U.S. patent number 3,920,838 [Application Number 05/393,710] was granted by the patent office on 1975-11-18 for amino acid therapy.
Invention is credited to George L. Blackburn, Jean-Pierre Flatt.
United States Patent |
3,920,838 |
Flatt , et al. |
November 18, 1975 |
Amino acid therapy
Abstract
The invention described herein is a method of treatment of
patients during periods of severe negative caloric balance due to
dysfunction or disuse of the gastro-intestinal tract for reasons
such as trauma, burn, sepsis, other illness or physician's
prescription. The method is based on the parenteral application of
amino acids while substantially withholding the patient's intake of
carbohydrates. This method of treatment allows for the development
of starvation ketosis in the patient, facilitating the utilization
of fat stores and substantially reducing, even totally eliminating,
net nitrogen losses. The method described herein is a break from
the common medical practice used in the treatment of such patients
which common method is designed to prevent starvation ketosis by
supplying at least 100 gm of glucose per day to the patient.
Inventors: |
Flatt; Jean-Pierre (Princeton,
MA), Blackburn; George L. (Cambridge, MA) |
Family
ID: |
23555914 |
Appl.
No.: |
05/393,710 |
Filed: |
September 4, 1973 |
Current U.S.
Class: |
514/400; 514/419;
514/423; 514/561; 514/562; 514/565; 514/567; 514/5.5; 514/1.4 |
Current CPC
Class: |
A61K
38/01 (20130101) |
Current International
Class: |
A61K
38/01 (20060101); A61K 031/195 (); A61K
037/18 () |
Field of
Search: |
;424/319,177 |
Other References
juergens et al. -- Chem. Abst. Vol. 68 (1968) p. 76201r. .
Mayer et al. -- Chem. Abst. Vol. 72 (1970) p. 40349p. .
Knauff -- Chem. Abst. Vol. 75 (1971) p. 144,015e..
|
Primary Examiner: Rosen; Sam
Attorney, Agent or Firm: Goldberg; Robert L.
Claims
We claim:
1. A method of treatment of patients suffering trauma, sepsis,
infection, injury or other diseases during periods of severe
negative caloric balance due to disuse of the gastro-intestinal
tract, said method comprising the steps of developing and
maintaining a metabolic state simulating caloric starvation by
substantially withholding exogeneous carbohydrates from the patient
while parenterally administering amino acid solutions to said
patients while maintaining a negative caloric balance, said
parenteral administration of amino acid solution continuing at
least until said patient begins to use the gastro-intestinal tract
to take oral nourishment, said amino acid solution containing amino
acids in an amount sufficient to replenish depleted amino acid
pools in said patient.
2. The method of claim 1 where said source of amino acids is
selected from the group of aqueous solutions comprising L-amino
acids, protein hydrolysates and dipeptides.
3. A method of treatment of patients suffering trauma, sepsis,
infection or injury during periods of severe negative caloric
balance due to disuse of the gastro-intestinal tract, said method
comprising the steps of developing and maintaining a metabolic
state simulating caloric starvation by withholding exogeneous
carbohydrates from the patient while parenterally administering
amino acid solutions to said patient while maintaining a negative
caloric balance, said parenteral administration of amino acid
solutions continuing at least until said patient begins to use the
gastro-intestinal tract to take oral nourishment, said amino acid
solution being an aqueous solution of a member selected from the
group of L-amino acids, protein hydrolysates, dipeptides and
mixtures thereof, the amino acid concentration not exceeding 6% by
weight of the solution and being sufficient to provide a dosage of
from 0.06 to 1 gram of amino acid per kilogram of patient body
weight per 24 hour period.
4. The method of claim 3 where said amino acid solutions are
aqueous solutions of L-amino acids.
5. The method of claim 4 where said parenteral administration is by
infusion into a peripheral vein.
6. The method of claim 5 where said concentration is 2.5 to
4.5%.
7. The method of claim 6 where the dosage is 60 to 110 grams of
amino acid per 24 hour period.
8. The method of claim 4 where said L-amino acids are a mixture of
essential and non-essential amino acids.
9. The method of claim 8 where said essential amino acids are
isoleucine, leucine, lysine, methonine, phenylalanine, theonine,
tryptophan and valine and said non-essential amino acids are
alanine, argininine, histidine, proline, serine, glycine and
cysteine.
Description
BACKGROUND OF THE INVENTION
1. Introduction
This invention relates to a method of treatment of patients and
more particularly, relates to a method of treatment of patients
suffering dysfunction or otherwise prevented from use of the
gastro-intestinal tract.
2. Description of the Prior Art
Patients who must receive all or most of their daily requirements
of water and electrolytes parenterally are obliged to do so because
of dysfunction or disuse of the gastro-intestinal tract and/or
because of physician's prescription. Such patients are thus
temporarily incapable of ingesting protein, carbohydrates, fats,
vitamins, and other nutrients, and must turn to endogenous sources
and to nutrients provided parenterally, for the energy required for
survival and convalescence.
Normal daily requirements for men and women leading a sedentary
life, as recommended by the Food and Nutrition Board of the
National Research Council, are about 1 gm of protein and 35 to 38
kcal/kg of body weight. Such an allocation will provide about 11 gm
of nitrogen and 2500 cal for a 70-kg man, or 1440 cal/m.sup.2 of
body surface area/day.
Basal metabolic requirements vary with age and sex, but most daily
requirements are met by a range of 850 to 1100 cal/m.sup.2 for men
and 720 to 960 cal/m.sup.2 for women. With relatively minimal
activity, provision of 1100 cal/m.sup.2 /day and 10 to 12 gm of
nitrogen as amino acids or as protein should thus be sufficient to
prevent starvation and use of endogenous sources of protein and fat
in patients who do not have an excessively increased metabolic
rate. Such, however, is not the case.
In Cuthbertson, D. P., "The Disturbances of Metabolism Produced by
Bony and Nonbony Injury, with Notes on Certain Abnormal Conditions
of bone," Biochem. J., 24: 1244, 1930, it was first reported that
there was a marked loss of nitrogen, phosphorus and sulfur in young
men suffering from long bone fractures who were on a diet presumed
adequate to maintain balance. Losses continued up to 2 months and
were at their peak 6 days after injury. Since that time, loss of
nitrogen following trauma, elective operation, sepsis and burns in
excess of that expected under normal conditions with an equivalent
caloric balance has been confirmed by many others and Cuthbertson
has greatly expanded on the subject in Cuthbertson, D. P. "further
Observations on the Disturbance of Metabolism Caused by Injury,
with Particular Reference to the Dietary Requirements of Fracture
Cases," Brit. J. Surg., 23:505, 1936. It is widely believed that
the incremental increase in nitrogen excretion after injury
reflects the mobilization of F. D., acids to meet increased demands
for metabolic fuels. Moore, F.D., "Bodily Changes During Surgical
Convalescence," Ann. Surg., 137:289, 1953 using serial measurements
of body composition concluded that the tissue loss during surgical
convalescence is approximately half fat and half lean body mass by
weight.
Patients, not taking nourishment orally for any reason such as
trauma, sepsis, disease, injury or because of dysfunction of the
gastro-intestinal tract, in the absence of the administration of
parenteral fluids containing nutrients, will obviously suffer
starvation. Total starvation without deprivation of water results
initially in nitrogen excretion at approximately the prestarvation
rate and is much greater in well-nourished, vigorous individuals
than in those with previously reduced protein intake or
pre-existing wasting diseases. Initial weight loss is rapid, up to
1 kg/day in an average adult male. Within 4 to 5 days there is a
decline in both nitrogen excretion and rate of weight loss, as an
increasing proportion of the total caloric needs are supplied from
body fat. Water and sodium retention occur and further reduce
apparent weight loss.
The amount of carbohydrate reserves in the body is small, perhaps
200 to 250 gm. This is soon utilized, and, unless replenished by
intake of exogeneous carbohydrate, glucose must be manufactured by
the liver in order to maintain an adequate fasting blood glucose
level of some 60 mg/100 ml, to supply sufficient glucose for the
brain and the nervous system as well as certain other tissues such
as bone marrow, renal medulla and red cells. The liver performs
gluconeogenesis during starvation using as substrates glycerol,
deaminated amino acids residues, lactate, and pyruvate. The body
supplies a large part of its own energy requirements by partial
oxidation of fatty acids to ketone bodies which are released into
the circulation together with free fatty acids. These ketones
bodies are the major metabolic fuels for most other tissues during
starvation. Low levels of blood glucose and insulin promote the
release of amino acids from muscle into the circulation. Several of
these amino acids are converted by the liver into glucose with the
nitrogen converted into urea. This accounts for relatively high
urea nitrogen losses early in starvation and explains why intake of
glucose orally or intravenously in reducing the need for
gluconeogenesis will reduce nitrogen losses.
It is known that severe loss of nitrogen accompanying severe weight
loss during trauma, sepsis, disease, injury or other illness is a
major contributor to morbidity and mortality in patients. It has
been reported by Studley, H. D., "Percent of Weight Loss: A Basic
Indicator of Surgical Risk," Jour. Am. Med. Assoc., 106:458, that a
mortality figure of 30% was reached with patients suffering from
ulcer, colitis, severe burns, acute renal failure, and peritonitis
when the patient's weight loss reached 20% of the original body
weight. In thos patients who had an acute 30% loss of original body
weight, there was a near 100% mortality rate. Taylor and Keys,
"Criteria of Physical Fitness in Negative Nitrogen Balance," Ann.
N. Y. Acid. Sci., 73:465, 1958 noted material changes in physical
fitness when protein loss exceeded 150 grams (or some 15% from a
total of about 1000 grams contained in the total cellular proteins
of an average male.)
In view of the above, it is customary to attempt to avoid
starvation in patients unable to take nutrients orally for extended
periods of time. Such patients, following trauma or surgical
procedures are usually treated by infusion of parenteral fluids,
typically receiving from 200 to 600 cal/day in the form of glucose
(carbohydrate), thereby avoiding complete starvation. It is
recognized that glucose, in addition to providing some substrate
for oxidation, reduces the urinary excretion of nitrogen and
therefore, the overall catabolism of labile protein by nearly 50
percent, and further reduces or prevents starvation ketosis.
Schwartz, Editor-in-Chief, "Principles of Surgery," The Blakiston
Division, McGraw Hill Book Company, New York, 1969, pp 77-81, in
particular, page 79. Thus, the art has sought to prevent
starvation, or at least the symptoms of starvation such as
starvation ketosis, by the administration of parenteral fluids
containing carbohydrate, typically glucose.
To further diminish nitrogen losses, which reflect decreases of the
lean body mass, it is customary to parenterally administer amino
acids, but always in combination with other substrates to meet the
energy requirements (carbohydrates). Thus Moore, F. D., "Metabolic
Care of the Surgical Patient," W. B. Saunders Company,
Philadelphia, 1959, recommended that parenteral protein (amino
acids) not be administered in excess of a ratio of 1 gm of nitrogen
to 150 cal. More recently, Lawson, L. G., "Parenteral Nutrition in
Surgery," Brit. J. Surg., 52:795, 1965, has again confirmed the
importance of administering amino acids or protein hydrolysates
simultaneously with carbohydrate and/or fat solutions. According to
Lawson, this therapy results in a reduction of negative nitrogen
balance, compared to the infusion of carbohydrate alone, but does
not prevent net nitrogen losses.
