A forty-year-old motorcyclist was admitted to the ITU following a road traffic accident involving a stationary vehicle. She sustained a fractured right distal radius and multiple left sided rib fractures, involving ribs 2 to 9, with a free floating flail segment. She developed respiratory distress due to underlying lung contusions and a haemopneumothorax and was treated with two left sided intercostal drains, endotracheal intubation and invasive ventilation. She developed ARDS with bilateral infiltrates and PF ratio of <200mmHg, with normal cardiac function on transthoracic echocardiography. She was tracheostomised on day 12, and had a protracted ventilatory wean further complicated by a ventilator associated pneumonia. She was enterally fed during this period but began to develop an ileus and gut dysmotility, resistant to prokinetic treatment, leading to large volume gastric aspirates. She became visibly malnourished and was commenced temporarily on parenteral nutrition and IV glutamine. The ileus resolved over the following week and weaning recommenced, having ceased due to diaphragmatic splinting. She eventually weaned from the ventilator and was discharged from the ITU on day 40. She was profoundly weak due to a critical illness acquired weakness.
What is the role of glutamine supplementation in critical illness?
Glutamine is a non-essential amino acid that becomes essential in times of physiological stress. Skeletal muscle is the major producer of glutamine and part of the profound catabolic depletion of skeletal muscle seen in critical illness is a reflection of the need to produce glutamine.
Glutamine is utilized in rapidly dividing cells in the splanchnic area. Quantitatively most glutamine is oxidized, but the availability of glutamine in surplus is important for synthesis of nucleotides and necessary for cell division and protein synthesis.
Glutamine is an important precursor of glutathione and has also been shown to induce heat shock proteins (HSP), so it may modulate both oxidative stress and inflammation. (1) Glutamine deficiency (defined as a low plasma concentration at ICU admission) is an independent mortality predictor. (2)
The current recommendation from ESPEN and ASPEN/SCCM is to add intravenous (IV) glutamine supplementation when total parenteral nutrition (TPN) is given to critically ill patients. (3)
It has also been shown that glutamine can play a role in preserving gut villous integrity. By this mechanism it is postulated to reduce the risk of bacterial translocation and gut permeability, which may, in turn, reduce the incidence of de novo infections such as ventilator associated pneumonias and catheter related blood stream infections in critically ill patients (4). However, a Scottish study which randomized 502 patients on critical care for over 48hrs to receive parenteral glutamine, selenium, or both, was unable to show any difference in infection rates or outcomes in terms of mortality. Secondary outcomes of length of stay and days of antibiotic use were also not affected. (5)
However a recently published study contradicts these findings. (7) The investigators conducted a blinded 2-by-2 factorial trial, assigning 1223 adults in 40 intensive care units in North America, Canada, and Europe (who had multi-organ failure and were ventilated) to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were given both intravenously and enterally. Primary outcome was 28-day mortality. They found increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%) adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were also significantly higher among those who received glutamine than those who did not. Glutamine was not shown to have an effect on rates of organ failure or infectious complications. In the other group, antioxidants had no effect on 28-day mortality.
Why might this be? It has been recognized for some time that overfeeding of ITU patients (8) may increase mortality by inducing metabolic derangement and systemic stress; as well as providing excessive nutrients for bacteria, and it may be that glutamine supplementation contributed to overfeeding. A study that measured plasma glutamine and replaced it only in deficient states might provide a different set of answers but would be difficult to undertake.
Antioxidants have also often been pointed to as potential novel treatments in sepsis and other conditions but this again has not been translated into evidential benefit. It may be that free radicals are actually useful in some disease states, assisting bacterial knock out by macrophages and priming abnormal cells for apoptosis, and suppressing them may attenuate host response to pathogens. Another theory is that the body has a perfectly good antioxidant system (involving superoxide dismutase) and supplementation has no increased benefit. The role of immuno-nutrition with trace elements such as selenium and amino acids such as glutamine may still yield useful results but the tide of opinion and evidence has yet to turn in their direction. Certainly following the study by Heyland et al. (7) it may be harder in future to start from a position of equipoise where glutamine is concerned.
1. Peng ZY, Zhou F, Wang HZ et al. The anti-oxidant effects are not the main mechanism for glutamine’s protective effects on acute kidney injury in mice. Eur J Pharmacol. 2013;705:11-19.
2. Oudemans-van Straaten HM, Bosman RJ, Treskes M, van der Spoel HJ, Zandstra DF. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med. 2001;27:84-90.
3. Van den Berghe G. Low glutamine levels during critical illness–adaptive or maladaptive? N Engl J Med. 2013;368:1549-1550.
4. Wischmeyer PE. Glutamine: role in gut protection in critical illness. Curr Opin Clin Nutr Metab Care. 2006;9:607-612.
5. Andrews PJ, Avenell A, Noble DW et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011;342:d1542.
6. Mitchell I, Bihari D. Glutamine-enriched enteral nutrition in patients with multiple trauma. Lancet. 1998;352:1553.
7. Heyland D, Muscedere J, Wischmeyer PE et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489-1497.
8. Wernerman J. Nutrition in the ICU–from overfeeding to starvation. Nutrition. 1997;13:914-915.