Prolonged continuous intravenous infusion of the dipeptide L-alanine- L-glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe traumatic brain injury

Abstract

Introduction: Low plasma glutamine levels are associated with worse clinical outcome. Intravenous glutamine infusion dose- dependently increases plasma glutamine levels, thereby correcting hypoglutaminemia. Glutamine may be transformed to glutamate which might limit its application at a higher dose in patients with severe traumatic brain injury (TBI). To date, the optimal glutamine dose required to normalize plasma glutamine levels without increasing plasma and cerebral glutamate has not yet been defined.

Methods: Changes in plasma and cerebral glutamine, alanine, and glutamate as well as indirect signs of metabolic impairment reflected by increased intracranial pressure (ICP), lactate, lactate-to-pyruvate ratio, electroencephalogram (EEG) activity were determined before, during, and after continuous intravenous infusion of 0.75 g L-alanine-L-glutamine which was given either for 24 hours (group 1, n = 6) or 5 days (group 2, n = 6) in addition to regular enteral nutrition. Lab values including nitrogen balance, urea and ammonia were determined daily.

Results: Continuous L-alanine-L-glutamine infusion significantly increased plasma and cerebral glutamine as well as alanine levels, being mostly sustained during the 5 day infusion phase (plasma glutamine: from 295 ± 62 to 500 ± 145 μmol/ l; brain glutamine: from 183 ± 188 to 549 ± 120 μmol/ l; plasma alanine: from 327 ± 91 to 622 ± 182 μmol/ l; brain alanine: from 48 ± 55 to 89 ± 129 μmol/ l; p < 0.05, ANOVA, post hoc Dunn's test).

Conclusions: High dose L-alanine-L-glutamine infusion (0.75 g/ kg/ d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamate or signs of potential glutamate-mediated cerebral injury. The increased nitrogen load should be considered in patients with renal and hepatic dysfunction.

Trial registration: Clinicaltrials.gov NCT02130674. Registered 5 April 2014.

Figure 1

Study protocol investigating the effects of continuously infusing L-alanine-L- glutamine (Dipeptiven® = L-alanine-L-glutamine; 82 mg L-alanine, 134.6 mg L-glutamine; 0.5 g glutamine/kg) for 24 hours (study 1) or 5 days (study 2) in six patients each suffering from severe traumatic brain injury. The representative computed tomography (CT) scan shows the position of the microdialysis catheter and intracranial pressure probe. ICP, intracranial pressure; CPP, cerebral perfusion pressure; ptiO₂, brain tissue oxygen; SjvO₂, jugular venous oxygen saturation; BIS EEG, bispectral index electroencephalogram.

Figure 2

Changes in plasma glutamine during the 24-hour and 5-day L-alanine-L-glutamine infusion phase. During the infusion phase plasma glutamine was significantly and reversibly increased compared to baseline values (*P <0.001, analysis of variance, post hoc Dunn’s test) which was sustained during the 5-day compared to the 24-hour infusion phase (⁺P <0.001).

Figure 3

Changes in plasma alanine during the 24-hour and 5-day L- alanine-L-glutamine infusion phase. During the infusion phase plasma alanine was significantly increased compared to baseline values (*p <0.001, analysis of variance, post hoc Dunn’s test), which was mostly sustained during the 5-day infusion phase compared to the 24-hour infusion (⁺P <0.001). Although elevated plasma alanine levels reached baseline values following the 24-hour infusion phase, plasma alanine levels remained increased following the 5-day infusion phase.

Figure 4

Changes in cerebral glutamine determined by cerebral microdialysis during the 5-day L-alanine-L-glutamine infusion phase. Cerebral glutamine remained unchanged during the infusion phase and showed a significant increase after the 5-day infusion period (*P <0.001, analysis of variance, post hoc Dunn’s test).

Figure 5

Changes in cerebral alanine determined by cerebral microdialysis during the 5-day L-alanine-L-glutamine infusion phase. Compared to baseline values cerebral alanine was significantly increased during the infusion phase and remained significantly elevated during the 48-hour post infusion observation phase (*P <0.001, analysis of variance, post hoc Dunn’s test).

Figure 6

Changes in cerebral glutamate determined by cerebral microdialysis during the 5 day L-alanine-L-glutamine infusion phase. Compared to baseline values cerebral glutamate was significantly decreased during the infusion phase and remained significantly reduced during the 48-hour post infusion observation phase (*P <0.001, analysis of variance, post hoc Dunn’s test).