Based upon the realization that excessive nitrogen loss is
detrimental, and possibly even fatal, as observed by Studley,
supra, and that nitrogen loss is greatly increased in patients that
are diseased, or affected by trauma, sepsis or other illness, as
described by Cuthbertson, Stephen and Randall, and Moore, supra,
there has been a constant search for a method of treatment that
would minimize nitrogen loss further, or even eliminate the same,
especially in treating patients undergoing a prolonged period of
severely negative caloric balance due to their inability to take
nourishment orally.
STATEMENT OF THE INVENTION
The invention described herein is a method of treatment of patients
during periods of severely negative caloric balance due to
dysfunction or disuse of the gastro-intestinal tract because of
trauma, sepsis, injury or other illness. This method of treatment
is characterized by a considerable reduction or prevention of
nitrogen losses in the patient during treatment, and in some cases,
the method even achieves a limited positive nitrogen balance.
The method of treatment of the invention comprises the parenteral
administration of a source of amino acids to the patient in the
substantial absence of carbohydrates. This therapeutic approach is
in sharp contrast with methods conventionally used in the prior
art, which require that amino acids be administered only in
combination with substantial amounts of carbohydrates, frequently
requiring the use of hyperosmolar infusates through a central
venous catheter.
The elimination of net nitrogen losses by the method of the
invention is indeed surprising since it is taught in the prior art
that carbohydrate infusion alone decreases nitrogen losses, which
is one of its major purposes. It is also surprising that the
treatment method of the invention can be carried out over a
prolonged period of time in the absence of carbohydrate intake
since carbohydrate is considered to be a necessary metabolic fuel,
necessary to prevent the symptoms of starvation such as starvation
ketosis, whereas the method described herein does not provide the
patient with exogenous carbohydrate, and yet this therapy can be
carried out over a prolonged period of time without endangering the
patient.
The invention described herein, in part, is based upon the
recognition that starvation ketosis occuring during severe negative
caloric balance allows more adequate fat mobilization, whereby
endogenous fat stores meet almost all energy requirements, with
little or no catabolism of protein, whereas administration of
carbohydrate impedes fat mobilization. The invention will be more
fully understood from the detailed description which follows.
DESCRIPTION OF THE DRAWINGS
In the drawings,
FIG. 1 is a schematic representation of energy metabolism in man
during prolonged starvation;
FIG. 2 is a schematic representation of a proposed metabolic fuel
regulatory system;
FIG. 3 presents nitrogen balance data of 9 patients receiving
intravenous peripheral protein sparing therapies;
FIG. 4 is a metabolic study protocol of a 70 year old woman
FIG. 5 is a metabolic study protocol of a 52 year old male;
FIG. 6 represents substrate profiles resulting from the
administration of different types of infusates to 10 patients;
FIG. 7 diagramatically represents fatty acid and nitrogen balance
during total or partial starvation;
FIG. 8 diagramatically represents a correlation between ketosis and
nitrogen balance during total and partial starvation;
FIG. 9 shows the relationship of glucose to insulin during total
and partial starvation;
FIG. 10 shows the relationship between insulin levels and nitrogen
balance during glucose infusion compared to acid infusion;
FIG. 11 graphically summarizes the urinary nitrogen loss of a 32
year old female suffering from a perforated duodenal ulcer;
FIG. 12 shows the fuel-regulatory scheme as a basis for comparing
metabolic consequences of glucose and amino acid infusions; and
FIG. 13 represents the accumulated nitrogen loss over four days in
patients receiving various infusates.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the description which follows, for a clearer understanding of
the invention, certain definitions will be given and certain
theoretical explanations will be offered, some of which might
appear to be redundunt in view of that described above. It is
repeated here, as necessary, to provide a complete description. It
should be clearly understood, however, that with respect to any
theoretical explanation offered, it is as currently understood, but
is not to be construed as binding or in any way limiting of the
invention.
The term "patient", as used hereafter, is intended to mean any
patient treated in accordance with the practice of the invention.
The reason for treatment by parenteral administration of amino
acids is not critical, it being understood that such treatment is
due to doctor's prescription necessitated by the condition of the
patient whether it be due to injury, sepsis, trauma or other
illness.
The term "amino acid" as used herein is intended to mean those
amino acids used in patient therapy such as those L-amino acids,
both essential and non-essential, conventionally infused into
patients along with glucose. The term is intended to include
protein hydrolysates and dipeptides.
The term "nitrogen balance" refers to the difference between intake
and excretion of nitrogen. A negative nitrogen balance therefore
refers to a loss situation where the excretion of nitrogen exceeds
intake.
The term "starvation" means the condition known in the art to exist
in a patent as a result of deprivation and lack of nourishment. As
used in relation to patients treated in accordance with this
invention, it is used in a slightly different sense as the patient
will exhibit the symptoms of starvation such as ketosis, but not
nitrogen loss.
The term "parenteral administration" is used in its conventional
sense to include intravenous infusion into peripheral veins as well
as other methods known to the art.
Since the process of the subject invention is a therapy involving
starvation in patients suffering stress, it is necessary to
understand the regulatory system which controls the availability
and utilization of metabolic fuels during starvation and the effect
of disease on adaptation to starvation.
Glucose and free fatty acids (FFA) are the major metabolic fuels
supplied by the blood to peripheral tissue for energy production.
Important metabolites of FFA oxidation in the liver are ketone
bodies cacetoacetate and 3-hydroxy-butyrate, which when released
into circulation by the lever can substitute for glucose as a
source of energy for parts of the body including the brain during
starvation.
Protein, when oxidized, yields 4 kcal/g. Approximately half of the
amount of protein lost during starvation is by direct oxidation of
amino acids, while the other half is used for the production of
glucose in the liver, via gluconeogenesis, a process which assumes
great significance when the supply of exogeneous carbohydrate is
restricted. This is important to supply glucose for the brain early
in starvation by providing ketone bodies (KB) as a substitute
source of energy for the brain. The body's metabolic adaptation to
starvation minimizes glucose utilization and the consumption of
protein.
FIG. 1 of the drawings describes energy metabolism in man during
prolonged starvation. The numbers shown near the double-lined
arrows express the daily calorie fluxes occurring to meet the
overall energy expenditure. It is of interest to note that protein
catabolism provides only 5% (90 in 1,900 kcal) of the total calorie
requirement, while ketone bodies supply the peripheral tissue with
some 500 cal, or 25% of the body's total calorie expenditure. The
remainder is covered by oxidation of FFA.
The efficiency of protein- and glucose-sparing in the body during
prolonged starvation is made possible by adaptive mechanisms for
using ketones as a major source of energy fuel. The rate of ketone
production was recently determined to be 130 g per day by the third
day of total starvation. Even the brain, which normally derives
100% of its energy from glucose, can substitute ketones to the
extent of 70% of its energy requirement.
Ketogenesis thus represents a vital mechanism in the physiologic
adaptation to starvation, facilitating the use of endogenous fat
stores by tissues which ordinarily cannot utilize FFA as such. When
the body's triglyceride reserves are used to supply most of its
energy requirements, nitrogen loss can be reduced to only 4 to 5 g
per day, late in starvation.
In a patient with a strongly negative caloric balance, therefore,
the presence of ketone bodies should be regarded as beneficial. It
is important to note that starvation does not lead to the
pathologic ketosis that occurs in decompensated diabetes. Ketone
bodies stimulate insulin secretion, and since insulin strongly
inhibits ketogenesis, a feedback control is established which
prevents ketosis from reaching pathological levels.
Failure to recognize this physiological role of ketogenesis in the
starved patient accounts for the common medical practice of
supplying at least 100 g of glucose per day to minimize ketosis as
discussed above. Unfortunately, making glucose available tends to
interfere with the metabolic pathways which enable the body to
conserve its protein under conditions of partial starvation.
It is helpful at this point to consider some of the major control
phenomena involved in the regulation of energy metabolism in men.
The structure of the "metabolic fuel regulatory system" proposed in
FIG. 2 is very simple yet it includes enough interactions to
explain how the integration of carbohydrate, fat and amino acid
metabolism takes place. FIG. 2 shows the concentrates of
circulating insulin (Ins), glucose (Gluc), free fatty acids (FFA),
ketone bodies (KB) and the various amino acids (AA). The plasma
concentration of each of these substances is determined by its
rates of release into and removal from the circulation.
The pathways for oxidative degradation of the various fuels lead to
terminal reactions which these pathways have in common. The
metabolic pathways thus serve as a metabolism funnnel. In this
integration of metabolic oxidations, the total energy generated
equals he energy expended. The interactions between insulin and the
metabolic fuels include three major feedback loops corresponding to
the major nutrient substrates.
Insulin facilitates peripheral uptake of glucose, in particular by
muscle, and adipose tissue, where it also stimulates the conversion
of glucose to glycogen, or triglyceride, respectively. Thus,
insulin lowers blood glucose levels, as illustrated in FIG. 2 by
the arrow which suggests that insulin "pushes" glucose levels down.
The release of insulin by the pancreas is stimulated by increasing
concentrations of blood glucose. Thus, glucose concentration "push"
blood insulin levels up, as suggested by another arrow in the
figure. Since glucose has a positive effect on insulin
concentration, and insulin, a negative effect on glucose
concentration, the interactions between glucose and insulin create
a negative feedback loop of the simplest possible design. The
existence of a negative feedback loop in a regulatory system has a
stabilizing effect, but it requires in addition a set point if the
system is to avoid drifting away from a particular operating
range.
A steady state condition is established when the inflows of glucose
and of insulin are equal to their outflows, and when their
concentrations thus remain constant. The most common steady state
condition is that encountered in the post-absorptive state. Under
these conditions glucose levels in man are adjusted so as to remain
within a relatively narrow range of 70 to 90 mg%. Insulin secretion
seems to occur to the extent required to achieve a fasting blood
glucose concentration which is near the physiological norm. This
norm apparently constitutes the primary set point in the glucose
insulin feedback loop.
Insulin decreases the release of free fatty acid from adipose
tissue by reducing cyclic AMP mediated activation of a hormone
sensitive lipase, as well as by increasing glycerol-phosphate
availability for FFA reesterification. Ketone body levels tend to
fluctuate in parallel with free fatty acid levels. Insulin has in
addition an antiketogenic action on the liver so that ketogenesis
can be suppresed even in a situation where FFA levels are high. The
effects of insulin on FFA and ketone body production thus tends to
lower the levels of these substrates in the blood as shown by an
arrow in FIG. 2.
Although FFA at very high levels, and perhaps more significantly
the ketone bodies, appear to be able to directly stimulate insulin
secretion, the major feedback effect on insulin secretion is
considered here to occur indirectly under normal physiological
conditions. Free fatty acids and ketone bodies can be used as
substrates for energy production by most tissues, where their
utilization is to a large extent proportional to their
concentration in the circulation. Since the total oxidation of
substrate is limited by the energy expenditure, elevation of FFA
and KB levels will reduce the consumption of glucose for energy
production in the body. The extent to which glucose can be spared
is demonstrated during prolonged starvation, when glucose oxidation
is reduced to some 50 grams per day. In reducing glucose outflow,
FFA and KB tend to elevate the levels of glucose, and they are thus
able to indirectly promote insulin secretion. This effect is
attenuated, however, because it operates through an intermediate,
glucose, subject to diverse influences. Furthermore this feedback
effect can function only to the extent required to reduce blood
glucose, but not necessarily FFA levels to near normal values.
