United States Patent 4,981,844
Alexander , et al. January 1, 1991
----------------------------------------------------------------------------
----
Method to improve immune response and resistance to infection following
surgery by diet composition
Abstract
The immune response of a patient can be improved pre-operatively by altering
the diet of a patient. When 20 to about 80% of the calories in a diet are
from linoleic acid which is an omega 6 fatty acid, the immune response
system and resistance to infection of the patient is substantially improved.
Likewise providing 100 to about 1,000 IU per day of vitamin E in the diet
also improves the immune response of the patient pre-operatively. This in
turn improves the survival rate of the patient.
----------------------------------------------------------------------------
----
Inventors: Alexander; J. Wesley (Cincinnati, OH); Peck; Michael D.
(Cincinnati, OH)
Assignee: University of Cincinnati (Cincinnati, OH)
Appl. No.: 253140
Filed: October 4, 1988
----------------------------------------------------------------------------
----
Claims
----------------------------------------------------------------------------
----
We claim:
1. A method of improving the immune response in patients comprising:
said patient ingesting a diet for at least 10 days prior to an operative
procedure, said diet having 20-60 kilocalories per kilogram body weight
wherein 20% to 80% of the calories in said diet are derived from linoleic
acid.
2. The method claimed in claim 1 wherein said diet includes 100 to 1,000 IU
per day vitamin E.
3. The method claimed in claim 1 wherein said diet contains from about 20 to
about 60% safflower oil.
----------------------------------------------------------------------------
----
Description
----------------------------------------------------------------------------
----
BACKGROUND OF THE INVENTION
Surgical procedures can act to seriously weaken the body of the patient.
Major surgeries are in fact an extreme assault upon the body which in turn
affects the immune response system of the patient. This in turn increases
the risk of post-operative infection. Such post-operative infection has a
significant effect upon the survival rate after major surgery.
Further many patients prior to surgery are already in a particularly
debilitated condition. Many patients who have digestive track problems which
require surgery have not been able to ingest sufficient calories to maintain
body weight and keep themselves in a healthy condition. Accordingly, many
patients require a pre-operative stay to obtain either an enteral or
parenteral diet to increase body weight and improve their health.
It has been shown that diet can affect the immune response system after
major assaults to the body. For example, The Importance of Lipid Type in the
Diet After Burn, Anals. of Surgery, Vol. 204, No. July, 1, 1986 reports that
the lipids contained in a diet have an effect on the immune response system
in burn patients. Specifically, it indicated that a diet high in omega 6
fatty acids such as linoleic acid have a significant immunosupressive
effect. On the other hand, diets high in omega 3 fatty acids improve the
immune response. In "The Effect of Dietary Unsaturated Fatty Acids and
Indomethacin on Metabolism and Survival after Burn" indicates that excessive
dietary polyunsaturated linoleic acid may influence immunocompetence after
burn. Accordingly, all indications are that omego 6 fatty acids have a
immunosuppressive effect.
SUMMARY OF THE INVENTION
The present invention is premised on the realization that prior to an
operative procedure the immune response system of a patient can be improved
by providing the patient with a diet very high in linoleic acid. More
particularly the present invention is premised on the realization that a
diet having from about 20 to about 60% of its total calories derived from
linoleic acid substantially improves the immune response system of patients
and acts as a preoperative diet to enhance the survival rate following major
operative procedures.
Further the present invention is premised on the realization that a diet
high in vitamin E has a similar effect on the immune response system. In
combination a diet high in vitamin E as well as a diet high in linoleic acid
provides a significant improvement in the immune response systems of
patients prior to operative procedures.
Other objects and advantages of the present invention will be appreciated in
light of the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
In order to improve the immune response system of surgical patients, the
patient is provided a diet which is high in the omega 6 fatty acid linoleic
acid and further is provided with a diet which is high in vitamin E. By
ingesting the diet prior to operative procedures the resistance to infection
by the patient is significantly improved.
For purposes of the present invention, major operative procedures would
include any operative procedure requiring general anethesia that has a risk
of infection including patients suffering from malnutrition. Basically the
resistance to infection of a patient prior to any operative procedure could
be improved by the present invention.
The diet for use in the present invention will include a source of protein,
a source of carbohydrate, and a source of fats, i.e., fatty acids. In
addition to these compositions the diet will include vitamin and mineral
supplement.
The diet which can be either designed to be a parenteral diet or an enteral
diet depending on the patient will be generally an aqueous mixture of
protein (amino acid), carbohydrate and fat along with vitamin and mineral
sources. The total calories in the diet which should be ingested by the
patient will be from about 20 to about 60 kilocalories per kilogram body
weight per day. The total energy needs vary according to the individual.
Generally acceptable limits are well known and are set forth by the National
Research Counsel in the Recommended Daily Allowance.
The total calories of the diet will be derived from the carbohydrates, the
protein and the fats. Generally it is desirable that from about 12 to about
25% of the total calories be provided by the protein. For an enteral diet
suitable sources of protein would include milk proteins, soy protein and
others. It is also preferable to include 1-2% arginine. For a parenteral
diet a combination of amino acids should be employed instead of the protein.
These can include leucine, lysine, valine, isoleucine, phenylalanine,
threonine, methionine, histidinine, tryptophan. These are considered the
essential amino acids. Other non-essential amino acids can include glutamic
acid, proline, aspartic acid, serine, arginine, alanine, glycine, glutamine
and tyrosine. These are considered the non-essential amino acids. These
would be provided generally in a total parental nutrition diet.
Further from about 10 to 70% of the total calories of the diet should be
provided by the carbohydrate source. A wide variety of simple sugars can be
used as a source of carbohydrates such as for example dextrose, fructose,
sucrose and the like in combinations. Enteral diets should include complex
carbohydrates such as corn starch and dextrins.
From about 20 to about 80% of the total calories of the diet should be
derived from lipids. Generally 20 to 60% of the diet calories will be
derived from lipid. From about 50 to about 100% and generally 50-70% of the
calories of these lipids should be derived from linoleic acid. A major
source of linoleic acid is safflower oil which contains from about 70 to
about 85% linoleic acid. However, linoleic acid can be purchased and used.
In addition to the protein, carbohydrate and fatty acid the diet should
include a source of vitamins as well as minerals. In particular the present
invention should be relatively high in vitamin E. The diet should include
about 100 to about 1,000 IU per day of vitamin E. Generally the amount of
vitamin E will be about 100 to 300 IU per day until the day immediately
prior to surgery when the amount of vitamin E should be increased to about
1,000 IU per day. In addition to vitamin E the diet of the present invention
should include 5,000-10,000 IU micrograms retinol equivalents vitamin A per
day, 400 IU per day of vitamin D, 1-5 grams per day of vitamin C, 0.4
milligrams of folic acid, 20 milligrams per day of niacin, 2 milligrams per
day of riboflavin, 1.5 milligrams per day of thiamine, 2 milligrams per day
of vitamin B6, 3 micrograms per day of vitamin B12, 1.5 grams per day of
calcium, 1.5 grams per day of phosphorous, 150 micrograms per day of iodine,
10 milligrams per day of iron and 400 milligrams per day of magnesium. With
the exception of the vitamin E the above components can be varied widely
and/or eliminated without departing from the present invention.
An exemplary enteral formulation of the present invention will include the
following:
______________________________________
Whey protein 20% total calories
Safflower oil 50% total calories
Dextrins 30% total calories
Vitamin A 5,000 micrograms retinol
equivalents/liter
Vitamin D 200 IU/1
Vitamin E 50 IU/1
Vitamin C 2 gms/1
Folic Acid 200 micrograms/liter
Niacin 10 mg/l
Riboflavin 1 mg/l
Thiamine 750 micrograms/liter
Vitamin B6 1 mg/l
Vitamin B12 1.5 micrograms/liter
Calcium 750 mg/l
Phosphorous 750 mg/l
Iodine 75 micrograms/liter
Iron 5 mg/liter
Magnesium 200 mg/liter
______________________________________
This diet has a caloric content of 1 calorie per ml.
The diet of the present invention is administered to a patient for a time
effective to improve the immune response of the patient. Generally it is
administered for 14 days prior to the operative procedure. The diet should
be administered to the patient at least 10 days prior to the operative
procedure. This can be increased up to six weeks depending upon the need of
the patient and the state of debilitation. In the event a weight gain is
necessary prior to the operative procedure the diet can be administered and
ingested by the patient for whatever period of time necessary to develop the
weight gain.
With respect to the vitamin E this can be excluded from the diet although it
provides substantial beneficial results and should be provided at about 100
to 300 IU per day. On the day immediately prior to surgery the diet should
be supplemented with additional vitamin E up to 1,000 IU per day in order to
further improve the immune response system.
In order to test the efficacy of the present invention animal models were
employed. In order to simulate the effect of major surgery the test animals
were fed various diets and then subjected to a burn as indicated below. They
were then infected with Pseudomonas aeruginosa. The survival rate of the
mice after two weeks then provided an indication of the effect of diet on
the immune system.
EXAMPLE
Female albino inbred (Balb/c) mice were obtained from Charles River
Suppliers and allowed to acclimate in laboratory facilities for one week.
