glutamine enriched reduce infection

8/7/2019 glutamine enriched reduce infection

1/6

Glutamine-enriched enteral nutrition decreasesinfectious complications in trauma patients

Dear Sir:

We read with special interest the article titled Glutamine: com-

mercially essential or conditionally essential? A critical appraisal

of the human data in a recent issue of the Journal (1). In this arti-

cle, Buchman attempted to analyze all the available human data on

the effect of a glutamine-enriched diet on morbidity and length of

hospital stay. Although his research seemed to be thorough at first

glance, we were surprised to find that his conclusions were super-

ficially and sometimes incorrectly drawn. In our comment, we

confine ourselves first to the way glutamine is proposed to exert itseffect on the mucosa and second to the way the study of Houdijk

et al (2) was presented and discussed by Buchman.

First, no data available in the literature provide evidence that

atrophy of the villi results in bacterial or endotoxin transloca-

tion. Therefore, we do not understand the rationale of the study

done by Buchman et al (3) in healthy volunteers as presented on

page 26 of Buchmans article (1). If the theory that glutamine

deficiency is solely responsible for the changes in intestinal mor-

phology and function is true, it would have been more appropri-

ate to measure the glutamine content of mucosal biopsy samples

instead of measuring plasma glutamine.

We also do not understand why the author focused solely on the

hypothesis that glutamine exerts its effect on intestinal morphol-

ogy; other theories have been proposed and may be more valuable.For instance, glutamine can increase arginine synthesis in the kid-

ney (4). Arginine is important for wound healing, plays a role in the

immune system, and is the precursor for nitric oxide. Nitric oxide

is important for regulating blood flow through vital organs, such as

the gut, the liver, the kidney, and the heart, especially during stress

(5, 6). Arginine plasma concentrations can be rate limiting under

certain circumstances. Prins et al (7) showed in a rat model that if

arginine concentrations are reduced by 50%, resembling aortic

surgery, a mild endotoxin challenge significantly reduces blood

flow through the gut. Thus, glutamine may be important in regulat-

ing blood flow by serving as a precursor for arginine synthesis.

Furthermore, glutamine might also exert its effect by increasing

plasma concentrations of taurine. Taurine is an important intracel-

lular osmolyte that can regulate cell volume and that therefore hasa major impact on the bodys fluid homeostasis (8). Because

Scheltinga et al (9) showed that glutamine restores body fluid dis-

tribution, it is conceivable that part of the beneficial effect of glu-

tamine is because of its enhancement of taurine availability.

Buchman discussed the study of Houdijk et al (2) within the sec-

tion on critical care (page 28). In describing this study, Buchman

mentioned a significant reduction in infectious complications. He also

pointed out that Houdijk et al suggested that the lesser occurrence of

gram-negative infections in the glutamine group might be explained

by reduced bacterial translocations. Houdijk et al stressed in their dis-

cussion that this was merely a suggested explanation of the results

showing fewer gram-negative infections in the glutamine group.

In his conclusion, Buchman stated that glutamine supplemen-

tation did not appear to be associated with a decreased incidence

of infection in the studies reviewed herein. However, earlier in

his article, Buchman described the significant reduction in infec-

tious complications that were seen in the study of Houdijk et al (2).

Therefore, his conclusion seems to be unfounded.

The positive effect of glutamine on infectious morbidity is also

substantiated by a recent report by Novak et al (10). In this report,

14 randomized trials of 737 adult patients (surgical and critically ill)

were reviewed. The authors concluded that glutamine supplementa-tion was associated with a reduction in infectious complication rates

and a shorter hospital stay without any adverse effect on mortality.

Petra G Boelens

Alexander PJ Houdijk

Henk JThM Haarman

Robert J Nijveldt

Paul AM van Leeuwen

Department of Surgery

Vrije University Medical Center

De Boelelaan 1117

1081 HV Amsterdam

NetherlandsE-mail: [email protected]

REFERENCES

1. Buchman AL. Glutamine: commercially essential or conditionally

essential? A critical appraisal of the human data. Am J Clin Nutr

2001;74:2532.

2. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomized trial of

glutamine-enriched enteral nutrition on infectious morbidity in

patients with multiple trauma. Lancet 1998;352:7726.

3. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is

associated with morphologic and functional changes in man. JPEN

J Parenter Enteral Nutr 1995;19:45360.

4. Houdijk APJ, van Leeuwen PAM, Teerlink T, et al. Glutamine

enriched enteral diet increases renal arginine production. JPEN J

Parenter Enteral Nutr 1994;18:4226.

5. Moncada S, Higgs A, The L-arginine-nitric oxide pathways. N Engl

J Med 1993;329;200212.

6. Jones SM, Thurman RG. L-Arginine minimizes reperfusion injury in a

low flow reflow model of liver perfusion. Hepatology 1996;24:1638.

7. Prins HA, Houdijk APJ, Wiezer MJ, et al. The effect of mild endo-

toxemia during low arginine plasma levels on oxygen blood flow in

rats. Crit Care Med 2000;28;19917.

Am J Clin Nutr2002;76:2538. Printed in USA. 2002 American Society for Clinical Nutrition 253

Letters to the Editor


2/6

8. Boelens PG, Houdijk APJ, van Leeuwen PAM. Glutamine enriched

enteral nutrition increases taurine plasma levels. Gut 2000;47

(suppl): A203 (abstr).

9. Scheltinga MR, Young LS, Benfell K, et al. Glutamine-enriched

intravenous feedings attenuate extracellular fluid expansion after a

standard stress. Ann Surg 1991;214:38595.

10. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation

in critically ill adults: a meta-analysis. Clin Nutr 2001;20:S3 (abstr).

Reply to PG Boelens et al

Dear Sir:

Boelens et al state that no data exist showing that intestinal atro-

phy results in bacterial or endotoxin translocation, and therefore

they may have failed to understand the rationale for my previous

study. I agree that no such human data are available; however, there

are many studies in rodent models, including those I cite here (13).

Our hypothesis in the 1995 study (undertaken in 1993) was that totalparenteral nutrition is not associated with clinically significant

intestinal atrophy in humans (4). We did not study bacterial or endo-

toxin translocation in the healthy volunteers because it would have

been unethical to do so. We found mild but clinically insignificant

intestinal hypoplasia and no atrophy after 2 wk of total parenteral

nutrition in this study in which patients had normal intestines at

baseline. Although we reported only plasma glutamine concentra-

tions (4), we also measured mucosal glutamine concentrations.

Mucosal glutamine was undetectable both at baseline and after 2 wk

of total parenteral nutrition. These data were not reported because at

the time we were unsure whether this was an error or whether the

human jejunum has a significant amount of glutaminase and gluta-

mine was rapidly metabolized. To my knowledge, there have been

no reported measurements of glutamine in human jejunum, only induodenum. Regardless of whether it is appropriate, glutamine defi-

ciency has been accepted as a diagnosis in the presence of

decreased plasma glutamine concentrations alone.

Boelens et al were concerned with 2 points: first, that I focused

solely on the hypothesis that glutamine exerts its effect via

intestinal morphology and, second, that I stated that Houdijk

et al (5) suggested that the decreased infectious complications

observed in their study may have been related to reduced bacter-

ial translocation (6).

Bacterial translocation was the only mechanism suggested in

Houdijk et als article. They never stated that increased arginine

may have been the reason for the fewer infections observed with

glutamine supplementation. Boelens et al suggest a role for taurine

as well. Taurine may mediate the glutamine-associated decrease inextracellular fluid, but this has no proven clinical significance.

The decrease in infections observed by Houdijk et al (5) in

association with glutamine supplementation is novel and appears

valid. However, this study should be carefully evaluated before

clinical recommendations are made. The inexplicably and inap-

propriately high infection rate in the control group may have

accounted for the difference in the infection rate alone, rather than

the glutamine supplement (7). Additionally, in several other

studies I cited in my review, glutamine was not associated with

decreased infection risk.

