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Continuous Administration of Enteral Lipid- and Protein-Rich Nutrition Limits Inflammation in a Human Endotoxemia Model

Lubbers, Tim MD, PhD1; Kox, Matthijs PhD2,3; de Haan, Jacco-Juri MD1; Greve, Jan Willem MD, PhD4; Pompe, Jan C. MD2; Ramakers, Bart P. MD2; Pickkers, Peter MD, PhD2; Buurman, Wim A. PhD1

doi: 10.1097/CCM.0b013e31827c0a17
Laboratory Investigations

Objective: An overzealous inflammatory response is an important cause of morbidity and mortality in surgical, trauma, and critically ill patients. Enteral administration of lipid-rich nutrition was previously shown to attenuate inflammation and reduce organ damage via a cholecystokinin-1 receptor–mediated vagovagal reflex in animal studies. The current preclinical study investigates the immunomodulatory potential of a custom-made enteral nutrition during systemic inflammation in man.

Design: Double-blind, randomized controlled trial.

Setting: Intensive care research unit.

Subjects: Male volunteers.

Interventions: After an overnight fast, 18 healthy male subjects received an IV bolus of Escherichia coli lipopolysaccharide (2 ng/kg). Subjects in the fasted group (n = 6) were deprived of food throughout the study, while subjects in the intervention groups were fed either custom-made lipid- and protein-rich nutrition (n = 6) or isocaloric control nutrition (n = 6) via nasojejunal tube, starting 1 hour prior to lipopolysaccharide administration until 6 hours afterward.

Measurements and Main Results: Bolus lipopolysaccharide administration resulted in a marked inflammatory response. Continuous postpyloric administration of nutrition significantly increased plasma cholecystokinin levels throughout the lipopolysaccharide-induced inflammatory response. Lipid- and protein-rich nutrition attenuated circulating levels of the proinflammatory cytokines tumor necrosis factor-α and interleukin-6 and the interleukin-1 receptor antagonist compared with control nutrition (all p < 0.05) and fasted subjects (all p < 0.05). In additional, lipid- and protein-rich nutrition augmented the anti-inflammatory response, reflected by increased plasma levels of interleukin-10 compared with fasted subjects (p < 0.0001).

Conclusions: The current preclinical study expands the immunomodulating effects of enteral nutrition as previously observed in rodents to man. Continuous administration of enteral nutrition resulted in a rapid anti-inflammatory effect. Furthermore, enrichment of the nutritional composition with lipid and protein was shown to enhance the anti-inflammatory potential. Therefore, continuous enteral administration of lipid- and protein-rich nutrition is a promising intervention to modulate the immune response in the early course of systemic inflammation in man.

Supplemental Digital Content is available in the text.

1Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands.

2Department of Anesthesiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

3Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

4Department of Surgery, Atrium Medical Center, Heerlen, The Netherlands.

Drs. Kox and de Haan contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by DANONE Research Centre for Specialised Nutrition, Wageningen, The Netherlands, and by AGIKO-stipendium 920-03-522 (to TL) from The Netherlands Organization for Health Research and Development. The funding sources had no involvement in study design and analysis or interpretation of data.

The authors have not disclosed any potential conflicts of interest.

Address requests for reprints to: Tim Lubbers, MD, Department of Surgery, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail:

© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins