per kilogram per day (Table VrII). This retention occurred while his urinary protein nitrogen averaged 0.12 Gm. per kilogram per day. The patient returned home still with active nephritis and has continued to receive 40 Gin. of casein digest per day added to his regular ~]iet. At the time of this writing, June 1, 1941, he continues to have intense proteinuria and usually has considerable edema. SUMMARY AND CONCLUSIONS I n e i g h t c h i l d r e n t h e u t i l i z a t i o n of a n e n z y m a t i c casein digest, A m i g e n , was s t u d i e d w h e n g i v e n in one or m o r e of t h e f o l l o w i n g w a y s : (1) as a s u p p l e m e n t to an o r d i n a r y d i e t ; (2) as a r e p l a c e m e n t of m eat , milk, a n d eggs~ in th e d ie t; a n d (3) as t h e o n l y a p p r e c i a b l e source of n i t r o g e n , g i v e n e i t h e r e n t e r a l l y , i n t r a v e n o u s l y , or b y t h e c o m b i n e d e n t e r a l a n d i n t r a v e n o u s routes. C o n c l u s i o n s w e r e as f o l l o w s : 1. I t was easily possible to i n c r e a s e a n o r d i n a r y n i t r o g e n i n t a k e of 0.4 t o 0.6 Gin. p e r k i l o g r a m of b o d y w e i g h t b y 50 p e r cent or m o r e w h e n casein d i g e s t was g i v e n as a s u p p l e m e n t to t h e r e g u l a r diet.
~ART]KANN E,T AL,. :
STUDIES OF A]V[IN0. ACID ADfC[INISTt~ATION
323
2. When casein digest was given enterally as a substitute for meat, milk, and eggs, positive nitrogen balances were maintained at essentially unchanged levels. 3. When almost the entire food nitrogen was replaced by an equal amount of casein digest nitrogen administered enterally, nitrogen retention as observed in single three-day balance periods was essentially unaffected. When the casein digest intake was approximately doubled, nitrogen retention doubled or tripled. In one patient when casein digest was the only appreciable source of nitrogen and half was given enterally and half intravenously, the nitrogen retention equaled that observed when the entire amount of casein digest was given enterally as: well as that when the nitrogen intake was derived from meat, milk, and eggs. In another patient in a similar study less nitrogen was retained when half of the casein digest was given entera]ly and half intravenously than when it was all given enterally or when meat, milk, and eggs were the chief sources of nitrogen. Because of the occurrence of reactions, a such as vomiting, chills, and fever, or phlebitis with edema, or because of unrelated intercurrent infections, attempts to obtain nitrogen balance data were unsuccessful when casein digest as the only appreciable source of nitrogen was given entirely by the intravenous route. REFERENCES 1. 2. 3. 4. 5.
Buglia, G.: Ztsehr. f. Biol. 58: 162, ]912. I-Ienriques, V., and Andersen, A. C.: Ztschr. f. physiol. Chem. 88: 357, 1913. Van Slyke, D. D., and Meyer, G . M . : g. Biol. Chem. 16: 197, 1913. 0shorn, T. B., and Mendel, L . B . : J. Biol. Chem. 26: 1, 1916. Mueller, A. J., ]~en~nerer, K. S., Cox, W. M., Jr., and Barnes, S. T. : J. Biol. Chem. 134: 573, 1940. 5u. Cox, W. M., and Mueller, A . J . : Proc. Soc. Exper. Biol. & Me d. 42: 658, 1939. 6. Elman, R., and Weiner, D. 0.: J . A . M . A . 112: 796, 1939. 7. Carbotfl~d, I., Clark, 1~. It., and McKechnie, 1%. E. : Am. J. Digest. Dis. 6: 185, 1939. 8. Fetzer, L. W.: Dallas M. 5. 25: 75, 1939. 9. Shohl, A. T., Butler, A. M., Blaekfan, K. D., and MacTachlan, E. : J. PEDIA~. 15: 469, 1939. ]0. F a r r , L. E., and MacFadyen, E. D.: Proc. Soe. Exper. Biol. & Med. 42: 444, ]939. 10a. F a r r , L. E. : J. PEDI/~T. 16: 679, 1940. 11. Altshuler, S. S., Hensel, H. M., Sayhum, M. : Am. J. M. Se. 200: 239, 1940. 12. Madden, S. C., Noehren, W. A., Waraich, G. S., and Whipple, G. If. : J. Exper. Med. 69: 721, 1939. 13. l~adden, S. C., Finch, C. A., Swalbach, W. G., and Whipple, G. It.: 5. Exper. 1Y[ed. 71: 283, ]940. 14. Holman, I~. L., and Mebane, 5. G. : 5. E x p e l Med. 71: 299, 1940. 15. Elman, R.: Proc. Soc. Exper. Biol. & Med. 43: ]4, 1940. ]6. l~cCanee, tr A., and Widdowson, E. M. : The Chemical Composition of Foo.ds, London, ]940, His M a j e s t y ' s Stationery Office. 17. Peters, 5. D., and Van Slyke, D. D. : Quantitative Clinical Chemistry, Baltimore, 1932, Williams and Wilkins Co., vol. 2, p. 518. *During the past year ~ much improved solution of Amigen has been furnished us by Mead Johnson & Co., and its use in concentrations of from 3 to 10 per cent is rarely followed by even mild reactions. In a later communication we intend to discuss the many" clinical uses for intravenously administered solutions of Amigen.
324
THE JOURNAL OF PEDIATRICS
ADDITIONAL PAPERS WHICH HAVE APPEARED SINCE THE COMPLETION OF OUR STUDY 1. 2. 3. 4. 5. 6. 7.
Shoht, A. T., and Blaekfan, I(. D.: J. N u t r i t i o n 20: 305, 1940. Elman, Robert: Ann. Surg. 112: 594, 1940. F a r r , I~. E., Emerson, K.~ Jr., and Fntcher, P. It.: J. PE~)IA~:. 17: 595, 1940. Farr, :L. E.: Connecticut M. J. 5: 24, 1941. Zetzel, L., and :Banks, B. M.: Am. J. Digest. Dis. 8: 2], 194I. Hill, Louis W e b b : J . A . M . A . 116: 2135, 1941. Madden, S. C., Turner, A. P., Ir A. P., and Whipple, G . H . : J. Exper. Med. 73: 571~ 1941. 8. Editorial: J. A. 1VI. t . 116: 838, 1941. 9. Cox, Warren M., Jr., Mueller, Arthur J., and Fiekas, Dallas: Personal communicatmu.