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Until recently glutamine had not been included in commercial parenteral nutrition solutions. This is because of concerns about its spontaneous degradation, which results in the formation of pyroglutamic acid and ammonia. However, the degradation rate is slower than previously thought, especially in dextrose containing parenteral nutrition solutions.1 ,2 Therefore, parenteral nutrition solutions containing free glutamine can be stored at 4°C for at least a few days before clinical use. The study by Powell-Tucket al (see page 82) is one of a handful of studies that has included free glutamine in parenteral nutrition solutions. Stable synthetic glutamine containing dipeptides are also available as an alternative source of glutamine. In considering how much glutamine should be added to parenteral nutrition solutions it is useful to refer to the normal dietary intake. Surprisingly, the quantities of glutamine in normal diets are not accurately known because food tables usually report glutamine and glutamate in combination (glutamine is liberated during hydrolysis of proteins and is converted to glutamate). However, it is estimated that roughly 5 g glutamine are ingested daily by healthy people, and a similar amount is probably delivered by enteral tube feeds. In Powell-Tucket al’s study 20 g glutamine was administered each day (3.8 g nitrogen, which is equivalent to about one third of the normal dietary nitrogen intake). Other studies have used even more glutamine (see later). Therefore, any effects of glutamine in such studies can be regarded as pharmacological. Conversely, the net inter-organ flux of glutamine in normal humans,3 which is at least 25 g/day (muscle, lung, adipose tissue produce glutamine, and splanchnic bed and lymphocytes utilise glutamine), approximates more closely to the daily dose of parenteral glutamine. In disease states the utilisation of glutamine often increases, with the result that there is a reduction in both the circulating glutamine concentration and the size of the free glutamine pool, which is largely located in muscle.
Powell-Tuck et al’s study differs from a number of others on glutamine containing parenteral nutrition in including patients with a broad range of diagnoses, age (18–85 years), and clinical status, although those selected for parenteral nutrition by the nutrition team were generally very sick, as shown by their high hospital mortality and prolonged hospital stay. As glutamine has been implicated in having a wide range of beneficial effects (e.g. on immune function, gut barrier function, cytokine responses, and improvement in the function of a variety of tissues, including the heart) it might also prove to be beneficial to a wide range of patients. Therefore, the study set out to test the hypothesis that glutamine could be beneficial in routine clinical practice. The number of patients in the study was 168, which was considered to be sufficiently large to detect a 10 day reduction (∼30%) in the length of hospital stay with an 80% power. No overall significant difference was found between the glutamine supplemented and control groups of patients in mortality (17 v 24% respectively), in the incidence of infective complications (38v 56% of patients), or length of hospital stay (32 v 35 days). It is possible that certain groups of patients benefited from glutamine supplementation, but the number of patients within these groups may not have been sufficiently large to test statistically this possibly. However, the significant reduction (p<0.03) in the length of hospital stay in the surgical patients (30 v 45 days) is of considerable interest, especially as another recent study reported that parenteral nutrition containing a glutamine dipeptide (0.2 g glutamine/kg/day) reduced the length of hospital stay in patients undergoing elective colonic surgery by six days (22v 16 days; p<0.05).4
The only other parenteral nutrition study that assessed the effect of glutamine on a very heterogeneous group of adult patients was that of Griffiths et al,5which involved critically ill patients in an intensive care unit (ICU). Eighty four patients were randomised to receive either 25 g glutamine/day or a mixture of non-essential amino acids (see table 6 for comparison of amino acid composition between groups in Powell-Tucket al’s study). Again, there was no significant reduction in the complication rates or mortality during their stay in the ICU or hospital, but the six month mortality, which included a post-discharge period, reached statistical significance in favour of the glutamine group (p<0.049). Other clinical studies have produced variable results. In adult bone marrow transplant patients receiving cytotoxic drugs a reduction in the length of hospital stay and infective complications was found in patients receiving glutamine enriched parenteral nutrition (0.57 g glutamine/kg/day) compared with the control group that received no glutamine.6 In contrast, glutamine enriched parenteral nutrition (26 g glutamine/day)7) or oral glutamine (15 g/day)8 ,9 in adult patients receiving chemotherapy has been reported to produce no benefit in relieving toxicity such as oral mucositis, which often causes pain and reduces food intake. Similarly, glutamine supplemented enteral feeding has also been reported to reduce the requirement for ventilation and time to full oral feeding in premature babies weighing less than but not in those weighing more than 800 g.10 An early report in adults suggests that glutamine supplemented enteral nutrition reduces infectious complications following multiple trauma.11
The routine inclusion of at least some glutamine in parenteral nutrition solutions can be regarded as rational because it “humanises” the intravenous diet. The use of large pharmacological doses of glutamine may be of benefit in some specific conditions but Powell-Tuck et al’s study fails to provide evidence of overall benefit in routine clinical practice.
Finally, it is appreciated that these studies are time consuming, often taking years to complete (∼20 months in the case of the Powell-Tuck study). Researchers must be persistent in adhering to their study design, remain blind to the treatment, and resist any changes in treatment that might interfere with the outcome of the study and therefore Powell-Tuck and colleagues’ study, which is the largest of its kind, has been a major undertaking. Large multicentre studies perhaps provide the only practical way of rapidly assessing the possible benefits of glutamine in large subgroups of patients.