Critical illness is characterized by glutamine depletion owing to increased metabolic demand. Glutamine is essential to maintain intestinal integrity and function, sustain immunologic response, and maintain antioxidative balance. Insufficient endogenous availability of glutamine may impair outcome in critically ill patients. Consequently, glutamine has been considered to be a conditionally essential amino acid and a necessary component to complete any parenteral nutrition regimen. Recently, this scientifically sound recommendation has been questioned, primarily based on controversial findings from a large multicentre study published in 2013 that evoked considerable uncertainty among clinicians. The present review was conceived to clarify the most important questions surrounding glutamine supplementation in critical care. This was achieved by addressing the role of glutamine in the pathophysiology of critical illness, summarizing recent clinical studies in patients receiving parenteral nutrition with intravenous glutamine, and describing practical concepts for providing parenteral glutamine in critical care.
The amino acid glutamine (Gln) plays a central role in human nitrogen, protein, and energy metabolism. Gln transports nitrogen between cells and/or organs and serves as a metabolic fuel—in addition to glucose or as an alternative—in rapidly proliferating cells. Gln is a precursor for protein, nucleotide, and nucleic acid synthesis and also regulates cellular pathways and related functions [
Under physiological conditions, sufficient endogenous Gln stores (as judged by normal intracellular concentrations) are maintained by both daily nutritional intake (80 g of mixed protein contains approximately 10 g Gln) and by endogenous synthesis which occurs mainly in skeletal muscle and the liver [
Routine Gln supplementation has long been recommended for critically ill patients receiving parenteral nutrition (PN) [
The first reports of muscle Gln depletion in trauma and critical illness emerged in the late 1970s and early 1980s [
Triggered by endocrine mechanisms, Gln-consuming organs, like the gut, gut-associated lymphoid tissue (GALT), and the kidneys, all enhance the uptake of Gln to support the synthesis of acute-phase proteins (e.g., heat shock proteins, HSP) [
Gln depletion is noticeable by marked reductions of Gln in muscle, immunologic tissues, and (in many cases) blood, with consequences such as reduced protein synthesis, muscle loss, and physical fatigue [
Consequences of glutamine depletion for the organism (modified from Wischmeyer 2003 [
It can be concluded that the consumption of Gln during metabolic stress is generally higher than Gln endogenous synthesis, and so the body lacks Gln to support essential pathways promoting healing processes. Thus, exogenous Gln supply is an important countermeasure to avoid the adverse consequences of Gln deficiency which may result in an increased risk of sepsis, MOF, and premature death [
Whilst Gln is a “natural” component of proteins added to enteral formulations, standard amino acid solutions for PN are lacking this amino acid. The major limitations preventing the addition of free Gln to parenteral amino acid preparations are (a) the poor solubility of Gln in water and (b) the generation of potentially toxic pyroglutamic acid from free Gln during heat sterilization and storage. To solve these problems Gln-containing dipeptides, L-alanyl-L-glutamine (Ala-Gln) and glycyl-L-glutamine (Gly-Gln), were developed. These alternative Gln sources for PN are stable and soluble. As Gln is bound at the N-terminal position of these dipeptides, the
Benefits of parenteral Gln dipeptides in critical care have been continuously and repeatedly demonstrated in numerous RCTs. Compared with Gln-free PN, Gln-supplemented PN improved nitrogen economy, normalized IGF-I levels [
For example, Déchelotte et al. [
These beneficial effects of parenteral Gln, proven in single-centre and larger multicentre studies, have been confirmed by recent meta-analyses [
Bollhalder et al., 2013 [
Beyond its most important clinical benefits in the ICU, Gln supplementation of PN is also economically attractive. An economic evaluation revealed that a PN regimen supplemented with Ala-Gln is more cost-effective than standard PN regimens. Incorporating data from 200 Italian ICUs in over 60000 patients, Pradelli et al. demonstrated reductions in mortality rate, infection rate, and hospital LOS with Ala-Gln. This resulted in a lower total cost per patient and treatment cost was completely compensated by savings on ICU and antibiotic costs [
In all the previously discussed trials, Gln was administered in-line with the clinical guidelines [
Indeed, the scientifically sound and accepted background to administer Gln to severely ill patients is to optimize nutritional support by including an obviously conditionally indispensable substrate [
All patients are at high risk of developing a negative Gln balance if they have undergone major surgery or trauma or are suffering from severe illness such as infection or organ failure, where vital functions need to be supported in the ICU by mechanical and/or pharmaceutical means for more than 72 hours (“critically ill patients”). If adequate nutritional support by the enteral route is not feasible, patients should receive total or supplemental PN providing sufficient energy, indispensable amino acids (routinely including Gln), and essential micronutrients [
Nearly all “positive” Gln studies excluded patients with severe liver and/or renal failure, or unresuscitated shock. The kidneys are central organs in Gln metabolism [
Likewise, because the liver has a central role in ammonia detoxification [
It is also important to note that not all types of organ failure represent a contraindication against the administration of Ala-Gln. Whilst it is important to exclude patients with severe renal and/or hepatic insufficiency, Ala-Gln supplementation is generally safe in patients with brain damage, lung damage with adequate technical support, gastrointestinal failure with recompensated circulatory shock, and resolved metabolic acidosis as well as normal substrate utilization. Of course, whenever the clinical situation forbids clinical nutrition in general, Gln supplementation is also contraindicated.
In the REDOX
Gln at a dose of up to 10 g/day, corresponding to the intake from a normal mixed diet, should be a mandatory part of any clinical nutrition regimen. In situations when this basic supply is insufficient, such as in critical illness, additional Gln should be given to provide sufficient Gln, up to a maximum total dose of 30 g/day. This Gln administration should be maintained throughout the hypercatabolic phase, signified by increased CRP, decreased prealbumin levels, and negative nitrogen balance. In accordance with present guidelines, supplemental Gln should be administered intravenously at a dose of 0.3–0.6 g Ala-Gln dipeptide/kg BW/day [
Gln is conditionally indispensable in critical illness for the maintenance of intestinal integrity and function, support of the immune system, and maintenance of antioxidative balance through multiple mechanisms. Data from controlled clinical trials and meta-analyses have confirmed that adhering to the well-established use of intravenous Gln, in combination with adequate nutritional support, reduces mortality, infectious complications, and ICU/hospital LOS, whilst also being an economically attractive treatment. Suitable candidates for intravenous Gln include, in particular, critically ill patients with burns, trauma, or malignancies. Although Gln is contraindicated in patients with severe renal and/or hepatic insufficiency, it is generally safe in patients with failures of other organs (e.g., brain damage or respiratory failure receiving adequate mechanical ventilation or gastrointestinal failure) with recompensated circulatory shock and resolved metabolic acidosis as well as normal substrate utilization.
Peter Stehle is consultant of Fresenius Kabi Deutschland GmbH. Katharina S. Kuhn is a consultant and received remuneration from Fresenius Kabi Deutschland GmbH.