Amino acid metabolism in parenteral nutrition: With special reference to the calorie: Nitrogen ratio and the blood urea nitrogen level

Amino Acid Metabolism in Parenteral Nutrition: With Special Reference to the Calorie:Nitrogen Ratio and the Blood Urea Nitrogen Level Wei-Jao A

clinical

made

and

parenteral

nutrition was

nitrogen urea

tween

the

the

of urinary

the

and

ratio

excretion

of urea and

caloric 450

tion

nitroni-

that

the

acid

directly

supply,

intake

is

in

and

calories

Blood

the

urea

during

for

complete

the

level

of amino

required of

ratio

cal-

can

be

acid utiliza-

nutrition.

not only by renal

also by calorie:nitrogen

for

proportional

nonprotein

nitrogen

parenteral

is influenced

is utilized

neighborhood

or 425

used as a parameter

the

amino

revealed

is

of 1 g of nitrogen

total

ories.

as beand

caloric

utilization

the

amino

synthesis

to the

a

cor-

Kasai

to which

protein

calorie:

as well

nitrogen, results

and

and Morio

extent

was

Good

infusate

level,

Ohashi,

during

glucose

between

nitrogen

Final

study

solution.

calorie:nitrogen

nonprotein

trogen.

with

of

Eisuke

metabolism

acid

noted

ratio

blood amount

acid

amino

relation

gen,

experimental

on amino

synthetic

Chen,

Its

level

function

but

of infusate.

A

LTHOUGH central venous hyperalimentation has been widely employed since it was reported by Dudrick et al. in 1967,‘*2 many metabolic problems remain to be solved. Amino acid metabolism is among the most important of these. It is well known that in order to effectively utilize amino acid for protein synthesis an adequate caloric intake is necessary. For this purpose, Moore3 recommended a nonprotein calorie:nitrogen ratio of 150-200. Lee et al.4 and Peaston,’ however, preferred more than 200 cal per 1 g of nitrogen. The optimal calorie:nitrogen ratio remains unknown. In our study of amino acid metabolism, we regularly measured the urea nitrogen of both blood and urine in patients receiving parenteral nutrition. The effect of infusing the solutions of varying calorie:nitrogen ratios upon the blood urea nitrogen levels was studied. Furthermore, effect of this upon the amount of urinary excretion of urea nitrogen, nonprotein nitrogen, and amino nitrogen wasobserved. The clinical results were further evaluated by animal experiments. MATERIALS

AND

METHODS

From July 1969 to the end of 1972. 32 infants and children received intravenous versity Hospital. examined

During

were checked

urea nitrogen,

Animal

nutrition

Reprint

of the Tohoku

Uni-

urea

nitrogen. urine

nitrogen

Except

and ammo

(Table

nitrogen.

blood

glucose and serum

was collected for sorbitol.

for analysis

01

which

was in-

I). glucose was the only source of nonprotein

calorie

G was the only protein source.

experiments

were carried out on ten adult mongrel

From the Second Department

University

blood

or once every 2 days. Daily

G solution

in age from 5 days to 8 yr

of Surgery

23 were males and nine were females. The last ten cases were

failing with the first three dogs in achieving

Receivedfor

varying

at the Second Department

parentera

daily

total nonprotein

cluded in the Sohamin and Sohamin

therapy

Of these patients,

in detail.

electrolytes

infusion

publication

oJ‘Surgery.

Tohoku

dogs weighing

fixation

that

would

from 5 to 8 kg. After have lasted for more

Llniversu?; School of Medicine.

Sendai. Japan.

May 30. 1974.

requests should be addressed School of Medicine,

c@1974 b,z Grune & Stratton.

Metabolism, Vol. 23, No.

a catheter

to Dr.

Seiryo-cho.

Wei-Jao

Chen. Second Department

of Surgery.

Tokohu

Sendai. Japan.

Inc.

12 (December),

1974

1117

1118

WEI-JAO

Table L-lysine

1.