Contrary to their statement, I covered such issues as glutamine

status during various medical and surgical conditions; intestinal

permeability; intestinal immune function; extracellular fluid

retention; nitrogen, energy, and electrolyte balance; effects on

the liver; infectious complications; T cell function; tumor necro-

sis factor concentrations; clinical severity of Crohn disease; diar-

rhea; quality of life; and hospital length of stay (6).

Although glutamine may increase arginine synthesis, the clin-

ical sequelae of this in humans are unknown. In addition, Boelenset al state that arginine is important in wound healing, but this has

not been shown in humans. In the only related human study of

which I am aware, arginine supplementation resulted in increased

hydroxyproline content in healing artificially created wounds, but

did not actually enhance or hasten wound healing (8).

Although arginine may be important for the immune system in

humans, no human evidence supports that theory. There are also no

data showing that arginine supplementation improves the human

immune response. Responses to concanavalin A and phytohemag-

glutinin cannot be described as valid and reproducible tests of

human immune function (8). Neither a glutamine-free diet nor a

glutamine-supplemented diet has any affect on intestinal immuno-

globulin A production or on gut-associated lymphoid tissue in

humans (9, 10), and such effects have not been universally shownin rats (11). Houdijk et al (5) showed that after 7 d of feeding a glu-

tamine-supplemented diet, plasma arginine and glutamine concen-

trations were not significantly different between supplemented and

control patients fed for a mean of 12 d each. The observed decrease

in sepsis prevalence occurred during a time when plasma glutamine

and arginine status may have equilibrated in both the experimental

and treatment groups. Houdijk et al reported all episodes of sepsis

to have occurred within the first 7 d of feeding.

Boelens et al suggest that glutamine supplementation leads to

increased arginine, which in turn leads to increased nitric oxide

production. If that is true, it is possible glutamine could be detri-

mental. Nitric oxide impairs the intestinal endothelial response to

endotoxinemia in rats (12). In addition, glutamine supplementa-

tion could increase intestinal inflammation because of stimulatedmucosal T cell function and increased nitric oxide synthesis (13, 14).

In this fashion, glutamine supplementation may have a further

negative effect on mesenteric blood flow in critical illness.

With regard to the meta-analysis of Novak et al (15), such

reports do not replace properly performed investigations. The

validity of any meta-analysis is in part related to the rigor of each

of its included studies, as well as their heterogeneity. Rather than

meta-analysis, what is needed are properly designed, controlled,

and analyzed clinical studies of glutamine supplementation. For

the most part, these have not been performed to date. Unfortu-

nately, clinical decisions with clinical consequences and expense

are being made on the basis of animal studies alone in the absence

of appropriate human investigations. That is why parenteral glut-

amine is not approved by the Food and Drug Administration foruse in the United States. When a nutrient is used as a drug, it

should be treated as a drug and regulated as a drug.

Alan L Buchman

Division of Gastroenterology and Hepatology

Northwestern University Medical School

676 North St Clair Street, Suite 880

Chicago, IL 60611

E-mail: [email protected]

254 LETTERS TO THE EDITOR


3/6

REFERENCES

1. McAndrew HF, Lloyd DA, Rintala R, van Saene HK. The effects of

intravenous epidermal growth factor on bacterial translocation and

central venous catheter infection in the rat total parenteral nutrition

model. Pediatr Surg 2000;16:16973.

2. Iba T, Yagi Y, Kidokoro A, et al. Total parenteral nutrition supple-

mented with medium-chain triacylglycerols prevents atrophy of the

intestinal mucosa in septic rats. Nutrition 1998;14:66771.

3. Jones WG II, Minei JP, Barber AE, et al. Bacterial translocation and

intestinal atrophy after thermal injury and burn wound sepsis. AnnSurg 1990;211:399405.

4. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is

associated with morphologic and functional changes in man. JPEN

J Parenter Enteral Nutr 1995;19:45360.

5. Houdijk APJ, Rijnsburger ER, Jansen J, et al. Randomized trial of

glutamine-enriched enteral nutrition on infectious morbidity in

patients with multiple trauma. Lancet 1998;352:7726.



2001;74:2532.

7. Mitchell I, Bihari D. Glutamine-enriched enteral nutrition in

patients with multiple trauma. Lancet 1998;352:1553 (letter).

8. Barbul A, Lazarou SA, Efron DT, et al. Arginine enhances wound

healing and lymphocyte responses in humans. Surgery 1990;108:

3316.9. Van der Hulst RRWJ, von Meyenfeldt MF, Tiebosch A, et al. The

effect of glutamine enriched parenteral nutrition on intestinal

mucosa immune cells. JPEN J Parenter Enteral Nutr 1997;21:3105.

10. Buchman AL, Mestecky Moukarzel A, Ament ME. Intestinal

immune function is unaffected by parenteral nutrition in man. J Am

Coll Nutr 1995;14:65661.

11. Spaeth G, Gottwald T, Haas W, Holmer M. Glutamine peptide does

not improve gut barrier function and mucosal immunity in total par-

enteral nutrition. JPEN J Parenter Enteral Nutr 1993;17:31723.

12. Yorganci K, Sayek I, Ismailoglu UB, Sahin-Erdemli I. Detrimental

effects of nitric oxide on mesenteric circulation during endotox-

aemia and its reversal by aminoguanidine. Eur J Surg 2000;166:

88893.

13. Den Hond E, Hiele M, Peeters M, et al. Effect of long-term oral

glutamine supplements on small intestinal permeability in patientswith Crohns disease. JPEN J Parenter Enteral Nutr 1999;23:711.

14. Akobeng AK, Miller V, Stanton J, et al. Double-blind randomized con-

trolled trial of glutamine-enriched polymeric diet in the treatment of

active Crohns disease. J Pediatr Gastroenterol Nutr 2000; 30:7884.

15. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation

in critically ill adults: a meta-analysis. Clin Nutr 2001;20:S3 (abstr).

Clinical nutrition: commercially or clinically

essential?

Dear Sir:

In a recent "Special Article" in the Journal, Buchman (1) has

yet again (2) expressed his views on the use of glutamine-

supplemented diets in clinical nutrition. However, I am con-

cerned about his lack of objectivity in many of the examples pro-

posed in his paper. For example, he 1) confuses the results of

poorly designed studies with those of well-designed studies, 2)

refutes the results of well-designed studies by emphasizing their

minor methodologic weaknesses, 3) states that particular studies

have flaws but does not substantiate these flaws, 4) combines the

results of studies of the effects of enteral and parenteral nutrition

even though the differences in glutamines effects with the route

of administration were emphasized in a remarkable analysis (3), 5)

does not mention the results of some important studies that do not

support his conclusions, and 6) says that the results of experimen-

tal studies should not be considered in the discussion of gluta-

mines effects; however, he cites such studies when it suits his pur-pose. From Buchmans review, it would have been just as easy to

conclude that enteral nutrition has no advantage over parenteral

nutrition, that parenteral nutrition is not efficacious in periopera-

tive nutrition, that the usefulness of early enteral nutrition remains

to be shown, or that fiber is not efficacious in enteral nutrition.

In particular, the author calls ornithine -ketoglutarate a gluta-

mine precursor (4). However, in an important paper published in

this Journal coauthored by Buchman, ornithine -ketoglutarate

administration restored growth in infants receiving long-term total

parenteral nutrition (5). Three different studies indicate that ornithine

-ketoglutarate improves wound healing in burn patients (68).

One can argue that the effects of ornithine -ketoglutarate are not

mediated by glutamine. This is possible but not certain (9, 10). In any

case, the literature supporting this finding should have been con-sidered by Buchman.

