Glutamine metabolism in critically ill patients.

Rationale:

Critically ill patients are likely to benefit from additional glutamine. Novak et al. demonstrated in their meta analysis that glutamine administration reduced morbidity and Oudemans-van Straaten showed that the magnitude of glutamine deficiency correlates with ICU mortality. In addition, low arginine and citrulline levels correlate with severity of inflammation in critically ill children. Although arginine administration can be beneficial for some groups of trauma and cancer surgery patients, its action as substrate for nitric oxide synthesis and subsequent hemodynamic instability and oxidative stress, may be responsible for disappointing results when supplied to severe critically ill patients. Since glutamine can generate arginine by the citrulline pathway in the kidney, supplying glutamine potentially may be a more physiologic and safe way to administer arginine in the metabolically stressed ICU patient. Hence, positive effects of glutamine could be partially due to the substrate that glutamine delivers for the synthesis of arginine. However, when the intestinal-renal axis is disturbed by renal failure, glutamine administration might not gain similar effects.

We hypothesize that exogenous, enteral provided glutamine contributes substantially to the de novo synthesis of arginine in critically ill patients, which is of clinical significance. Furthermore we hypothesize that patients suffering from acute renal failure have a lower de novo arginine synthesis.



Objective:

The objective of this clinical study is: To study whether L-glutamine given enterally as the dipeptide L-alanyl-L-glutamine enhances the de novo arginine synthesis in critically ill patients. Secondary objective is to determine the relative contribution of the splanchnic bed to this metabolic route. Tertiary objective is to study whether patients with acute renal failure metabolize amino acids (including glutamine) differently.



Outcome:

The whole body rate of appearance of glutamine, citrulline and arginine, as well as the conversion of endogenous and exogenous, enteral supplied glutamine into citrulline and arginine at the whole body level.

First pass effect of the gut will be calculated using the difference between the whole body rate of appearance of the amino acids when the tracers are given intravenously or enterally.

Renal metabolism will be calculated by comparing the tracer whole body rate of appearance of the amino acids in a group with normal kidney function and a group with ARF.



Design:

This is an randomized, clinical trial with 2 groups of 10 critically ill patients.
Patients are randomly assigned to one of the two groups:

Group 1 (control group): 10 patients receive enteral nutrition in the small intestine.

Group 2 (treatment group): 10 patients receive isonitrogenous enteral nutrition including 0.5 g/kg L-alanyl-L-glutamine/hr (=0.475 g/kg glutamine and 0,165 g/kg/day alanine) in the small intestine.

Group 3 (ARF group): 5 patients receive enteral nutrition in the small intestine.

Number of patients:

n=25 (control: n=10; treatment n=10, ARF n=5).
Description of subjects and main criteria for inclusion:

Critically ill patients, staying one week or longer on the ICU, receiving enteral nutrition by a feeding tube.

Tracers: A primed, continuous infusion of L-[2-15N]glutamine; L-[5-13C-4,4,5,5,2H4]citrulline; L-[ring-2H5] phenylalanine; L-[2H2]tyrosine; L-[ring-2H4]tyrosine; L-[guanidino-15N2]arginine (enteral or parenteral).

Route of administration, duration of protocol and tracer infusion:

Group 1 and group 3 (control group and ARF group): Patients will receive enteral tube feeding, containing 1.5 g/kg protein/day ( including 0.15 g/kg/day glutamine ) for at least 5 days.

Group 2 (treatment group): Patients will receive enteral tube feeding for 5 days + 0.5 g/24hr L-alanyl-L-glutamine containing 1.5 g/kg protein (including 0.475 g/kg/day glutamine).

Both groups: The tracer protocol will be performed on the 4th and 5th day after (after at least 3 days of enteral feeding). In randomized order the tracers will be given enterally or parenterally.

Within 2 of the patients (1 control; 1 intervention), the tracer protocol will additionally be conducted at a third and fourth day (day 6 and 7), in which enteral feeding will be stopped 2 hours in advance to enable postprandial measurements and comparison. Tracers will be given intravenously and enterally alternately.

For group 3, tracers will be given intravenously after a minimum of 3 days of enteral feeding. Tracers will be administered when CVVH filter change is necessary.

We hypothesize that exogenous, enterally provided glutamine contributes substantially to the de novo synthesis of arginine in critically ill patients.

On day 4 and 5 (group 1 and 2 only) after ICU admission, stable isotopes will be given to quantify metabolic routes.

1. Group 1 (control group): 10 patients will receive enteral tube feeding, containing 1.5 g/kg protein/day ( including 0.15 g/kg/day glutamine ) for at least 5 days;

2. Group 2 (treatment group): 10 patients will receive enteral tube feeding for 5 days + 0.5 g/24hr L-alanyl-L-glutamine containing 1.5 g/kg protein (including 0.475 g/kg/day glutamine ).



Each group will receive stable isotopes of glutamine, citrulline, arginine, phenylalanine and tyrosine on two consecutive days, enterally and intravenously in a randomized cross-over manner.

Within 2 patients the tracer protocol will also be performed on the 6th and 7th day. Feeding will be stopped two hours in advance.



3. Group 3 (acute renal failure (ARF)): 5 patients will receive enetral tube feeding, containing 1.5 g/kg protein/day (including 0.15 g/kg/d glutamine) for at least 5 days.

Patients will receive stable isotopes of glutamine, citrulline, arginine, phenylalanine and tyrosine intravenously.