Experimental human endotoxemia: a model of the systemic inflammatory response syndrome?

Abstract

Background: The normal human intravenous endotoxin model has been used for more than 50 years. It was once considered a possible model of sepsis, but, because no infection is present, it is better described as a model of systemic inflammation. We demonstrate herein that at least three of four systemic inflammatory response syndrome (SIRS) criteria are achieved with the model.

Methods: Otherwise healthy human volunteers were given Escherichia coli endotoxin 2 ng/kg intravenously. Vital signs were monitored, and blood samples were collected over time for assessment of white blood cells (WBCs), cytokines, counter-regulatory hormones, and monocyte receptors.

Results: The means of three variables (core temperature, heart rate, WBC) met the SIRS criteria. Compared with baseline, cytokines were elevated acutely, with tumor necrosis factor-alpha (TNFα) exhibiting temporal primacy over the other cytokines. Counter-regulatory hormones (cortisol, epinephrine) also were elevated acutely. Finally, the monocyte cell-surface receptors cluster of differentiation molecule (CD) 11b and TNF receptor-II were elevated and decreased, respectively.

Conclusions: The experimental human endotoxin model satisfies SIRS criteria and probably is best described as a model of Toll-like receptor 4 agonist-induced systemic inflammation.

Figures

FIG. 1.

Omnibus symptom scores (mean±standard error) in normal human volunteers (n=66) receiving intravenous endotoxin. One-way repeated-measure analysis of variance was performed; endotoxin effect was significant at p

FIG. 2.

Response of systemic inflammatory response syndrome (SIRS) variables in normal human volunteers receiving intravenous endotoxin (LPS, 2 ng/kg) at time 0. (A) Core (rectal) temperature (n=72). (B) Heart rate (n=72). (C) Respiratory rate (n=5). (D) White blood cell count (n=60). Graphs depict mean±standard error. Dashed lines indicate SIRS criterion value for each variable. Hypothermia is not so indicated for core temperature (panel A) because that criterion is off-scale. Both leukopenia and leukocytosis are indicated in panel D. One-way repeated-measures analysis of variance was performed. For all variables, endotoxin effect was significant at p<0.0001.

FIG. 3.

Plasma cytokine responses in normal human volunteers receiving intravenous endotoxin (LPS, 2 ng/kg) at time 0. (A) Tumor necrosis factor-alpha (n=24). (B) Interleukin (IL)-6 (n=32). (C) IL-8 (n=30). (D) IL-10 (n=31). Graphs depict mean±standard error. One-way repeated-measures analysis of variance was performed. For all cytokines, endotoxin effect was significant at p<0.0001.

FIG. 4.

Plasma counter-regulatory responses in normal human volunteers receiving intravenous endotoxin (LPS, 2 ng/kg) at time 0. (A) Cortisol (hydrocortisone)(n=22). (B) Epinephrine (n=6). Graphs depict mean±standard error. One-way repeated-measures analysis of variance was performed. For cortisol, endotoxin effect was significant at p<0.0001; for epinephrine, effect was significant at p<0.01.

FIG. 5.

Blood monocyte cell-surface inflammatory receptor responses in normal human volunteers given intravenous endotoxin (LPS, 2 ng/kg) at time 0. (A) Cluster of differentiation molecule (CD)11b [n=11]. (B) Tumor necrosis factor receptor-II (n=11). Graphs depict mean±standard error. One-way repeated-measures analysis of variance was performed. For both receptors, endotoxin effect was significant at p<0.0001.