Composition

of Sohamin

G*

(HCI)

1920 700

L-methionine

680

660

L-phenylalanine

960

L-valine

640

L-orginine

(HCI)

1090

L-histidine

(HCI)

470

Glycine

600

Total

9020

Effective

nitrogen

1313

Sorbitol

500

Japan.

than 2 wk, we devised a technique parenteral

nutrition

was collected

that enabled

for periods varying

from the cystostomy.

cases. A relatively wider variation

(mg/dl)

1000

L-isoleucine

Osaka,

AL.

300

L-leucine

*Tonobe,

ET

Solution

L-threonine

L-tryptophon

CHEN

small amount

us to keep the remaining

ratio.

gradually

for the dogs were similar

acid (0250.3 Infusion

at intervals

were collected every day in order to estimate

7 dogs under

15 days to 268 days. In the last four

The infusates

of amino

of calorie:nitrogen

100, and this ratio increased

from

g/kg/day)

was started of 3-6

excretion

complete

dogs, urine

to those for clinical

was used in order to permit from

a calorie:nitrogen

days. Twenty-four-hour

of urea nitrogen,

nonprotein

urine

a

ratio

of

samples

nitrogen,

and

amino nitrogen. Nonprotein

nitrogen

was measured

sured by the copper

method,

method using 0.02-ml

samples.

The caloric

while

level of the infusate

by the micro-Kjeldahl urea

nitrogen

method.

was determined

in this series, except where specially

Amino by the

nitrogen

was mea-

diacetylmonooxime

mentioned,

represents

the

total caloric level.

RESULTS

Clinical Results In patients who received parenteral nutrition, an inBlood urea nitrogen. crease of the caloric intake while maintaining a relatively constant amino acid intake was found to be followed by a decrease in the levels of blood urea nitrogen. Similarly a decrease of the caloric intake led to a rise in the levels of blood urea nitrogen (Fig. I). Data obtained from three children who received complete parenteral nutriton and who were free from abnormal liver function revealed that there is an inverse linear correlation between the blood urea nitrogen levels and calorie:nitrogen ratios of the infusates (r = 0.85; p < 0.001). When the data obtained from the first 3 days of parenteral nutrition, from the first 3 postoperative days, and from the day when blood transfusions were performed were excluded, the correlation became more evident (r = 0.90; p < 0.001) (Fig. 2). The total daily Urinary excretion urea nitrogen and nonprotein nitrogen. excretion of urea nitrogen in urine was correlated directly with its concentration in the blood. When blood urea nitrogen levels were low, the amount of the urea nitrogen excreted in the urine was also low. The amount of the nonprotein nitrogen excreted in the urine is also roughly correlated with the urea nitrogen.

of

AMINO

ACID

1119

METABOLISM

w

z

2o

/dl

10

gm

I

3%

BUN

x.x

\ “-x-l-<-”

,a

/“\“._/”

,,,’ ,,*’

“. ,I-x-‘-~-_~_l .X.dr,~

Nitrogen

3

balance

45

LO

35

30

25

20

15

10

day

Fig. urea

Changes

1.

nitrogen,

nutrition.

White

excretion

of

gen;

black

and

of

the

blood

nonprotein bars

above

nonprotein bars,

urea

nitrogen, the

base

nitrogen; nitrogen

nitrogen

and line, base

levels,

nitrogen amino line

to

the

balance

amount in

a

N supply;

white

the

of

level

-x-,

of

daily

IO-mo-old bars

below

urinary

urinary boy the

excretion

during base

excretion

line, of

of

parenteral urinary

urea

nitro-

balance.

However, when total nonprotein nitrogen excretion decreased, the percentage of the urea nitrogen in the nonprotein nitrogen showed a significant decrease as well (Fig, 1). Amino nitrogen excreted in the urine was Amino nitrogen and creatinine. about 2’33-4% of the amino acid that had been infused. Without regard to the amount of nitrogen intake, creatinine output remained relatively constant during parenteral nutrition. Results oj’ Animal

Experiments

Results obtained from animal experiments were similar to those of the chnical cases. Blood urea nitrogen. Maintaining a constant intake of amino acid and increasing the caloric intake led to a decrease of the blood urea nitrogen. With a

Fig.