What does "commercially essential" in the title of Buchmans

article mean? Available products are marketed by companies whose

job it is to make money, which permits a reinvestment in research.

Luc A Cynober

Laboratoire de Biochimie A

Hopital Hotel Dieu

1 Place du Parvis Notre Dame

F-75181 Paris Cedex 04

France

E-mail: [email protected]. Biol.

REFERENCES



2001;74:2532.

2. Buchman AL. Glutamine: is it a conditionally required nutrient for

the human gastrointestinal system? J Am Coll Nutr 1996;15:

199205.

3. Alpers DH. Is glutamine a unique fuel for small intestinal cells?

Curr Opin Gastroenterol 2000;16:1559.

4. Le Bricon T, Cynober L, Baracos VE. Ornithine -ketoglutarate lim-

its muscle protein breakdown without stimulating tumor growth in

rats bearing Yoshida acites hepatoma. Metabolism 1994;43:899905.

5. Moukarzel AA, Goulet O, Salas JS, et al. Growth retardation in

children receiving long-term total parenteral nutrition: effects ofornithine -ketoglutarate. Am J Clin Nutr 1994;60:40813.

6. De Bandt JP, Coudray-Lucas C, Lioret N, et al. A randomized con-

trolled trial of the influence of the mode of enteral ornithine alpha-

ketoglutarate administration in burn patients. J Nutr 1998;128:5639.

7. Donati L, Ziegler F, Pongelli G, Signorini MS. Nutritional and clin-

ical efficacy of ornithine alpha-ketoglutarate in severe burn patients.

Clin Nutr 1999;18:30711.

8. Coudray-Lucas C, Le Bever H, Cynober L, De Bandt JP, Carsin H.

Ornithine alpha-ketoglutarate improves wound healing in severe

burn patients: a prospective randomized double-blind trial versus

isonitrogenous controls. Crit Care Med 2000;28:17726.

LETTERS TO THE EDITOR 255


4/6


5/6

I am unaware of any data proving that manufacturers and

hawkers of glutamine use their profits from this product to con-

duct research in humans, as Cynober stated. Perhaps if as much

money were spent on glutamine research as is spent on market-

ing it, there would be better data from which one could make

more appropriate conclusions.

Alan L Buchman

Division of Gastroenterology and Hepatology

Northwestern University Medical School

676 North St Clair Street

Suite 880

Chicago, IL 60611


REFERENCES

1. Nurjhan N, Bucci A, Perriello G, et al. Glutamine: a major gluco-

neogenic precursor and vehicle for interorgan carbon transport in

man. J Clin Invest 1995;95:2727.

2. Kotetz RL, Lipman TO, Klein S. AGA technical review on par-

enteral nutrition. Gastroenterology 2001;121:9701001.

3. Lipman TO. Grains or veins: is enteral nutrition really better than

parenteral nutrition? A look at the evidence. JPEN J Parenter

Enteral Nutr 1998;22:16782.

4. Moukarzel AA, Goulet O, Salas JS, et al. Growth retardation in chil-

dren receiving long-term total parenteral nutrition: effects of

ornithine -ketoglutarate. Am J Clin Nutr 1994;60:40813.

5. Krassowski J, Rousselle J, Meeder E, Felber JP. The effect of

ornithine alpha-ketoglutarate on growth hormone and prolactin

release in normal subjects. Endokrynol Pol 1986;37:115.

6. De Bandt JP, Coudray-Lucas C, Lioret N, et al. A randomized

controlled trial of the influence of the mode of enteral ornithine

alpha-glutarate administration in burn patients. J Nutr 1998;128:

5639.

7. Coudray-Lucas C, Le Bever H, Cynober L, et al. Ornithine alpha-

ketoglutarate improves wound healing in severe burn patients: a

prospective randomized double-blind trial versus isonitrogenous

controls. Crit Care Med 2000;28:17726.

