title: Physiologic variability at the verge of systemic inflammation: multiscale entropy of heart rate variability is affected by very low doses of endotoxin.
abstract: BACKGROUND
  Human injury or infection induces systemic inflammation with characteristic neuroendocrine responses. Fluctuations in autonomic function during inflammation are reflected by beat-to-beat variation in heart rate, termed heart rate variability (HRV). In the present study, we determine threshold doses of endotoxin needed to induce observable changes in markers of systemic inflammation, investigate whether metrics of HRV exhibit a differing threshold dose from other inflammatory markers, and investigate the size of data sets required for meaningful use of multiscale entropy (MSE) analysis of HRV.
  
  
  METHODS
  Healthy human volunteers (n = 25) were randomized to receive placebo (normal saline) or endotoxin/lipopolysaccharide (LPS): 0.1, 0.25, 0.5, 1.0, or 2.0 ng/kg administered intravenously. Vital signs were recorded every 30 min for 6 h and then at 9, 12, and 24 h after LPS. Blood samples were drawn at specific time points for cytokine measurements. Heart rate variability analysis was performed using electrocardiogram epochs of 5 min. Multiscale entropy for HRV was calculated for all dose groups to scale factor 40.
  
  
  RESULTS
  The lowest significant threshold dose was noted in core temperature at 0.25 ng/kg. Endogenous tumor necrosis factor α and interleukin 6 were significantly responsive at the next dosage level (0.5 ng/kg) along with elevations in circulating leukocytes and heart rate. Responses were exaggerated at higher doses (1 and 2 ng/kg). Time domain and frequency domain HRV metrics similarly suggested a threshold dose, differing from placebo at 1.0 and 2.0 ng/kg, below which no clear pattern in response was evident. By applying repeated-measures analysis of variance across scale factors, a significant decrease in MSE was seen at 1.0 and 2.0 ng/kg by 2 h after exposure to LPS. Although not statistically significant below 1.0 ng/kg, MSE unexpectedly decreased across all groups in an orderly dose-response pattern not seen in the other outcomes.
  
  
  CONCLUSIONS
  By using repeated-measures analysis of variance across scale factors, MSE can detect autonomic change after LPS challenge in a group of 25 subjects using electrocardiogram epochs of only 5 min and entropy analysis to scale factor of only 40, potentially facilitating MSE's wider use as a research tool or bedside monitor. Traditional markers of inflammation generally exhibit threshold dose behavior. In contrast, MSE's apparent continuous dose-response pattern, although not statistically verifiable in this study, suggests a potential subclinical harbinger of infectious or other insult. The possible derangement of autonomic complexity prior to or independent of the cytokine surge cannot be ruled out. Future investigation should focus on confirmation of overt inflammation following observed decreases in MSE in a clinical setting.
authors.affiliation: *Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey; and †Division of Trauma Services, Department of Surgery, East Texas Medical Center, Tyler, Texas.
authors.forename: Georg N
authors.initials: GN
authors.lastname: Herlitz
authors.forename: Renee L
authors.initials: RL
authors.lastname: Arlow
authors.forename: Nora H
authors.initials: NH
authors.lastname: Cheung
authors.forename: Susette M
authors.initials: SM
authors.lastname: Coyle
authors.forename: Benjamin
authors.initials: B
authors.lastname: Griffel
authors.forename: Marie A
authors.initials: MA
authors.lastname: Macor
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Lowry
authors.forename: Steve E
authors.initials: SE
authors.lastname: Calvano
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gale
mesh_terms: D000328:Adult; D001831:Body Temperature / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D019277:Entropy; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000097:blood; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D011897:Random Allocation; D055815:Young Adult
chemical_list: D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides