January 2011 Issue

Glutamine Supplementation — Evidence Indicates It May Benefit Patients With Critical Illness
By Megan Tempest, RD, LDN
Today’s Dietitian
Vol. 13 No. 1 P. 40

In the ever-evolving nutrition field, the facts and theories about glutamine may perplex even the most astute clinician. The benefits of supplemental glutamine have been widely studied during the past decade, and this single nutrient remains a hot topic in the realm of clinical nutrition therapy.

Background on Glutamine
A conditionally essential amino acid, glutamine is made from glutamic acid, another amino acid, by the action of the enzyme glutamine synthetase. The majority of glutamine is stored in skeletal muscle tissue, with the remainder in the lungs, liver, brain, and stomach. A healthy, unstressed body is highly efficient at synthesizing all the glutamine it needs.

Glutamine fulfills many roles in the human body, including facilitating nitrogen metabolism, fueling the cells that line the intestine, supporting protein synthesis, and serving as a critical substrate for the cellular immune response. The speculated health benefits of glutamine supplementation are vast. Glutamine may enhance immune function in individuals who are critically ill and immune suppressed, prevent infection in postsurgical patients, and support the integrity of the gut mucosa in the face of intestinal damage. Supplemental glutamine may speed healing of skin conditions such as severe burns or pressure ulcers due to its role in the inflammatory response, cell proliferation, and collagen formation.

Reasons for Supplementation
In the presence of critical illness and catabolic stress, the body’s glutamine consumption exceeds the normal supply. Glutamine is rapidly released from muscle stores to provide fuel to the absorptive cells lining the intestine (enterocytes and coloncytes) and to proliferating immune cells as well as to maintain the acid-base balance in the kidneys.1 Plasma glutamine levels may decrease by 58% during critical illness and remain depleted for up to three weeks.1 Glutamine depletion has been associated with increased risk of infectious complications, organ failure, and death.2

During this critical period, glutamine becomes an “essential” amino acid that must be obtained from dietary sources (eg, beef, chicken, fish, eggs, beans, dairy products), oral glutamine supplements, or glutamine-enriched enteral and parenteral nutrition. While little harm has been reported from glutamine, supplementation may be contraindicated in the presence of certain drug therapies and medical conditions (eg, in liver disease when the conversion of glutamine to glutamate and ammonia may worsen hepatic encephalopathy). Enteral glutamine supplements, typically in the form of L-glutamine, are available individually in powder, tablet, capsule, and liquid forms and are often added to protein supplements.3 Doses of up to 1,500 mg/day are considered safe for adults aged 18 and older, but healthcare professionals have provided higher doses for therapeutic purposes.3 Studies have shown that the route of administration plays a role in the effectiveness of supplementation. High-dose parenteral administration of glutamine (greater than 0.5 g/kg/day through an IV) has demonstrated better outcomes in hospitalized patients than lower doses given enterally.2 Historically, glutamine was not added to commercial parenteral nutrition solutions due to instability. The development of stable dipeptide glutamine analogues overcame this barrier.

Carolyn Banner, RD, LDN, CNSD, of the University of Chicago Medical Center, has experience with the supplemental use of glutamine for patients with burns and complex wounds, such as Stevens-Johnson syndrome, toxic epidermal necrolysis syndrome, and other necrotizing soft tissue infections. “The primary reason I use glutamine is as a complementary therapy, intended to optimize a patient’s gut health by replacing depleted levels of glutamine and fueling the enterocytes, thereby enhancing a patient’s chance of optimal healing and immune function,” explains Banner, who typically recommends supplementing 0.25 to 0.5 g/kg/day of enteral L-glutamine for adult patients with burns or complex wounds generally with greater than 20% total body surface area.

Looking beyond the role of glutamine in treating severe burns and wounds, Banner is enthusiastic about its other potential benefits, adding, “I’d be excited to see glutamine used in septic and post-op patients due to newer research on glutamine’s role in heat shock proteins.”

Do physicians support Banner’s recommendations to supplement glutamine in this population? From Banner’s perspective, they do: “The burn and critical care physicians at our institution are enthusiastically on board with providing glutamine to burn and ‘burn equivalent’ patients.”

New Research
In the past year alone, the amount of published research addressing glutamine supplementation has been significant. Some studies have provided further support for previously reported benefits while others have uncovered new findings. A team of Brazilian researchers recently published findings from an experimental study review intended to precisely assess the action of glutamine in patients who were critically ill.2 They identified multiple mechanisms by which glutamine may protect cells, tissues, and whole organisms from stress and injury. Those mechanisms include attenuation of nuclear factor-kappa B activation (a protein complex that controls DNA transcription and is involved in the cellular response to stress), the balancing of proinflammatory and anti-inflammatory cytokines that mediate the immune response, a reduced accumulation of destructive neutrophils, improvement in gastrointestinal integrity, and enhanced expression of heat shock proteins, which are essential to cellular survival under stressful conditions.2

In the May 2010 online issue of the Journal of Critical Care, Cetinbas and colleagues reported that glutamine-supplemented parenteral nutrition suppressed inflammation in patients with systemic inflammatory response syndrome, as evidenced by reduced leukocyte and natural killer cell count. In the June 2010 issue of the journal Nutrition, Mondello and colleagues reported that glutamine-supplemented parenteral nutrition increased the lymphocyte count in anorectic patients, suggesting that the amino acid stimulated the immune response and enhanced overall immune function.