Since, on the other hand, insulin levels directly affect FFA
release from adipose tissue, the feedback regulation between
insulin and FFA plus KB is asymmetrical in nature.
The organism's ability to regulate carbohydrate metabolism is
commonly determined by performing glucose tolerance tests. When the
removal of a glucose load proceeds more slowly than under
standardized post-absorptive conditions, this is taken to indicate
an "impairment in carbohydrate tolerance." However, to the extent
that this is due to elevation of FFA levels, a reduced rate of
glucose removal is due to a physiologically normal phenomenon, of
crucial importance in sparing glucose when carbohydrate intake is
restricted. Under these conditions a decrease in the rate of
glucose removal from the circulation should perhaps not be regarded
so much as an "impairment," but rather as an indication of the
organism's ability to adapt to carbohydrate or caloric deprivation.
The qualification implied by the term "impairment" could then be
reserved for situations where a reduced ability to utilize
exogenous glucose is due to causes different, or manifest beyond,
an elevation of FFA levels.
Insulin enhances the uptake of amino acids by peripheral tissues,
where it promotes the conversion of amino acids into proteins,
while its effects on different amino adids is variable, the
predominant action of insulin is to lower plasma amino acid
concentration (arrow pointing downwards in FIG. 2). As in the case
of glucose, the action of insulin includes stimulation of
transport, stimulation of synthesis, resulting in the deposition of
glycogen, fat or protein, and inhibition of the rate of breakdown
of these substances.
Glucogenic amino acids are converted to glucose in the liver and to
a limited extent in the kidney. Amino acids thus increase glucose
formation. This tends to elevate blood glucose levels (arrow in
FIG. 2), which in turn stimulates insulin release. This indirect
effect of amino acids on insulin levels is similar to that of the
FFA in the feedback loop involving fat metabolism: in one case this
is due to increasing glucose formation while in the other case it
is achieved by reducing glucose utilization. Furthermore, just as
ketone bodies can stimulate insulin secretion directly, certain
amino acids can directly increase the release of insulin. This
stimulation operates most effectively when prevailing glucose
concentrations are relatively elevated. The arrow describing the
direct effect of amino acids on insulin levels is therefore shown
in a manner suggesting that this action is subordinated to, and
reinforces the effect of glucose in driving insulin levels up.
In order to maintain a constant body composition, food consumption
must be adjusted to energy expenditure in terms of total calories,
and the oxidation of carbohydrates, fats and amino acids must be
adjusted to the proportion of these nutrients in the food ingested.
The efficiency with which this goal is achieved is illustrated by
the fact that a relatively stable body composition is maintained
during long periods in the life of an organism, even though the
proportions of different nutrients ingested varies widely. Certain
minimum requirements for amino acids, vitamins, and minerals must
of course be satisfied without which various forms of malnutrition
would develop, but this is not pertinent to the discussion of fuel
metabolism presented here. Maintenance of a constant lean body mass
is sought by the organism even when the intake of calories does not
match the caloric expenditure. Thus excesses or deficits in the
caloric balance are translated largely into changes in the amounts
of fat stored in adipose tissue. The nitrogen balance remains close
to zero even during periods during which intakes of protein and
calories are high. This shows that the degradation of amino acids
can vary over a considerable range in order to match protein
intake.
It warrants an important conclusion, namely that amino acid
oxidation can be rapid in spite of the prevalence of anabolic
conditions associated with high insulin levels. Indeed
administration of large doses of insulin can adversely affect the
nitrogen balance, by increasing the need for gluconeogenesis from
protein. On the other hand, during periods of deprivation, where
low insulin levels prevail, the consumption of metabolic fuels
shifts so as to minimize amino acid degradation and to preserve
body protein masses with remarkable efficiency.
In order to function under such variable conditions, a considerable
degree of integration between amino acid, carbohydrate and fat
metabolism must be possible. To the extent that the metabolic fuel
regulatory system described in FIG. 2 gives a correct description
of the major physiological regulatory interactions in the system,
it appears that this integration is achieved primarily by the use
of a component common to the three feedback loops involved in the
control of carbohydrate, lipid and amino acid metabolism. This
common component is insulin, and its importance in the control of
all aspects of energy metabolism has been increasingly
recognized.
The structure of the regulatory system is such that glucose, more
than the other metabolic fuels is able to influence insulin levels.
This is enhanced by the ability of the B-cells in the pancreas to
perceive, and to react to changes in glucose concentration.
Furthermore the maintenance of normal fasting blood glucose levels
appears to provide the fundamental set point in the metabolic fuel
regulatory system. Carbohydrates constitute more than half or
sometimes most of the nutrients ingested, and glucose is
qualitatively and quantitatively one of the most important
substances for energy production in peripheral tissues. Fluxes
through the glucose pool must therefore be able to vary widely, but
with glucose levels remaining within a relatively narrow
concentration range, to avoid hypoglycemia or glucosuria, and this
in spite of a rather limited capacity for storage of carbohydrate.
Thus it is not surprising that glucose should play a predominant
role in the regulation of insulin levels.
In the regulatory system discussed here no explicit provision is
made for hormones or other agents which directly enhance catabolism
of glycogen, fat, or protein. Some of these are short lived
"emergency" signals, which have priority over fuel economy. The
others are considered to be inversely related to the concentration
of insulin. Thus, for example, FFA release will increase when
insulin levels become low. Whether the release is due to a relative
lack of insulin or to relatively high levels of lipolytic signals
does not need to be specified in the simplified model developed
here.
