A priming endotoxin bolus amplifies the inflammatory response in low-dose human endotoxemia

Introduction

The response to an inflammatory stimulus is highly variable in critically ill patients and may differ from that of healthy volunteers. One of several distinguishing characteristics between the two groups is an elevated plasma level of cytokines in patients. We hypothesized that an acute elevation in TNF-α, as evoked by a priming dose of purified Escherichia coli endotoxin (LPS), would enhance the inflammatory response to LPS, and we investigated this hypothesis in healthy volunteers in a randomized, double-blind, crossover design.

Methods

Following approval by the local Human Ethics Committee, 13 volunteers underwent three interventions each, receiving two bolus injections, spaced 90 min apart and consisting of either saline + LPS (0.2 ng/kg) (LPS-0.2), saline + LPS (0.4 ng/kg) (LPS-0.4), or LPS (0.2 ng/kg) + LPS (0.2 ng/kg) (LPS-0.2+0.2). Physiological variables were monitored throughout until 8 hours after the last dose; blood samples were drawn for measurement of plasma TNF-α, IL-6, C-reactive protein (CRP), white blood cell (WBC) and differential counts. Interventions were spaced at least 1 month apart. A repeated-measures multivariate ANOVA (intervention-by-time) with Bonferroni corrections was performed. P < 0.05 was considered significant.

Results

Flu-like symptoms occurred during all three interventions; the frequency was increased in groups LPS-0.4 and LPS-0.2+0.2 as compared with LPS-0.2. The heart rate, body temperature, CRP, WBC, and the neutrophil count increased more, and the lymphocyte count was more reduced, during LPS-0.2+0.2 compared with both LPS-0.2 and LPS-0.4. Levels of TNF-α and IL-6 were higher during LPS-0.2+0.2 (mean peak TNF-α ±, 44.6 [95% CI, 25.8–63.3] mg/l) compared with LPS-0.4 (28.0 [16.8–39.3] mg/l) and LPS-0.2 (12.7 [6.1–19.3] mg/l) (P < 0.001), as well as during LPS-0.4 compared with LPS-0.2.

Conclusion

In healthy humans, induction of a low-grade inflammatory response by a priming bolus injection of LPS amplifies the clinical and paraclinical inflammatory response to a subsequent LPS injection. This may explain the potent proinflammatory response seen in some critically ill patients.