E D I T O R I A L C O M M E N T S Nutrition Vol. 13, No. 4, 1997

Glutamine Saves Lives! What Does It Mean?

Glutamine-supplemented amino acid solutions are being uti- lized more frequently, especially following Food and Drug Ad- ministration approval and commercial availability of glutamine (Gln) dipeptides for parenteral infusion in Europe. It is im- portant now, through evidence-based clinical investigation, to determine the appropriate patient groups who will benefit from this advancement. In the initial clinical outcome study, patients undergoing bone marrow transplantation were randomized to receive a Gin-supplemented parenteral mixture or standard Gln- free intravenous nutrition. I In the Gin-supplemented group, in- fection was decreased, length of stay was reduced, and hospital cost was significantly tess) The Gin-supplemented patients had a greater lymphocyte count at the time of bone marrow recov- ery, with T-cell subsets predominating. 3 These findings have been supported by other clinical investigations. Individuals re- ceiving Gin-containing parenteral nutrition following bone mar- row transplantation or major operation have a greater leukocy- tosis, 4 improved T-cell DNA synthesis, 5 the enhanced ability to express the anti-inflammatory cytokine interleukin-106, and the increased capacity to secrete the less toxic cystinyl-leuko- trienes. 6 Gin administration has also been associated with de- creased complications, improved nitrogen balance, and a re- duced length of hospital stay. 4'6'7

In addition to these effects on immune function, Gln also supports the bowel, particularly by enhancing gut-barrier func , tion. 8 This clinical effect is most dramatically observed in pre- mature infants who are born with an immature, leaky bowel. 9 Infants receiving Gin-fortified formulas reduced their bowel- related infection rate from 30.2 to 11.4%.

These and possibly other unknown effects of Gln may be important in interpreting the study by Griffiths et al. 1° published in this issue of Nutrition. This intensive-care team selected for study the most difficult group of patients cared for in their unit: those severely ill septic patients who required mechanical ventilation, couldn't be fed by the enteral route, and had a high incidence of multiple-organ failure. Only patients with liver failure and end-stage cancer (plus pregnant women and chil- dren) were excluded from this trial. Because of the heterogene- ity and high mortality of this group, these patients are infre- quently studied; yet it is this same patient group that requires new therapy in order to improve their outcome. One-half of the patients studied were randomized to receive a Gin-containing parenteral solution and the other half received conventional total parenteral nutrition. At entry, the groups were well matched as determined by multiple assessment criteria, includ- ing a variety of techniques to evaluate health status. As the study progressed, patient deaths occurred, initially from the underlying disease process but later from the consequences of sepsis and multiple-organ failure. Of significance, however, was the difference in late mortality observed in the two groups. In those patients fed > 10 d, 12/17 (71%) of controls died versus only 5/18 (28%)of the, Gin-fed patients (P = 0.03). At 6 mo, significantly more patients receiving Gln were alive

than those who received conventional feedings (24 versus 14; P = 0.049).

Why should this be so? First, we have already catalogued a number of biochemical mechanisms and physiologic functions that are influenced by Gin, and these effects may be highly beneficial to such critically ill patients. However, I would propose that Gin is playing a more global regulatory role by modifying the endogenous inflammatory response, possibly by attenuating the elaboration of proinflammatory mediators, and/or by upregulating anti-inflamma- tory factors. These effects could be mediated through the enhanced synthesis of the important intracellular antioxidant glutathione, which occurs with Gin administration, 11 but I suspect additional mechanisms are involved. To address such a question, one would need to harvest both serum and cells from shnilar patients so that circulating mediators and the cells' capacities to generate these signal proteins could be evaluated and the responses of these two patient groups compared.

Blinded studies in acutely ill patients that extended for years (in this case 3 y, 9 mo) require unwavering faith in the scientific process. The unit must resist subtle changes in care that would jeopardize the study, and investigators must stay motivated and committed to the recruitment of patients and performing the details involved with such an investigation. All individuals in- volved with direct patient care must remain blinded.

This seminal study demonstrates the enormity of such a commitment; the value of this report will be even further enhanced as confirmatory data emerge and additional mecha- nisms of Gln effects are discovered. Those characteristics that stimulated and motivated this group of intensive-care unit physicians to perform this study--persistence, tenacity, intellectual curiosity, desire to improve patient care- -have provided us with a provocative report that appears to be a major step forward in the improvement of nutritional care for all critically ill patients.

DOUGLAS W. WILMORE, M.D. Department of Surgery

Brigham and Women's Hospital Boston, Massachusetts 02115

REFERENCES

1. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition following bone marrow transplantation: a double-blinded, randomized, con- trolled trial. Ann Intern Med 1992; 116:821

2. MacBurney M, Young LS, Ziegler TR, Wilmore DW. A cost- evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients. J Am Diet Assoc 1994;94:1263

3. Ziegler TR, Bye RL, Persinger RL, et al. Glutamine-enriched paren- teral nutrition increases circulating lymphocytes after bone marrow transplantation. JPEN 1994; 18:17S

4. Jacobi CA, Ordemann J, Wenger F, et al. The influence of gluta- mine substitution in postoperative parenteral nutrition or immuno-

Nutrition 13:375-387, 1997 ©Elsevier Science Inc. 1997 Printed in the USA. All rights reserved. ELSEVIER 0899-9007/97/$17.00

376 EDITORIAL COMMENTS

logic function. First results of a prospective randomized trial (ab- stract). Shock 1997;7(S):605