Thus, as a result of its basic structure, the regulatory system
allows for one of the metabolic fuels to influence the metabolism
of the others. The important point of the above is that from this
scheme, it can be submitted that infusion of amino acids without
carbohydrates may allow more efficient utilization of endogenous
fat stores than accompanied by carbohydrate, allowing a metabolic
state to develop simulating total starvation, where amino acid
oxidation is reduced, and where the administered amino acids can be
effectively used for protein synthesis. The validity of this
approach to protein sparing therapy is established by the following
test procedures.
Nineteen surgical patients requiring intravenous fluid replacement
were treated with the following parenteral solutions: (1) 5%
dextrose solution (D5W) to deliver 100 grams of dextrose per 24
hours, (2) 3% crystalline L-amino acid solutions containing
essential and nonessential amino acids delivered 90 grams of amino
acids per 24 hours and (3) solutions containing 3% L-amino acids
and 5% dextrose to deliver 70 grams of amino acids plus 100 grams
of dextrose per 24 hours. The compositions of the L-amino acid
solution is as follows:
g in 2.5 L of isotonic (3%) Amino acid g/100 mL solution
______________________________________ Isoleucine 0.21 5.25 Leucine
0.27 6.75 Lysine 0.27 6.75 Methonine 0.16 4.00 Phenylalanine 0.17
4.25 Theonine 0.12 3.00 Tryptophan 0.05 1.25 Valine 0.20 5.00 All
essential 1.45 36.3 Alanine 0.21 5.25 Argininine 0.11 2.75
Histidine 0.08 2.00 Proline 0.33 8.25 Serine 0.18 4.50 Glycine 0.63
15.75 Cysteine 0.01 0.25 All amino acids 3.0 75.0 g amino acid N
0.45 11.3 Protein equivalent 2.8 70.0 Calories 120 300
______________________________________
Urine was collected over a successive 24 hour period beginning
immediately after the 7:00 A.M. blood specimen was obtained. The
volumes were measured and aliquots were frozen at -20.degree.C
until analysis of total nitrogen, urea nitrogen, and creatinine
were completed.
Glucose, lactate, pyruvate, B-hydroxybutyrate and acetoacetate were
determined enzymatically after deproteinization with perchloric
acid. Free fatty acids were titrated acidmetrically. Insulin was
measured by radioimmunoassay and urinary nitrogen by a
microKjeldahl method.
Daily urinary nitrogen excretion was determined on 24 hour urine
collections. The .DELTA.Nu corresponds to the urinary nitrogen loss
when on total fast or on dextrose infusions, or to the difference
between the grams of nitrogen administered in the form of infused
amino acids and the urinary nitrogen excretion. The overall
nitrogen balance was calculated by adding 11/2 grams of nitrogen to
the urinary nitrogen loss to account for fecal and cutaneous
losses.
The following table represents a clinical description of 10
patients receiving 2 to 3 liters of parenteral infusion per day for
10 to 14 days.
______________________________________ Weight (kg) Age Sex
______________________________________ JS 58.6 56 M Obstructing
cancer of colon LM 56.3 52 F Pelvic abscess FC 61.2 69 F Small
bowel obstruction CW 54.5 52 M Reactive hepatitis, subhepatic
abscess IC 76.2 28 M Stab wound of liver JY 89.5 64 M Gunshot to
abdomen with peritonitis BH 64.3 37 F subheptatic abscess with
perforated duodenal ulcer RW 54.5 47 M Emphysema, Chronic lung
disease, ileus LS 60.0 42 M Pancreatitis and pseudocyst SW 32.0 56
F Subtotal gastrectomy and dumping syndrome
______________________________________
The following table represents a clinical description of the
remaining 9 patients receiving a similar therapy but who were
generally more severely ill and demonstrated a higher protein
catabolism.
______________________________________ Weight (kg) Age Sex
______________________________________ K.A. 84 F 40% Burn J.B. 54.1
54 M Pancreatitis R.B. 106.4 46 M Multiple trauma W.C. 63.6 26 M
Pancreatitis A.D. 55.9 36 F Cholongitis T.G. 55.9 73 M CA of
sigmoid colon W.M. 61.4 40 M Perforated duodenal ulcer, subphrenic
abcess, pelvic abcess J.P. 109.1 25 F Subphrenic abcess A.V. 61.8
74 F Entero cutaneous fistula
______________________________________
No adverse effects could be attributed to the intravenous therapy
in any patient; no infections, cellulitis, thrombosis or pyrogenic
responses occurred. Except in one patient, (C.W.) with reactive
hepatitis, serum enzymes (SGOT and LDH), bilirubin and ammonia
levels remained within normal limits.
The first 10 patients represented moderate protein catabolism,
averaging a daily nitrogen loss of 7.1 g .+-. 3.5 g on
administration of dextrose in water. This is equivalent to loss of
44 g of protein per day (6.25 g of protein/gN), which, if this
protein was mobilized from muscle tissue, represents a loss of
about 0.5 pounds per day of muscle tissue.
Infusion of an amino acid solution, instead of the routinely used
5% glucose infusate, resulted in a reduction in the nitrogen loss
from -8.5 to -1.0 gN/day. The infusion of a mixture of glucose and
amino acids resulted in some improvement in the nitrogen balance
but not to the degree observed with amino acid infusion alone.
In the subsequent study of the 9 additional patients, the infusion
of amino acids instead of glucose resulted in a reduction in
nitrogen loss from -11.8 to -1.0 g/day, as shown in FIG. 3.
