BackgroundHyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. Methods and ResultsPressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20±4 % and 13±3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7±3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. Conclusions and SignificanceIn conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

Animal studies have shown that previous exposure to lipopolysaccharide (LPS) can limit ischemia-reperfusion injury. We tested whether pretreatment with LPS also protects against ischemia-reperfusion injury in humans in vivo. Fourteen volunteers received bolus injections of incremental dosages of LPS on 5 consecutive days (LPS group). Before the first and 1 day after the last LPS administration, the forearm circulation of the non-dominant arm was occluded for 10 min, with concomitant intermittent handgripping to induce transient ischemia. After reperfusion, 0.1 mg of ( 99m)Tc-labeled annexin A5 (400 MBq) was injected intravenously to detect phosphatidylserine expression as an early marker of ischemia-reperfusion injury. Similarly, the control group (n = 10) underwent the ischemic exercise twice, but without pretreatment with LPS. Annexin A5 targeting was expressed as the percentage difference in radioactivity in the thenar muscle between both hands. Endotoxin tolerance developed during 5 consecutive days of LPS administration. Annexin A5 targeting was 12.1 +/- 2.2% and 10.4 +/- 2.1% before LPS treatment at 1 h and 4 h after reperfusion, compared to 12.2 +/- 2.4% and 8.9 +/- 2.1% at 1 h and 4 h after reperfusion on day 5 (P = 1.0 and 0.6, respectively). Also, no significant changes in annexin A5 targeting were found in the control group. So, in this model, LPS-tolerance does not protect against ischemia-reperfusion injury in humans in vivo.

Because severe sepsis is frequently complicated by multiple organ failure, it is of importance to monitor organ function. Unfortunately, conventional liver function markers are either relatively unspecific or have a long half-life, which make them poor predictors of acute liver injury. Glutathione S-transferase A1-1 (GSTA1-1) has a relatively short half-life (1 h), is more specific, and is rapidly released into the blood after liver damage. In the present study, we measured plasma GSTA1-1 levels by enzyme-linked immunosorbent assay in seven healthy volunteers after repeated experimental endotoxemia induced by 2 ng kg Escherichia coli endotoxin per day (to investigate inflammation-induced hepatic injury) and in 21 patients within 12 h after the occurrence of severe sepsis/septic shock (to investigate its ability to predict an increase of transaminases on day 7). During repeated experimental endotoxemia in healthy volunteers, TNF-alpha and IL-6 levels increased from undetectable levels to 1,425 (474-1,949) and 1,739 (989-2,047) pg mL, respectively, whereas GSTA1-1 levels did not exceed the normal range, indicating that no (sub)clinical liver injury occurs in this model of inflammation. In septic patients, GSTA1-1 levels had a specificity of 88%, resulting in a positive predictive value for liver injury of 86% and a positive likelihood ratio of 6 to indicate an increase in transaminases on day 7. Furthermore, GSTA1-1 levels did not correlate with IL-6 levels but did with dobutamine infusion rate (Spearman r = 0.94; P = 0.02), suggesting that the extent of hemodynamic instability and not the degree of inflammation could be of importance for the occurrence of liver damage. In septic shock patients, GSTA1-1 may represent a useful marker for early liver injury.

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