Continuous enteral and parenteral feeding each reduces heart rate variability but differentially influences monocyte gene expression in humans.

During critical illness, hypermetabolism and decreased nutritional intake lead to malnutrition within days, which can complicate recovery. As an adjunct to care, specialized nutritional support, delivered as enteral or parenteral feedings, provides macro-and micronutrients until oral dietary intake can resume. By helping in part to offset the hypermetabolism of critical illness, early nutritional delivery is known to improve overall outcome and has become an essential component of modern critical care. While parenteral (intravenous) nutrition (PN) held considerable promise during its development, comparisons between parenteral and enteral feedings generally demonstrate fewer infectious complications and better clinical outcomes with enteral nutritional (EN) delivery. Therefore when no barriers to gut feeding exist, enteral feedings have emerged as the standard of care.(1–3) Pre-clinical studies of different nutrition modalities suggest that EN helps to sustain both innate and adaptive immune function more effectively than PN.(4–7)Compared to enterally fed animals, those that received parenteral nutrition demonstrated increased gut bacterial translocation(8)and had increased mortality when challenged with bacterial lipopolysaccharide (endotoxin) or with intraabdominal infection.(9) Dysregulation of both innate and adaptive immune functions are believed to influence these adverse outcomes. Most clinical analyses of the influence of feeding modality on immune function document increased levels of pro-inflammatory cytokines in post-operative patients that had received pre-operative PN versus those fed enterally.(10,11) Similarly, studies in healthy volunteer subjects suggest that the route of nutrition influences innate immune responsiveness. We have previously shown that a seven day period of continuous PN in healthy subjects resulted in an enhanced systemic inflammatory and acute phase response after subsequent in vivo challenge with endotoxin compared to those receiving intermittent enteral feedings.(12)Interestingly, however, a later study by Santos and others in 1994 failed to reveal differences in systemic inflammatory mediators after endotoxin-challenge between normal subjects fed orally compared to those who received seven days of PN.(13) Proposed mechanisms underlying the relationship between innate immunity and route of nutritional delivery, enteral versus parenteral, include the alterations in the balance of gut-mediated autonomic nervous system outflows. In particular, efferent vagus nerve activity appears to highly influence peripheral immune cell populations. This “cholinergic anti-inflammatory pathway” (14–16)involves the nutrient-mediated release of cholecystokinin (CCK), which acts both centrally and locally via vagal afferent pathways to stimulate α-7-nicotinic acetylcholine receptors on immune cells, especially macrophages, by way of vagal efferents. Although the influence of specialized nutrition support upon this pathway has not, to the best of our knowledge, been examined in humans subjected to differing routes of feeding, pre-clinical studies suggest that intestinal luminal nutrients influence autonomic activity, in part, by modulating vagal afferent signals and the balance of efferent autonomic signals. Intestinal gavage with long chain lipids enhances afferent vagus nerve activity via stimulation of intestinal cholecystokinin receptors.(17,18) This nutrient specific stimulation of parasympathetic activity is also associated with improved survival in a model of acute hemorrhagic stress. (19) These observations of parasympathetic stimulation by enteral feedings led us to conduct a preliminary study with the hypothesis that differing routes of nutrient delivery, enteral versus parenteral, might have a systemic impact on autonomic activity and on the pattern of gene activation within peripheral immune cell populations. To determine if an autonomic impact was detectible in healthy subjects we compared measures of heart rate variability (HRV)to determine if continuous EN or PN differentially influenced outputs, with orally fed subjects as controls. HRV analysis is a non-invasive technique of studying patterns between successive QRS complexes using continuous EKG over various time and frequency scales. It is used to detect physiologic complexity and can reflect homeostatic feedback between organ systems such as the central nervous system and the heart. Specifically, vagal and parasympathetic tone, and sympathovagal balance can be evaluated with this technique.(20) To assess the impact of differential feeding on patterns of peripheral blood monocyte (PBM) gene expression, microarray analysis was utilized to compare continuous EN and PN groups.