The metabolic study of a 70 year old female with bowel obstruction
secondary to adhesions is shown in FIG. 4. Intravenous infusion of
isotonic dextrose (D5W) or L-amino acids (3%) solutions were given
in amounts shown in terms of calories delivered per day. A
significant amount of protein was spared with the amino acid
infusion as evidenced by a sharp improvement in nitrogen balance
(.DELTA.Nu). The addition of carbohydrate to the amino acid
infusate did not improve the nitrogen balance. When the
administration of amino acid infusates was discontinued, the
nitrogen balance became negative. The protein sparing which
occurred with the infusion of amino acids is associated with a
decreased level of insulin and blood glucose and increased levels
of serum free fatty acids and ketone bodies.
A metabolic study in a 52 year old man with a duodenal fistula,
subhepatic abscess and reactive hepatitis is shown in FIG. 5. Serum
glutamic oxalacetic transaminase levels averaged 1,800 mU/ml and
bilirubin was 11 mg per cent. Although the clinical studies had to
be interrupted early because of the patient's condition (day 9),
the data clearly show that the nitrogen balance was better with the
infusion of amino acids (days 14 to 17) than with glucose. When the
infusate was changed from glucose (100 g per day) to amino acids
(70 to 90 g per day) the nitrogen balance rapidly returned to
normal. (See days 7 to 8 and 13 to 14). Furthermore, the addition
of glucose to the amino acid infusion (day 18) had an unfavorable
effect.
FIG. 6 gives the substrate profiles with the administration of
different types of infusates as well as the daily nitrogen
balances. When 100 g of glucose was delivered per day, the daily
nitrogen deficits were 8.5g. This figure is about half the nitrogen
deficit seen in the initiation of a period of total starvation.
Thus, the infusion of isotonic glucose solution had a definite
protein-sparing effect, which is a well known fact. Nevertheless,
the cumulative N loss (.DELTA.Nu) over a 4 day period amounted to
28.9 g .+-. 4 g which is equivalent to the loss of about 2 pounds
of muscle tissue. The substrate profile does not show the
characteristic pattern of starvation, that is, elevated levels of
free fatty acids and mild ketosis, even though the caloric balance
is severely negative.
The addition of amino acids to the glucose infusion improved the
nitrogen balance, and the nitrogen loss over a 4 day period
amounted to 15 g .+-. 6 g. The substrate profile was not
significantly altered from that observed with glucose alone.
In sharp contrast, the substrate profile during the administration
of amino acids alone show the elevation of free fatty acids and
ketone bodies which are typical of starvation. The nitrogen balance
(.DELTA.Nu) during peripheral infusion of amino acids alone is
practically zero, demonstrating that amino acid infusion achieves
protein-sparing to the extent that nitrogen loss was reduced to
fecal and skin losses which are insignificant when compared with
urinary nitrogen excretion.
The substrate profile data indicates that the success achieved with
the infusion of amino acids alone is due to better adaptation of
the organism to a state of severely negative caloric balance
mobilizing its fat reserves readily as rapidly as it does during
total starvation. The limited effectiveness of peripheral
protein-sparing therapy which includes glucose seems to be related
to the interference of exogenous glucose with the normal
physiological adaptation to a state of severe negative caloric
balance.
In FIG. 7 daily nitrogen balance (.DELTA.Nu) and serum free fatty
acid levels are shown as determined in the three metabolic
situations studied. The greatest nitrogen losses are seen to occur
when free fatty acids are the lowest, which is typically the case
in the surgical patients receiving D5W. The same patients when
treated with amino acids infusions showed a significant increase in
FFA levels, from 0.4 .+-. 0.2 to 1.0 .+-. 0.2 mEq/L. After two to
three weeks of adaptation, the nitrogen balance in the patients
undergoing total starvation shows a deficit of some 6 g per
day.
Associated with elevation of FFA was the appearance of ketone
bodies in the circulation. FIG. 8 shows the correlation between
ketosis and nitrogen balance. The surgical patients receiving
intravenous glucose essentially had no ketonemia (serum
.beta.-hydroxybutyrate and acetoacetate = 0.1 .+-. 0.05mM). The
prevention of ketosis by limited carbohydrate administration has
been one of the expressed purposes of therapy with intravenous D5W.
The same patients, when given isotonic amino acid infusions,
developed ketosis within 36 hours, which was associated with
considerable improvement in the nitrogen balance. Ketosis did
increase with time during intravenous feeding with amino acids,
reaching values of some 2mM.
The release of insulin by the pancreas increases with the
concentration of glucose in blood. FIG. 9 shows the relationship of
glucose to insulin in the four physiological situations studied.
The highest value for glucose and insulin were found in the
patients receiving 5% dextrose in water. The substitution of
glucose by amino acids in the infusate led to significant decreases
in the level of glucose from 123 .+-. 15 to 85 .+-. 11 mg%: and
insulin from 31 .+-. 6 to 23 .+-. 5 U/ml. Stimulation of insulin
secretion by amino acids at this level of protein intake, and when
blood glucose concentrations are low, is thus relatively weak.
Since insulin is considered to be the key anabolic hormone, the
relationship between insulin levels and nitrogen balances is
illustrated in FIG. 10. As previously described substitution of
glucose by amino acid infusion has the effect of decreasing insulin
levels but this is associated with a striking improvement of the
nitrogen balance. The success of amino acid infusion for protein
sparing in surgical patients during periods of semi-starvation with
intravenous feedings hinges on the ability of the absorbed amino
acids to be utilized to replenish the amino acid pools which
sustain protein synthesis rather than being expended primarily for
the production of energy.