2.

children

Dota

obtained

revealed

verse

linear

blood

urea

that

correlation

(r

tained the days,

the

0.001).

more

the

first days

were

p < 0.001;

the

3 on

The

corby

circles)

ob-

feeding

of

postoperative which

performed y = 446

the infu-

evident

(open

inthe

and

of

parenteral

3 days,

and

<

data

from

first

transfusions 0.90;

p

became

excluding

levels

ratios

= 0.85;

relotion

three

is an

between

nitrogen

calorie:nitrogen sates

from there

-

blood (I

17.7x).

=

A-.

2

L

6

a

10

12

14 BUN

16

18

(mgldl)

20

1120

WEI-JAO

9

gm

800

1

XX

xxx

xx

Y

x

600~~

x

YX

BUN

,’

15

10

,’

x

,’

x

CHEN

ET AL

9 dl

5 5

400.~

10

Fig. 3. oknitrogen

20

30

40

50

60

70

Dog 4: Changes of blood urea nitrogen levels corresponding ratios of the infusates during parenteral feeding.

60

93

to the changes

of the cal-

relatively constant caloric supply, increasing the amino acid intake resulted in a rise in blood urea nitrogen levels. The blood urea nitrogen level decreased to a level of 2-4 mg/dl when the calorie:nitrogen ratio reached 450. After this, further increase of the caloric intake was not followed by a decrease of the blood urea nitrogen levels. Even if the amino acid was withdrawn from the infusates while maintaining the caloric intake at a constant level and glucose infused alone, further decreases in blood urea nitrogen level did not occur (Fig. 3). Data obtained from three of the dogs again demonstrated an inverse linear correlation between the calorie:nitrogen ratios of the infusate and blood urea nitrogen levels similar to that observed in the clinical cases (Fig. 4). Figure 5 demonUrinary excretion of urea nitrogen and nonprotein nitrogen. strates urinary excretion of nonprotein nitrogen, urea nitrogen, and amino nitrogen during parenteral nutrition with infusates of varying calorie:nitrogen ratios during a 3-mo period (Fig. 5). With a constant amino acid intake a gradual increase of caloric intake resulted in a gradual decrease of the urinary excretion of nonprotein nitrogen, urea nitrogen, and amino nitrogen. In a state of high nitrogen output (low calorie:nitrogen ratio), more than SS”,d of the total

f E

400

..

" P s!

300'~

3

200 .~

1°:i:: 2

4

6

8

10

12

IL

16

BUN (mg/dl)

18

Fig. 4. Data obtained from three dogs again demonstrated an inverse linear correlation between the blood urea nitrogen levels and the calorie:nitrogen ratios of the infusotes up to a ratio of 450.

AMINO

soil!

1121

ACID METABOLISM

‘\

-4-l i 1

ml-

_

NPN

( ,I 1 dmlnoN(%!

~,__

‘\

.~ ‘A_

199

1

.__ Lx 2

%3

- -~-~~---10 12 IL 3

A

Fig. 5. Correlation between the colorie:nitroratios of the infusater and the amount of urinary excretion of urea nitrogen, nonprotein nitrogen (OS gram) and amino nitrogen (as percentage of amino acid N supply). The horizontal linegen

1,

OLD__ az L il

urea N (gm)

A

-,.

gm

5

%

16

segments

show

the

standard

errors

(Dog 6, nitrogen intake 1.2 g/day

of

means.

or 0.25 g/kg/

day.)

nonprotein nitrogen was urea nitrogen. However, put (high calorie:nitrogen ratio), the percentage nonprotein nitrogen fell to less than 60’3”.

