Glutamine: More Evidence, More Promise
By Kudsk, Kenneth A
Pancreatitis is a nasty disease. It attacks young and old alike, often occurring without warning signs. Fortunately, most cases are rather mild and resolve spontaneously. However, a subpopulation of patients develops life-threatening disease, spending a month (usually longer) in the hospital with a large part of the stay spent in the intensive care unit (ICU). The disease poses several management problems for the clinician. First, the patients are hypermetabolic, rapidly immobilizing lean tissues in an aggressive catabolic state. Second, infectious complications-both respiratory and intra-abdominal (infected pancreatic tissue, retroperitoneal abscesses, etc)-present a difficult management problem requiring aggressive ICU care, antibiotic (often multiple) therapy, respiratory support, and frequently, surgical debridement. Although enteral access can be safely obtained during laparotomy and successfully used for postoperative enteral nutrition,1 operative therapy occurs weeks rather than days into the course of the disease process. During the acute preoperative phase, a massive retroperitoneal phlegmon impairs gastric emptying, precluding any form of intragastric nutrition support. The inflamed, edematous duodenum usually makes advancement of a nasojejunal tube technically impossible. Hence, in addition to hemodynamic, respiratory, and other critical care therapies, parenteral nutrition provides the primary method of nutrition support for these patients, often for prolonged periods of time. Even if enteral access is obtained at laparotomy, advancement of jejunostomy feedings is often slow, requiring a very gradual transition from parenteral to enteral therapy.
In the article by Fuentes-Orozco and colleagues in this issue of the Journal of Parenteral and Enteral Nutrition (JPEN),2 the authors chose to study a very ill group of patients with pancreatitis. By limiting recruitment to patients with evidence of at least 30% of pancreatic necrosis on computed tomography (CT) with high APACHE II and Ranson scores, they selected a population who would receive IV nutrition support in almost every institution. In this study, patients were randomized to isonitrogenous, isocaloric formulas consisting of either a parenteral solution with standard amino acids or a formula containing L-alanyl-L-glutamine along with standard amino acids. Like many other studies of glutamine-supplemented parenteral nutrition, improvements in infectious complications were noted with a trend toward reduced mortality. Clearly, the authors should be commended for studying such a challenging group of critically ill patients.
Metabolically, glutamine is a very important substrate. Glutamine is the most abundant free amino acid in the cytosol and the plasma. Under conditions of stress and injury, it becomes conditionally essential as serum and intracellular levels plummet. Its role in hypermetabolic conditions has been extensively investigated and well established.3,4 In stress, the amounts of glutamine released from muscle far exceed that accounted for by the amount present in muscle protein itself. This augmented release occurs as a result of transamination of alpha-ketogluterate within the stressed cell. This occurs simultaneously with up-regulation of the transamination of pyruvate to alanine. As a result, alanine and glutamine become the most abundant amino acids released from stressed muscle. Alanine is transported back to the liver, where it is deaminated to provide pyruvate for gluconeogenesis. Glutamine, however, provides an energy source for enterocytes (which receive no enteral stimulation during severe illness) and for lymphocytes, particularly T lymphocytes, which produce cytokines and serve other functions. Under these conditions of stress, when glutamine becomes conditionally essential, supplementation with exogenous glutamine has been studied as a potential therapeutic intervention.
Unfortunately, doing this is not all that easy. Free glutamine has several very undesirable characteristics. First, it is difficult to dissolve into solution. Once it is in solution, it becomes relatively unstable over time-particularly during heat sterilization of glutamine containing solutions-to produce a toxic product, pyroglutamate. Thus, unless amino acid supplementation with glutamine is prepared relatively soon (at least by commercial preparation time frames) before administration, the potential for risk of injury with this amino acid limits its commercial availability. Most hospitals and other agencies supplying parenteral nutrition do not wish to undertake the risk and difficulties associated with preparation of glutamine formulations. As a result, these glutamine-containing solutions are relatively limited to research studies. Fortunately, both solubility and stability become easier using dipeptide forms such as L-alanyl-L-glutamine, a fairly expensive product that dissociates into free glutamine soon after infusion into the vascular system.5 Although L-alanyl-L-glutamine solves the problems of solubility and instability, its availability for research in the United States, at least, is relatively limited.
Fuentes-Orozco et al2 chose this dipeptide as their primary nutrient manipulation. The clinical results were impressive. Infectious complications associated with pancreatitis were reduced from approximately 73% to 41% using this nutrient. This was not due to alterations in the incidence of central venous infections seen in other clinical trials but through reductions in pneumonia, infected pancreatic necrosis, and intra-abdominal sepsis. Although one can dicker with the diagnostic criteria used to confirm pneumonia (bronchoalveolar lavage with quantitative cultures are arguably more reliable), the authors used established and acceptable criteria to diagnose this complication. In addition, they recruited evaluators blinded to the treatment arm to evaluate x-rays.
When I evaluate articles such as this, I look for consistency in data. If there is an actual reduction in infectious complications, it should be reflected in other metabolic parameters. The study by Fuentes-Orozco and colleagues2 provides data on the acute phase protein response, which allows such confirmation. The acute phase protein response is driven by interleukin-6 (IL-6), a cytokine released in high concentrations into the splanchnic system.6 IL-6, among other things, alters protein production by the liver to increase production of serum acute phase proteins (here measured as C-reactive protein) and reduce levels of serum constitutive proteins (here measured as albumin).7 Usually, levels of total serum proteins move in parallel with serum albumin levels. Consistent with the reduction in infectious complications, the authors confirmed a blunted acute phase response by documenting reductions in IL-6 and C- reactive protein levels simultaneously with increases in serum albumin in the glutamine-supplemented group. The measurements of these interrelated outcome variables remained consistent with the clinical findings.