8. Donati L, Ziegler F, Pongelli G, Signorini MS. Nutritional and clin-

ical efficacy of ornithine alpha-ketoglutarate in severe burn patients.

Clin Nutr 1999;18:30711.

9. Alpers DH. Is glutamine a unique fuel for small intestine cells? Curr

Opin Gastroenterol 2000;16:1559.

10. Buchman AL. Personal and government regulation of nutritional

supplements: what we want and what we should expect. J Lab Clin

Med (in press).

Dairy products, calcium, and1,25-dihydroxyvitamin D3 concentrations

Dear Sir:

The report by Chan et al (1) on the intake of dairy products

and dairy calcium in relation to plasma concentrations of 1,25-

dihydroxyvitamin D3 does not take into account the enhance-

ment of calcium absorption by lactose. This action of lactose

has been known since as long ago as 1929 and is attributable to

an increased facilitated absorption in the ileum, which is unreg-

ulated, although the rise in circulating calcium may lead to a

decrease in the regulated duodenal absorption of protein-bound

calcium (2).

The lower concentration of 1,25-dihydroxyvitamin D3 in the

men with the high intake of dairy products may have been due,

at least partly, to their greater absorption of lactose-enhanced

calcium. This possibility is supported by the stronger inverse

association of skim milk calcium than of dairy calcium with theconcentration of 1,25-dihydroxyvitamin D3, because skim milk

has a greater lactose content than does whole milk.

Chan et al included the calcium intake from cheese in their

dietary assessment; however, they did not report its associa-

tion with the concentration of 1,25-dihydroxyvitamin D3. Most

cheeses are lacking in lactose, so I would not expect cheese cal-

cium to show a significant inverse association with 1,25-dihy-

droxyvitamin D3. The authors should have published their find-

ings for cheese calcium.

Unregulated calcium absorption with retention as a result

of a high intake of lactose is one explanation proposed for the

epidemiologic suspicion that a high intake of lactose might be

a dietary risk factor for ischemic heart disease (3). A common

mode of action of calcium retention in lesions of atheroscle-rosis and adenocarcinoma of the prostate, particularly

metastatic disease, might be the stimulation of cells with an

osteoblastic potential.

Jeffrey J Segall

308 Cricklewood Lane

London NW2 2PX

United Kingdom

REFERENCES

1. Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM, Giovannucci

EL. Dairy products, calcium, and prostate cancer risk in the Physi-

cians Health Study. Am J Clin Nutr 2001;74:54954.

2. Pansu D, Bellaton C, Bronner F. Effect of lactose on duodenal-binding protein and calcium absorption. J Nutr 1979;109:

50812.

3. Segall JJ. Epidemiological evidence for the link between dietary

lactose and atherosclerosis. In: Colaco CALS, ed. The glycation

hypothesis of atherosclerosis. Austin, TX: Landes Bioscience,

1997:185209.

Reply to JJ Segall

Dear Sir:

Segall presents an interesting point regarding the potential

interaction between calcium and lactose and prostate cancer risk.

He suggests that we provide results for cheese consumption

because cheese has less lactose than does milk. As stated in our

article, of the 5 dairy foods we assessed, only skim milk was sta-

tistically significantly associated with prostate cancer risk.

Although this result is consistent with Segalls hypothesis, there

LETTERS TO THE EDITOR 257


6/6

was too little statistical power to assess this directly. Cheese con-

sumption accounted for a far smaller proportion of total dairy

calcium intake than did skim milk (24% compared with 57%)

and was probably measured with less accuracy than was milk.

Thus, the lack of a significant association may simply have been

due to too little exposure or to measurement error. This potential

interaction may be important, and we concur that further consid-

eration of this hypothesis is warranted.

June M Chan

Departments of Epidemiology and Biostatistics and of Urology

University of California, San Francisco

3333 California Street

Suite 280

San Francisco, CA 94143-1228


258 LETTERS TO THE EDITOR

glutamine enriched reduce infection

Documents