in a state of low nitrogen outof urea nitrogen to the total

DISCUSSION

Although the protein-sparing effect of the caloric intake is widely known, the definite caloric requirement for complete utilization of a protein source remains uncertain. Moore recommended I%200 nonprotein cal for I g of nitrogen because this is the normal ratio in the natural food.’ However, it does not follow that by using this calorie:nitrogen ratio a maximal utilization of a protein source will take place. Our clinical and experimental results suggest that for a certain amount of amino acid intake, the amount of the amino acid that is utilized for protein synthesis is directly proportional to the amount of caloric intake. The greater the caloric intake, the greater the extent to which the infused amino acid is utilized for protein synthesis and the less the extent to which it is broken down. Once a calorie:nitrogen ratio of 450 was reached, a further increase of caloric intake was not followed by a continued decrease of blood urea nitrogen. Urinary excretion of urea nitrogen at 450 was very close to the level at 500. This suggests that utilization of the amino acid may have reached a maximal limit by supplying 450 cal for 1 g of nitrogen. Why did blood urea nitrogen levels not decrease when the calorie:nitrogen ratio increased above a ratio of 450? Two factors may be considered. First, since there exists an obligatory protein catabolism of the body, no matter how many calories are supplied, there is a continuous breakdown of tissue protein, and, hence, urea is also produced continuously. Second, there may be an imbalance in the composition of amino acid solution used such that in spite of a relatively high caloric supply complete utilization is not possible. Since excluding amino acid and giving only glucose to maintain the caloric intake at a constant level at a calorie:nitrogen ratio of over 450 did not lead to a further

1122

WEI-JAO

CHEN

ET AL.

decrease of the blood urea nitrogen level, it is reasonable to assume that the minimal urea nitrogen level in the blood is mainly due to the unavoidable basal catabolism of the body’s proteins. Thus, we may conclude that the required caloric level for complete utilization of I g of nitrogen is in the neighborhood of 450 cal. The fact that when using a calorie:nitrogen ratio of 150P200, a rather significant portion is broken down as an energy source instead of synthesized for protein appears to be important. It has been mentioned by Rose’ that different protein sources require different calories in order to maintain a nitrogen balance. In the light of this observation, it is reasonable to suspect that the caloric requirement for the complete utilization of different protein sources will vary. While Sohamin required 450 cal for the complete utilization of 1 g of nitrogen, it is possible that the caloric requirement for casein, casein hydrolysate, and other amino acid solutions differs from this value. It is also suspected that among individuals, or even in the case of a single individual, this caloric requirement will vary according to general physical conditions.6 The three children on whom the data presented were based experienced relatively stable conditions during central venous hyperalimentation. One of them had been operated on for esophageal atresia and the other for intestinal obstruction. In these two cases, the effect of surgical intervention in the change of the blood urea nitrogen levels is not evident. Blood urea nitrogen levels in the initial 3 days of total intravenous nutrition showed a relatively low value, possibly because of low-protein intake before total intravenous nutrition. In general, the response of the blood urea nitrogen to a change in the calorie: nitrogen ratio of the infusates followed a similar pattern in both infants and children as well as in the adult dogs. It is known that urea is a main end product of protein degradation. The blood level of urea nitrogen is determined by both the rate at which it is produced in the body and the rate at which it is passed through the kidney. Renal function plays an important role in the control of the blood urea nitrogen level. Studies by Addis and Watanabe,’ Mosenthaly and Mackay and Mackay loconcerning the blood urea nitrogen levels in normal individuals revealed that in such individuals the blood urea nitrogen level is more or less directly proportional to protein intake. These studies, however, have neglected an important factor-caloric intake. Results obtained from our clinical and experimental studies showed that the blood urea nitrogen level is not only affected by protein intake but is also affected by simultaneous caloric intake. Furthermore, it is directly proportional to the calorie:nitrogen ratios of food intake. What we call the normal range of blood urea nitrogen may exist only because the calorie: nitrogen ratio of natural food is confined to a relatively narrow range. For patients receiving nutrition by the intravenous method alone, infusates with a wider range of calorie:nitrogen ratios become possible. A wide fluctuation of the blood urea nitrogen level during parenteral nutrition is frequently reported. “Jo When one interprets the blood urea nitrogen values of such patients, it is necessary to take this factor into consideration. High-calorie infusion therapy has been widely applied to the care of uremic patients. Our study clearly demonstrates that a minimal amount of protein