The significant increases in lymphocytes and IL-10 found in the study by Fuentes-Orozco and colleagues2 are intriguing. Our work investigating mucosal immunity shows that parenteral feeding of mice results in significant decreases in CD4-positive cells in Peyer’s patches and lamina propria of the intestine,8 with decreases in intestinal IL-10 levels.9 Both the number of T lymphocytes and levels of IL-10 (as well as IL-4, another Th-2 cytokine) seem to affect the ability of the mucosal- and gut-associated lymphoid tissue to produce secretory immunoglobulin A (IgA).9 Secretory IgA provides the primary specific immune globulin to protect the most mucosal surfaces of the respiratory and gastrointestinal tracts. Glutamine supplementation of the parenteral solution normalizes these cytokines in mice studies,10,11 improves resistance to respiratory infection in the mice,12 and reduces mortality after gut ischemia and reperfusion.13 Because the vascular system is used to transport T (and B) lymphocytes from Peyer’s patches to the lung, upper respiratory tract, and the lamina propria of the gastrointestinal tract, it is conceivable that the increases in CD4 lymphocytes noted by Fuentes-Orozco and colleagues2 reflect maintenance of transport within the mucosal-associated lymphoid tissue in humans. This would be consistent with the lower rates of pneumonia in glutamine-treated patients because glutamine maintains established immune defenses in the respiratory tract of mice that is otherwise lost with unsupplemented parenteral nutrition. IL-10 is a Th-2 cytokine produced by T cells, which stimulates IgA production and appears important to support mucosal immunity. Therefore, the clinical and laboratory results noted by Fuentes-Orozco and colleagues2 are consistent with laboratory work. To me, the results are believable and consistent with other studies of glutamine in pancreatitis.
The important question for clinicians in the United States becomes, when is this product going to be available to us? When will we have L-alanyl-L-glutamine or other glutamine dipeptide- supplemented solutions available for larger, randomized clinical trials that are designed to answer the question of its usefulness in critically ill patients once and for all? Clearly, both laboratory and clinical data suggest its usefulness in states of critical illness other than just pancreatitis. Years ago at the University of Tennessee, Memphis, we were prepared to start a large clinical trial using a glutamine-supplemented parenteral nutrition funded by a European company. The protocols had been approved by the institutional review board of 4 different institutions. Unfortunately, the project was abandoned before a single patient had been recruited. A business analysis of the costs required to meet regulatory requirements vs potential profitability was unfavorable. We spend countless dollars collecting data and implementing protocols for questionable markers of “quality assurance” for government agencies but cannot get access to a potentially inexpensive product such as glutamine to test its effectiveness. Unfortunately, the people who may pay the price are the critically ill patients. Glutamine needs to be vigorously studied just as Fuentes-Orozco and colleagues2 have done. But how and when can we do it? References
1. Kudsk KA, Campbell SM, O’Brien T, Fuller R. Postoperative jejunal feedings following severe complicated pancreatitis. Nutr Clin Pract. 1990;5:14-17.
2. Fuentes-Orozco C, Cervantes-Guevara G, Mucino-Hernandez, et al. L-alanyl-L-glutamine-supplemented parenteral nutrition decreases infectious morbidity rate in patients with severe acute pancreatitis. JPEN J Patentet Enteral Nutt. 2008;32:403-411.
3. Wilmore DW, Smith RJ, O’Dwyer ST, et al. The gut: a central organ following surgical stress. Surgery. 1988;104:917.
4. Souba WW. Glutamine: a key substrate for the splanchnic bed. Annu Rev Nutr. 1991;11:285.
5. Vazquez JA, Daniel H, Adibi SA, et al. Dipeptides in parenteral nutrition: from basic science to clinical applications. Nutr Clin Pract. 1993; 8:95-105.
6. Ohzato H, Yoshizaki K, Nishimoto N, et al. Interleukin-6 is a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery. 1992;111-201-209.
7. Kudsk KA, Minard G, Wojtysiak SL, et al. Visceral protein response to enteral vs parenteral nutrition and sepsis in trauma patients. Surgery. 1994;116:516-523.
8. Li J, Kudsk KA, Gocinski B, et al. Effects of parenteral and enteral nutrition on gut-associated lymphoid tissue. J Trauma. 1995;39:44-52.
9. Wu Y, Kudsk KA, DeWitt RC, Tolley EA, Li J. Route and type of nutrition influence IgA-mediated intestinal cytokines. Ann Surg. 1999;229:662-668.
10. Kudsk KA, Wu Y, Fukatsu K, et al. Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. JPEN J Parenter Enteral Nutr. 2000;24:270- 275.
11. Fukatsu K, Kudsk KA, Wu Y, Zarzaur BL, Hanna MK, DeWitt RC. TPN decreases IL-4 and IL-10 mRNA expression in lamina propria cells but glutamine supplementation preserves the expression. Shock. 2001;15:318-322.
12. DeWitt RC, Wu Y, Renegar KB, Kudsk KA. Glutamine-enriched TPN preserves respiratory immunity and improves survival to a Pseudomonas pneumonia. J Surg Res. 1999;84:13-18.
13. Ikeda S, Zarzaur BL, Johnson CD, Fukatsu K, Kudsk KA. Total parenteral nutrition supplementation with glutamine improves survival after gut ischemia/reperfusion. JPEN J Parenter Enteral Nutr. 2002;26:169-173.
Kenneth A. Kudsk, MD
Financial disclosure: none declared.
From the Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison.
Address correspondence to: Kenneth A. Kudsk, MD, Box 7375 Clinical Science Center-H4, 600 Highland Avenue, Madison, WI 53792; e-mail: kudsk@surgery.wisc.edu.
Copyright American Society for Parenteral and Enteral Nutrition Jul/ Aug 2008
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