Glutamine: the struggle for proof?

W e can generally agree that deficits in nutrition will have some impact on the outcome of our patients because when it is extreme, lives are put at risk. However, proving that just one particular component of a nutritional mixture makes a difference to outcome is not easy, especially in a complex process of care such as the critically ill. Therefore, the article by Grau et al (1) is surprisingly encouraging because it adds further weight to the argument that enhancing glutamine provision may have benefits and that our nutritional practices are not yet optimal (2). They study 127 patients predominantly surgical in character recruited from across 12 intensive care units in Spain drawn from a sicker population who required parenteral nutrition (24% of those requiring any artificial feeding). Patients randomized to the glutamine arm completing at least 4 days of feed (per protocol analysis) demonstrated significantly reduced nosocomial pneumonia and urinary tract infections. Glycemic control was improved requiring half the insulin dose. How is it possible that the addition of this one amino acid to the parenteral nutrition was necessary for this improved outcome? Is it plausible? Why should something as simple as a little extra of one amino acid make this difference? The mistake is to think of glutamine in terms of a “drug” action and to assume that glutamine has a singular pharmacologic action rather than a multilayered metabolic role in a complex system (3). Since the 1970s (4), research has shown that glutamine is one of the most abundant amino acids, freely manufactured in many cell systems, and held free in solution in muscle at a concentration gradient of 32:1 over plasma levels, which transport it in near millimolar concentrations around the circulation. Thus, it has seemed inconceivable that it could become nutritionally essential and was classed traditionally as a nonessential amino acid. However, detailed tracer studies show that it is a major player in many metabolic processes with a very high turnover of approximately 1 g glutamine per kilogram per day (5). This is approximately ten times the normal dietary intake and hence endogenous production is fundamental to maintain an adequate supply. The critically ill patient sustains two pressures on this glutamine supply system; the demand rises (eg, with immune activation and reparative processes) while production is compromised (eg, by immobility and insulin resistance) that leads to a state of conditional essentiality and a functional deficiency ensues. This lack is further compounded when from the 1960s the traditional amino acid solutions for ease of manufacture did not include the less soluble and heat-stable L-glutamine because it was deemed nonessential! Therefore, we should not consider this to be an addition of glutamine but more a restoration of glutamine. Indeed, 20–40 g of glutamine in some patients barely restores plasma levels to normal (6). The functional impact that replacing glutamine has on outcome is to correct the consequence of low glutamine availability on many cellular systems (synthetic, secretory, protective) where it has been shown that function is compromised within the biologic range observed in our patients (7). It is for this reason that glutamine becomes an essential immune nutrient in the critically ill (8). It is not surprising therefore that a low plasma glutamine has been shown independently related to a worse outcome (9) and why single-site studies of its restoration have indicated an improved survival that is related to duration and dose (10, 11). Overcoming the demands for glutamine with its restoration is therefore integral to recovery. Confirming this in larger multisite studies is a real challenge if the study design does not adequately address the physiological evidence of a progressive deficiency that increases with severity and duration of illness and does not allow for recovery. Designing a study as if glutamine were a simple “drug” in which only dose and delivery matter ignores the consequence of the degree of deficiency and how much is required to keep on correcting the deficiency. The opposite is also true in that less ill patients early on that may not manifest a deficiency do not show any benefit from extra glutamine (12). In the study by Grau, they have rightly selected higher risk patients, attempted to optimally feed their patients, undertake an acceptable degree of glucose control, and delivered a good dose of glutamine. Sadly, as a result of curious licensing restrictions, they could not provide 9 days’ supply of glutamine, which may explain why they are unable to show any significant longerterm outcome effect on mortality (intention-to-treat 6-month mortality not significantly improved at 28% vs. 34%). This capping of the duration of feed results in an average of only 5–6 days of glutamine provision, which was only approximately half the average intensive care unit stay. Any potential benefit to the high-risk long stay intensive care unit patients is effectively withdrawn. A 10-day limitation of therapy also occurred in 114 intensive care unit patients in a French multicentered randomized controlled trial that similarly showed a significant reduction in complicated outcomes related to reduced infectious rate and pneumonias (13). This study also showed improved glycemic control. Previous studies had suggested that survival outcome advantages were seen in those fed for at least 5 days and generally 10 days when glutamine was administered for as long as parenteral nutrition required, ie, until they were recovering from gastrointestinal failure (10). A similar weakness in study design and a failure to adequately address the continued glutamine conditional deficiency is seen in a study as yet only presented at conferences, Scottish intensive care glutamine or selenium evaluation trial (SIGNET) (14), which appears to show no outcome benefit. Said to be the largest study to date, it produced a *See also p. 1263.