AMINO

1123

ACID METABOLISM

source in combination with a relatively high caloric intake may lead to a decrease of urea nitrogen. The fact that endogenous urea or exogenous urea can be utilized as a nitrogen source for synthesis of nonessential amino acids has G) been reported.‘3-‘5 Since the protein source used in this study (Sohamin contains much more essential amino acid than nonessential amino acid (E/N ratio = 3.48), the possibility that the decrease of blood urea nitrogen levels through an increase in caloric intake was the result of reutilization of the endogenous urea has been considered. It is our impression that the extent of reutilization of urea nitrogen is relatively limited if present at all. with the amount used of Sohamin G. Blood urea nitrogen levels obtained at the time of infusion of a solution with calorienitrogen ratio of more than 450 did not differ significantly from those obtained by the infusion of glucose alone. The caloric intake itself was kept constant. Changes of the blood urea nitrogen level and of levels of urinary excretion of various nitrogens in this series are the result of a shift in protein metabolism rather than due to reutilization of the endogenous urea. REFERENCES I

Dudrick

Growth

SJ.

Rhoads

JE.

of puppies receiving

quirement

Vars

HM:

all nutritional

by vein. Fortschr

Parenteral

re-

Ernah-

2. Wilmore

DW,

Dudrick

of an infant

Moore FD:

203:860.

Metabolic

gtcal Patient. Philadelphia, 3

Lee HA.

33:Sl. 5

Care

and

Sur-

in renal failure.

Postgrad

Med J

1967

during intensive

Maintenance

patient

care.

of metabolism Postgrad

Med

Rose WC,

Coon

MJ,

Lambert

of man.

VI.

GF:

The

The

role

of the caloric intake. J Biol Chem 210:331. Tweedle

DEF.

Spivey

Choice of intravenous use after

surgical

amino

1954

J. Johnston

DA:

acid solutions

for

Metabolism

22:

operation.

173. 1973 vartation blood

Mackay

Hays

DM,

RF:

following

T.

Watanabe

CR:

in the concentration

of young

healthy

The

causes of

of urea

adults.

Arch

in the Intern

Med 19:507. 1917 9. Mosenthal

HO:

in nephritis

MS,

tndi-

Mahour

<;H.

infusion

in low-berth-wetght

problems

encountered.

Sur-

gery 7 I :X34, 1972

venous

JM, RD,

Heird

WC.

Winters

alimentation

tn

Schullinger

RW:

Total

JN. tntra-

low-birth-\setght

report.

J Pediatr

in-

X1:145.

1972 13. Rose WC. of nitrogen

Dekker

EE: Urea

for the biosynthesis

J Biol Chem 223:107, 14. Giordano

as a source

of amtno

actd.

1956

C: Use of exogenous

dogenous urea for protein

and en-

synthesis in normal

subjects. J Lab Clin

Med

62 231.

1963 15. Snydermann Roitman J Nutr

SE, Holt

LE Jr. Dancts

E, Bover A. Balis ME:

nitrogen: A limiting Metabolism

of normal

High-calorie

surgery

infants: Metabolic

4.

1977

Kaplan

Strauss J, Huxtable

HO Vol

LL: The concen-

blood

viduals. J Clin Invest 4:295,

and uremic

8. Addis

EM,

of urea in the

fants: A preliminary

amino acid requirement 7

tration

Gongaware J

Mosenthal

1922. p 3 I I

Appleton,

12. Driscoll

Peaston MJT:

RG,

New York.

therapy

1959

P, Ames AC: Paren-

Ji:.? 17, 1967 6

Hoskins

and Metabolism.

II.

1968 of the

Saunders.

Sharpstone

teral nutritiun

SJ: Growth

receiving all nutrients

exclusively by vein. JAMA 3

LF.

IO. Mackay

rung 2: 16, 1967 development

tn Barker

(eds): Endocrinology

78157, 1962

factor

J.

“Unessential”

for human

growth.