Glutamine kinetics in critically ill patients

Critical illness, defined as a life-threatening organ failure, entails an extreme stress that results in a pathophysiology of its own. The abnormal metabolism of these patients causes a severe muscle wasting that is poorly understood. One hypothesis is that the muscle is sacrificed to provide the body with key metabolic substrates, such as the amino acid glutamine. Both low and high plasma glutamine concentrations at Intensive Care Unit (ICU) admission are associated with a higher mortality. However, the mechanisms behind these associations are unknown. It has been suggested that there is an increased demand for glutamine in critical illness and that its availability is crucial for proper function of the immune system and the intestine. Hence, several intervention studies on glutamine supplementation in the ICU have been conducted. However, design and included patients varies widely and thus the results are heterogenous and problematic to compare. In order to explore the hypothesis that low plasma glutamine concentration in critical illness represents a shortage that may motivate glutamine supplementation, glutamine kinetics in these patients needs to be characterized.

The first step was to establish and validate a bolus injection method to measure glutamine endogenous rate of appearance (endoRa) for studying endogenous glutamine production in the ICU setting. When this method was applied, a positive correlation was detected, where 35% of variability in plasma glutamine concentration could be related to endoRa during critical illness. The second part of the thesis consists of observational studies on plasma glutamine concentrations in connection to outcome and specific diagnoses. In the post ICU period, plasma glutamine concentration was within the reference range and was not related to mortality. In liver failure, regardless of aetiology, severity and course of illness, a high plasma glutamine concentration was a common finding, although most frequent in patients with acute fulminant and acute-on-chronic liver failure. There was a positive correlation between the severity of liver failure and plasma glutamine concentration. Admission hyperglutaminemia (≥930 μmol/L) was an independent predictor for high mortality. A majority of the hyperglutaminemic patients had a liver condition, although hyperglutaminemia was also observed in patients without signs of liver affection. The role of glutamine in critical illness is still not settled. Our observations give no indication that a high plasma glutamine per se is toxic. The finding that low plasma concentrations correlates with a lower endogenous production keeps the possibility open that there is a cohort of critically ill patients with too low glutamine availability, who would benefit from exogenous glutamine supplementation. The ultimate question if plasma glutamine concentration is just a biomarker or if it also gives signal of a deficit and/or an impaired handling of glutamine is still pending. Therefore, glutamine kinetics in critical illness needs to be further clarified.

List of scientific papers

I. A Tracer Bolus Method for Investigating Glutamine Kinetics in Humans. Mori M, Smedberg M, Klaude M, Tjäder I, Norberg Å, Rooyackers O, Wernerman J. Plos One. (2014) 9(5):e96601.
https://doi.org/10.1371/journal.pone.0096601

II. Plasma Glutamine Concentration After Intensive Care Unit Discharge: An Observational Study. Smedberg M, Nordmark Grass J, Pettersson L, Norberg Å, Rooyackers O, Wernerman J. Critical Care. (2014) 18:677.
https://doi.org/10.1186/s13054-014-0677-8

III. Plasma Glutamine Concentrations in Liver Failure. Helling G, Wahlin S, Smedberg M, Pettersson L, Tjäder I, Norberg Å, Rooyackers O, Wernerman J. Plos One. (2016) 11(3):e0150440.
https://doi.org/10.1371/journal.pone.0150440

IV. Endogenous Production of Glutamine and Plasma Glutamine Concentration in Critically Ill Patients. Smedberg M, Rooyackers O, Norberg Å, Tjäder I, Wernerman J. [Submitted]

V. Hyperglutaminemia at Intensive Care Unit Admission: An Observational Study. Smedberg M, Helleberg J, Tjäder I, Norberg Å, Rooyackers O, Wernerman J. [Submitted]