Elsevier

Clinical Nutrition

Volume 27, Issue 2, April 2008, Pages 297-306
Clinical Nutrition

Original article
Metabolic effects of enteral versus parenteral alanyl-glutamine dipeptide administration in critically ill patients receiving enteral feeding: A pilot study

https://doi.org/10.1016/j.clnu.2007.12.003Get rights and content

Summary

Background

Glutamine (Gln) may become conditionally indispensable during critical illness. The short-term metabolic effects of enteral versus parenteral Gln supplementation are unknown in this clinical setting.

Objectives

We studied metabolic effects of intravenous (IV) alanyl-Gln dipeptide (AG) supplementation and enteral (EN) AG supplementation on plasma Gln concentration, antioxidant status, plasma lymphocyte subset number, gut permeability and nitrogen balance in adult critically ill patients requiring tube feeding compared to a control group not receiving Gln supplementation.

Methods

In a double-blind, pilot clinical trial, 44 medical and surgical ICU patients received identical Gln-free tube feedings 24 h/day and were randomized to either isonitrogenous control (n = 15), EN AG (n = 15) or IV AG (n = 14) groups (AG). Twelve patients were discontinued from the study. The goal AG dose was 0.5 g/kg/day. Biochemical and metabolic endpoints were measured at baseline and on day 9 (plasma Gln, antioxidant indices, lymphocyte subsets; serum IGF-1 and IGF-binding protein-3; intestinal permeability). Nitrogen balance was determined between study days 6 and 8.

Results

Illness severity indices, clinical demographics, enteral energy and nitrogen intake and major biochemical indices were similar between groups during study. Plasma Gln was higher in the IV AG (565 ± 119 μM, mean ± SEM) vs the EN AG (411 ± 27 μM) group by day 9 (p = 0.039); however, subjects in the IV AG group received a higher dose of AG (IV AG 0.50 versus EN AG 0.32 ± 0.02 g/kg/day; p < 0.001). EN AG subjects showed a significant increase in plasma α-tocopherol levels over time and maintained plasma γ-tocopherol concentrations. There were no differences between groups for plasma concentrations of vitamin C, glutathione, malondialdehyde (MDA), T-lymphocyte subsets, intestinal permeability or nitrogen balance.

Conclusions

This study showed that alanyl-Gln administration by enteral or parenteral routes did not appear to affect antioxidant capacity or oxidative stress markers, T-lymphocyte subset (CD-3, CD-4, CD-8) number, gut barrier function or whole-body protein metabolism compared to unsupplemented ICU patients requiring enteral tube feeding. Enteral Gln appeared to maintain plasma tocopherol levels in this pilot metabolic study.

Introduction

Catabolic states are associated with high levels of oxidative stress, body protein wasting, antioxidant depletion, impaired intestinal barrier function and immuno-suppression.1, 2 Glutamine (Gln) is the most abundant free amino acid in the body.3 It serves as a major metabolic fuel for rapidly dividing intestinal epithelial cells and lymphocytes and is a precursor for the biosynthesis of glutathione (GSH), one of the major antioxidants in the body.4, 5 During critical illness, Gln may become conditionally indispensable as evidenced by the fall in plasma and tissue concentration apparently as a result of Gln utilization exceeding endogenous production.5, 6, 7 Previous studies suggest that improved plasma Gln concentrations may be beneficial for patients with critical illnesses to improve GSH biosynthesis in tissues,8 nitrogen balance,9 immune function,10, 11, 12 intestinal permeability13 and the incidence of hospital-acquired infection.9, 11

Gln at doses up to 40 g/day is known to be safe when administered with enteral or parenteral nutrition (EN or PN, respectively)7, 8, 9, 13; however, it is unclear which route of delivery is superior. There is evidence suggesting that Gln supplementation in PN may be superior to the enteral route in terms of clinical outcomes11 and repletion of plasma Gln.12 However, in critically ill patients possessing active intestinal function and receiving EN, whether Gln should be given enterally or parenterally is not clear as data comparing the metabolic effects of intravenous Gln versus enteral Gln in critically ill patients are lacking.14, 15 Therefore, the purposes of this study were to compare metabolic effects of alanyl-Gln given by enteral and parenteral routes versus an unsupplemented control group and to obtain initial data on the potential effects of route of Gln administration. We hypothesized that parenteral administration of alanyl-Gln dipeptide (AG) would result in higher blood concentrations of Gln and would therefore be associated with superior effects on antioxidant status, immune function and nitrogen balance in adult critically ill patients requiring tube feeding.

Section snippets

Study subjects

This randomized, double-blind, placebo-controlled study was conducted at Emory University Hospital (EUH), Atlanta, GA. This study was approved by the Institutional Review Board of Emory University and the GCRC Scientific Advisory Committee. Study subjects requiring non-elemental tube feeding for at least 8 days were identified by the Nutrition and Metabolic Support Service (NMSS) of EUH, who were consulted on all patients receiving enteral tube feeding at EUH. Additional inclusion criteria

Results

This study was initiated in September 1999. In May 2003, the study was terminated and the data analyzed because study drug was no longer available. Forty-four subjects were enrolled, but 12 of the subjects were discontinued from the study before the day 9 measurements (six randomized to the control group, three to the IV AG group, and three to the EN AG group. Reasons for subject drop-out were: tube feedings were no longer required or indicated (n = 4), subject transferred to another hospital (n = 

Discussion

Little data are available comparing the metabolic effects of Gln when given by enteral versus parenteral routes.14, 26 Also, metabolic results with enteral Gln administration have been inconsistent across studies.27, 28 The current study is the first to directly compare whether intravenous AG was superior to enteral AG in terms of short-term metabolic endpoints in tube-fed ICU patients. Consistent with previous findings,6, 11, 12 we observed below-normal baseline plasma Gln concentrations in

Conclusions

In this pilot study, intravenous alanyl-Gln appears to be superior to enteral alanyl-Gln administration as a method to increase systemic plasma Gln concentrations in catabolic ICU patients. Enteral Gln also appeared to maintain plasma α- and γ-tocopherol levels in these individuals. Route of Gln administration otherwise did not appear to differentially effect antioxidant capacity or oxidative stress markers, T-lymphocyte subsets, intestinal permeability, IGF-1 levels or nitrogen balance.

Conflict of interest statement

Fresenius-Kabi provided study glutamine dipeptide and partial financial support for the study. The authors report no other conflict of interest.

Acknowledgements

The authors thank the Emory GCRC research staff, the Emory University Hospital ICU nurses and Ms. Susan Rogers of the Emory University Hospital Investigational Drug Service for their help with the protocol. The authors gratefully acknowledge Ewald Schlotzer, PhD, of Fresenus-Kabi, and Carolyn Accardi and Nisha Dave for their assistance. This study was supported by NIH R03 DK54823, Emory General Clinical Research Center M01 RR00039, a grant from Fresenius-Kabi, and a grant from the American

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