They were housed five in a cage in a room with twelve hour alternating light
and dark cycles and given water and natural chow (Wayne Rodent Blox) ad
libitum. The animals were then weighed and begun on experimental diets ad
libitum. The mice were fed several different diets prior to the burn. The
natural diet is composed of soybean meal, fishmeal, corn and wheat and by
weight contains 24% protein, 4% fat, and 4.5% fiber. A purified diet was
formed by weight containing 20% protein as casein, 65% carbohydrate as
sucrose and corn starch, 5% fat as corn oil, 5% fiber as purified cellulose
and vitamins and minerals. The purified diet was then modified by
substituting other fat sources and for a high fat diet, increasing the fat
content. When the amount of fat was increased to 20% a weighted reduction in
sucrose and corn starch was made. Thus the low fat diets contained 5% by
weight fat which was 12% of the total calories and 15% of non-protein
calories. The high fat diets contain 20% fat by weight which is 40% of the
total calories and 50% of the non-protein calories.
The fatty acid compositions of the fat sources were determined with gas
liquid chromatography. The oils, coconut oil, corn oil, oleic acid and
safflower oil were all of food grade and obtained from ICN Biochemicals. The
MaxEPA oil was donated by R. P. Ssherer Corporation.
Chromatographic analysis of the fats used in the diets yielded the following
results. The fatty acid composition of the corn oil was 45% myristic acid,
31% linoleic acid and 23% palmitic acid. Composition of corn oil used in the
purified control diet was 50% linoleic acid, 29% oleic acid and 16% palmitic
acid. The composition of the MaxEPA oil was 28% palmitic acid, 18% oleic
acid and 18% eicosapentaenoic acid, 15% docosahexaenoic acid and 4% linoleic
acid. The total omega 3 content of MaxEPA was thus 37%. The fatty acid
composition of natural chow used for control was 47% linoleic acid, 24%
oleic acid and 17% palmitic acid and 5% linoleic acid. The composition of
the food grade oleic acids in the diets was 78% oleic acid, 14% palmitic
acid, 4% linoleic acid and 4% myristic acid. The composition of the
safflower oil was 91% linoleic acid, 8% palmitic acid (which represents a
higher amount of linoleic acid than was commonly found in safflower oil
usual range 70-80%).
At the end of two weeks they were again weighed and the fur was clipped from
their back. General anesthesia was obtained with methoxyfluorane and a 1.5
inch by 2 inch Teflon template was applied to the dorsum of the animal. The
exposed area was saturated with 95% ethanol and ignited for 12 seconds. The
animal was then fluid resuscitated with 1 ml PBS. Sixteen to eighteen hours
after burning 2.5.times.10.sup.5 viable Pseudomonas aeruginosa were injected
subeschar. Mortality was noted over the next week and the survivors were
sacrificed with CO.sub.2 euthanasia. The first experiment compared the
natural control diet to the purified high fat diets, i.e., the diet with
high safflower oil content (20% by weight) and the high MaxEPA fat content
(20% by weight). The second experiment compared the natural control diet to
the purified low fat diets, i.e., the low safflower oil diet (5% by weight)
and the low MaxEPA oil diet (5% by weight). The third experiment compared
the purified control diet to the purified high fat diets. The fourth
experiment compared four high fat diets using coconut oil, MaxEPA, oleic
acid and safflower oil all at 20% by weight.
The survival rate of the mice and their respective diet are listed in Table
I.
TABLE I
______________________________________
Experiment 1
Natural Chow 33%
MaxEPA (20%) 40%
Safflower Oil (20%)
67%
Experiment 2
Natural Chow 41%
MaxEPA (5%) 39%
Safflower Oil (5%)
47%
Experiment 3
Purified Diet 44%
MaxEPA (20%) 18%
Safflower Oil (20%)
54%
Experiment 4
Safflower Oil (20%)
87%
Oleic Acid (20%) 53%
Coconut Oil (20%) 55%
MaxEPA (20%) 30%
______________________________________
In a related experiment Balb/c mice were subjected to a 20% total body
surface area third degree flame burn under general anesthesia and
resuscitated. Viable Pseudomonas aeruginosa were injected subeschar the next
day. Three groups were tested. Vitamin E was given by Gavage in doses of 2.5
IU, 25 IU and 250 IU on four consecutive days, the two days before burn the
day of burn and the day of infection. Survival was improved in the 25 and
250 IU/kg groups compared to control. Vitamin E was then given by Gavage on
day 0, day 1 or day 2 in three doses. Mortality in the 2.5 and 25 IU groups
on day 1 was worse than control or high dose. Accordingly, providing vitamin
E given at least 25 IU (greater than 10 times the RDA for mice) by Gavage
prior to injury and continued thereafter for two days does improve survival.
The benefit is not seen if vitamin E is not started prior to injury.
This accordingly provides a very useful pre-operative diet including both a
high concentration of linoleic acid and a high (greater than 10 times RDA)
vitamin E content. A patient's ingesting this diet prior to operative
procedures will substantially reduce the likelihood of developing an
infection.
The preceding has been a description of the preferred embodiment of the
present invention as well as the best mode of the invention currently known.
However, the invention is to be defined only by the appended claims wherein
we claim:
-