5. O'Riordain M, Fearon KC, Ross JA, et al. Glutamine supplemen- tal parenteral nutrition enhances T-lymphocyte response in surgi- cal patients undergoing colorectal resection. Ann Surg 1994; 220:212

6. Motion B J, Krller M, Wachtler P, et al. Influence of L-alanyl-L- glutamine (ALA-GLN) dipeptide on the synthesis of leukotrienes and cytokines in vitro (abstract). Shock 1997;7(S):604

7. Schloerb PR, Amare M. Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications (a randomized double-blind study). JPEN 1993; 17:407

8. Van der Hulst RRWJ, Van Kreel BK, Von Meyenfeldt et al. Gluta-

mine and the preservation of gut integrity. Lancet 1993;334: 1363

9. Roig JC, Bowling D, Dallas M, et al. Enteral glutamine supplemen- tation decreases nosocomial infection and alters T-cell subsets in the very low birth weight (VLBW) (< 1250g) neonate. Pediatr Res 1995;37:285A

10. Griffiths RD, Jones C, Palmer TEA. Six month outcome of critically ill patients given glutamine supplemented parenteral nutrition. Nu- trition 1997; 13:295

11. Hong RW, Rounds JD, Helton WS, et al. Glutamine preserves liver glutathione after lethal hepatic injury. Ann Surg 1992; 215:114

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How Best to Determine Magnesium Status: A New Laboratory Test Worth Trying

The article by Sacks, Brown, Dickerson and their col- leagues ~ considers the limitations of tests that determine mag- nesium status before and after magnesium therapy to restore depleted levels of ten critically ill patients identified as magne- sium deficient on the basis of low serum values. Because the added risk of complications from magnesium depletion in pa- tients already at high risk from their injuries has been cited, the authors provided a continuous 24-h intravenous infusion containing magnesium (0.5 or 0.75 mmol/kg as MgSO4). They attempted to evaluate the efficacy of treatment, not only by changes in serum values but by white blood cell (mononuclear) determinations, which is considered a better index of tissue magnesium content. It was unanticipated that the mononuclear blood cell magnesium would be less indicative of response to the magnesium infusion than were the serum levels.

The authors considered several possible explanations for the failure to demonstrate repletion by this blood cell test. They suggested that variability in the assay, in conjunction with the small number of patients in their study, and a possible presump- tive lowered renal threshold for magnesium reabsorption, might account for failure to retain sufficient magnesium to replete tissue levels. However, the elevation of serum magnesium levels and correction of hypocalcemia (a consequence of magnesium deple- tion's impairment of parathyroid hormone secretion, which the authors cited) indicate that the infusion corrected those manifes- tations of magnesium deficiency. They also consider it possible that the amount of magnesium infused was insufficient to replete tissue stores in critically ill patients. All these points are valid, but caution must be exercised in increasing the magnesium load in a 24-h infusion to avoid levels that might produce hypermag- nesemia. Patients with decreased renal reabsorption of magne- sium would be at low risk of hypermagnesemia. Patients with impaired renal clearance would be at high risk of high circulating magnesium, which can cause sufficient peripheral vasodilatation to trigger hypotension and even shock, and might slow cardiac conduction, with risk of bradycardia and even heart block, z3 Abbott and Rude 4 have found lower infusion doses of pareriteral

magnesium ( 12-24 mmol mg/d) given for 3-5 d, followed by long-term repletion with orally administered magnesium (300- 600 mg/d), to be effective in repairing magnesium deficiency, even when characterized by acute signs, in critically ill patients.

Whether the measurement of blood cell magnesium is neces- sarily the best test to evaluate response to magnesium infusion is uncertain. Arnold et alp evaluated the magnesium status in erythrocytes and mononuclear blood cells in 15 critically ill patients whose magnesium depletion had been diagnosed by the magnesium-load test. They found no significant difference in plasma, red cell, and mononuclear blood cell magnesium levels between magnesium depleted and nondepleted groups, and concluded that a diagnosis of magnesium depletion cannot be excluded despite normal values in plasma, erythr0cytes, or mononuclear blood cells.

In the serum magnesium test, the more indicative of those used by Sacks et al., 1 serum magnesium comprises only 0.3% of the body's magnesium (of about 24 g or 1 mol) and is made up of protein-bound, complexed, and free ionic magnesium, which constitutes 71% of the amount in serum, and is the fraction that is biologically active. 6'7 There are now several ion-selective electrode (ISE) instruments that are commercially available. 7-I° Which of the devices is best to use is still controversial. The prototype of the NOVA Biomedical instrument, used by Altura and col- leagues, 7,m~ has provided the most data. They have fotmd that their ISE is selective for Mg 2÷, and exhibits little or no interfer- ence from pathophysiologic concentrations of ionic calcium, so- dium, potassium, hydrogen, ammonium, or heavy metals (e.g., ionic iron, copper, zinc, cadmium, mercury, or lead) in serum. Importantly, silicon (as found in vacutainer tubes) does not inter- fere with measured levels--an important attribute in collecting and transporting samples for analysis. Using this device, Altura et al. 7'11'n have found [Mg2+]o to be 71% of the total magnesium in serum, it varies from subject to subject, but has been remarkably consistent in sequential samples from an individual. Use of specific ISEs for [Mg 2÷ ]o has disclosed that Mg 2+ levels often exhibit significant differences from normality, despite no change in total