FIG. 11 summarizes the urinary nitrogen loss in a study conducted
on a 32 year old female suffering from a perforated duodenal ulcer
caused by a subphrenic abscess. Urinary nitrogen loss averaged 6.7
g/day while receiving 5% dextrose solution intravenously. The
infusion of isotonic dextrose was replaced by the infusion of
isotonic solutions of essential and nonessential amino acids, there
was no significant increase in her urinary nitrogen excretion.
After 17 days the patient returned to convention protein sparing
therapy using 5% dextrose in water. Despite a sharp reduction in
nitrogen intake, only a slight reduction in urinary nitrogen
excretion took place. Thus total amino acid degradation during
amino acid infusion without glucose is not much greater than during
glucose infusion. However since the amino acid mixture supplies
approximately 9 g of amino acid nitrogen per day, the nitrogen
balance can become essentially equal to zero. This protein sparing
effect was associated with lowering of blood glucose from 7.2mM
(130 mg) to 3.8 mM (70 mg) and a corresponding insulin level
decrease from 30 to 15 .mu.U/ml. Free fatty acids and ketone bodies
raised to 1 mM (=1mEq/liter) and 2.0 mM respectively. Fistula
drainage decreased and the fistula was closed by the 25th day of
treatment.
It should be noted above that the conventional metabolic care of
severely ill patients includes the administration of some 100 to
150 gm of carbohydrate per day by peripheral intravenous infusion
of 5% dextrose in water. The aim is to replace the glucose
catabolized by the patient, and to spare his tissue proteins by
reducing the need for gluconeogenesis. The limitation with this
therapy is that glucose administration provokes an insulin response
which impedes the mobilization of endogenous fat, preventing
endogenous fat to be used maximally for energy production. Some of
the infused glucose is therefore needed to make up for reduced
oxidation of FFA and KB, thus sparing endogenous fat rather than
protein. The extent to which caloric contribution from fat stores
will be reduced depends on the degree of insulin resistance, which
in turn is related to the severity of the injury, sepsis or
disease, as well as the nutritional status. Thus the
protein-sparing efficiency of small amounts of carbohydrate varies
a great deal. At best in the moderately injured patient, nitrogen
losses can be reduced only to some 7 to 8 g per day. The peripheral
infusion of amino acids in addition to isotonic glucose seems to be
of little value in improving nitrogen balance. The inflow of both
glucose and amino acids elicits an especially sharp insulin
response which may reduce fat mobilization to such an extent that
the infused nutrients need to be used mainly for energy
production.
The invention described herein approaches the problem of preserving
the body's protein masses by administering amino acids infusates
containing no glucose, thus allowing the development of starvation
ketosis. With energy production supported largely by FFA and KB
oxidation, as in total starvation, the infused amino acids can be
used to replenish the pools of amino acids available for protein
synthesis.
FIG. 12 shows the fuel-regulatory scheme as a basis for comparing
the metabolic consequences of glucose or amino acid infusions.
These two types of protein-sparing therapy differ in two main
aspects: (1) their effects on glucose and insulin levels and hence
on the intensity of the anabolic signal conveyed by insulin to
muscle and adipose tissue, and (2) their direct relevance to the
purpose of maintaining adequate amino acid pools for protein
synthesis.
Under conditions of caloric deprivation, rapid mobilization of
endogenous fat stores is crucial if amino acids and endogenous
proteins are to be preserved efficiently. FIG. 12 shows the
advantage of administering amino acids for protein-sparing.
Infusion of amino acids will lead to a lesser inhibition of fat
mobilization, including ketogenesis than when glucose is given
facilitating the organism's adaptation to conditions of negative
caloric balance, while at the same time replenishing the amino acid
pools supporting protein synthesis.
The metabolic studies performed on patients receiving peripheral
intravenous infusions indicate that protein-sparing therapy with
amino acid infusates is far more effective and that it may be
subject to less variability in reducing protein losses than the
conventional treatment with isotonic glucose solutions. The studies
presented here show a reduction in nitrogen loss of some 8 to 10 g
per day by using amino acids instead of glucose.
As soon as amino acid infusions are initiated, an appreciable
inflow of amino acid nitrogen becomes available to offset nitrogen
losses. This alone results in immediate improvement in nitrogen
balance, even before the effects of starvation ketosis becomes
operative. The 70 to 90 g of amino acids which can be administered
intravenously by peripheral isotonic or near isotonic infusions
provides 11 to 14 g of amino acid nitrogen. This is sufficient to
achieve a satisfactory nitrogen balance even when amino acid
degradation is not as efficiently reduced as when starvation
ketosis is fully established. (FIG. 13)
In terms of dosage, the amino acids are administered in amounts
sufficient to restore amino acid pools in a patient and may vary
within relatively broad limits dependent upon body weight of the
patient and related variables including the extent of injury or
disease. Typically, using 3% amino acid solutions, though solutions
containing up to 6% amino acids are possible and solutions
containing from 2.5 to 4.5% are preferred, rate of infusion is
adjusted so that from about 50 to 130 grams of amino acid are
delivered per 24 hours and preferably from 60 to 100 grams or
approximately 0.6 to 1 gm of amino acids per kg body weight per
day.
The amino acids delivered are the L-amino acids that have been used
in the prior art in combination with glucose being delivered as
hyperosmotic solutions through a central venous catheter. These
materials are well known and need no further elucidation. However,
it should be noted that various amino acids provide specific
functions and a therapy using selected amino acids in specified
proportions can be formulated.
Finally, it should be noted that the amino acids may be in the form
of protein hydrolysates or dipeptides and may be combined in
aqueous solution with suitable electrolytes, fats, pH adjusters and
the like, other than carbohydrate, typically used in parenteral
administration.
* * * * *