As the primary fuel for the cells lining the small intestine and colon, glutamine in supplemental form may significantly enhance gastrointestinal integrity in vulnerable populations. An experimental study on mice, published in 2010 in the Journal of Parenteral and Enteral Nutrition, found that when subjecting the mice to intestinal damage, the provision of enteral glutamine decreased intestinal permeability and preserved the integrity of gut mucosa compared with those that did not receive glutamine. Along similar lines, a study published in the January 2010 issue of the American Journal of Surgery reported the effects of glutamine-enriched early enteral nutrition on intestinal mucosal barrier injury following liver transplantation in rats. Posttransplantation, the intestinal mucosa of the rats was seriously damaged at 12, 24, and 48 hours and subsequent changes to the intestinal mucosa were observed. In this study, glutamine-enriched early enteral nutrition was found to provide strong protection against intestinal mucosal barrier injury after liver transplant.

Among the most serious side effects of total parenteral nutrition is liver damage, with infants being the most vulnerable population due to their physiological immaturity. Adult and animal studies have shown that parenteral glutamine supplementation may have a hepatoprotective effect, a theory supported by a recent study published in the June 2010 issue of Clinical Nutrition. Researchers analyzed 30 parenteral nutrition-dependent infants of very low birth weight (defined as weighing less than 1,500 g) and analyzed hepatic function of a glutamine-supplemented group to a control group. The results showed that serum levels of aspartate aminotransferase and total bilirubin—both of which become elevated in the presence of liver damage—were decreased in the infants given parenteral glutamine compared with the control group.

Providing support for the positive impact of glutamine-enriched enteral nutrition in the critically ill, a review of randomized controlled trials conducted since 1976 was published in October 2009 in the Chinese Journal of Burns. Of the seven trials that met criteria for inclusion, the researchers concluded that providing glutamine-enriched enteral nutrition to patients who were critically ill lowered nosocomial infection rate and reduced length of hospital stay. They cautioned that further studies with larger samples are needed to better assess the cost-effectiveness and efficiency of glutamine-enriched enteral nutrition for lowering mortality rate in the critically ill.

A meta-analysis of randomized controlled trials by Wang and colleagues, published in 2010 in the Journal of Parenteral and Enteral Nutrition, sought to evaluate the effects of glutamine dipeptide-supplemented parenteral nutrition on surgical patients. They observed a reduction in length of hospital stay by four to five days and a significant decrease in infectious complications.

A study by Alonso and colleagues in 2010 in the Spanish journal Nutrición Hospitalaria attempted to find evidence that glutamine-supplemented parenteral nutrition reduced the need for antibiotics, reduced the risk of liver disease, and decreased the length of hospital stay in 68 bone marrow transplant patients requiring parenteral nutrition due to oral mucositis. Unlike in the previously described studies, these researchers observed no apparent benefit to supplemental glutamine in relation to these three variables.

Implications for Clinical Practice
Should clinicians routinely consider glutamine supplementation for relevant patient populations as identified in the literature? Given the significant potential benefits of supplemental glutamine and the expanding body of evidence, this critically important amino acid certainly warrants nutrition professionals’ attention. Parenteral glutamine is often considered costly and difficult to produce, yet the potential health benefits of supplementation—and savings to a hospital—may outweigh the perceived cost. The European Society for Clinical Nutrition and Metabolism (ESPEN) has indicated that “over the last 10 years an extensive evidence base for safety and beneficial clinical outcome has been built, such that its [glutamine’s] parenteral use can now be considered a standard of care.”4 Also according to ESPEN, no studies to date have shown IV glutamine (l-glutamine or dipeptide) to have harmful effects in the critically ill, and doses of 10 to 30 g of glutamine over 24 hours are safely tolerated and adequate to restore plasma glutamine levels.4

Banner concedes that she cannot easily pinpoint a specific outcome that she’s observed from glutamine supplementation, given that cause and effect from nutrition therapy can be difficult to isolate. Nonetheless, clinicians should be aware of and educated about the potential benefits and feel empowered to recommend a glutamine supplement when appropriate. Banner concludes, “It makes good clinical sense that if there is an understood deficiency of glutamine levels after acute periods of stress, then we should replete this vital amino acid to provide our patients with the best opportunity for survival and healing.”

— Megan Tempest, RD, LDN, works at Presbyterian/St. Luke's Medical Center in Denver and is a freelance writer.

 

References
1. Wischmeyer PE. Clinical applications of L-glutamine: Past, present, and future. Nutr Clin Prac. 2003;18(5):377-385.

2. Oliveira GP, Dias CM, Pelosi P, Rocco PR. Understanding the mechanisms of glutamine action in critically ill patients. An Acad Bras Ciênc. 2010;82(2):417-430.

3. University of Maryland Medical Center. Glutamine. Last reviewed June 20, 2009. Available at: http://www.umm.edu/altmed/articles/glutamine-000307.htm

4. Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: Intensive care. Clin Nutr. 2009;28:387-400.

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