Microvascular permeability during experimental human endotoxemia: an open intervention study

Abstract

Introduction Septic shock is associated with increased microvascular permeability. As a model for study of the pathophysiology of sepsis, endotoxin administration to humans has facilitated research into inflammation, coagulation and cardiovascular effects. The present study was undertaken to determine whether endotoxin administration to human volunteers can be used as a model to study the sepsisassociated increase in microvascular permeability.Methods In an open intervention study conducted in a university medical centre, 16 healthy volunteers were evaluated in the research unit of the intensive care unit. Eight were administered endotoxin intravenously (2 ng/kg Escherichia coli O113) and eight served as control individuals. Microvascular permeability was assessed before and 5 hours after the administration of endotoxin (n = 8) or placebo (n = 8) by three different methods: transcapillary escape rate of I 125 -albumin; venous occlusion straingauge plethysmography to determine the filtration capacity; and bioelectrical impedance analysis to determine the extracellular and total body water. Results Administration of endotoxin resulted in the expected increases in proinflammatory cytokines, temperature, flu-like symptoms and cardiovascular changes. All changes were significantly different from those in the control group. In the endotoxin group all microvascular permeability parameters remained unchanged from baseline: transcapillary escape rate of I 125 -albumin changed from 7.2 ± 0.6 to 7.7 ± 0.9%/hour; filtration capacity changed from 5.0 ± 0.3 to 4.2 ± 0.4 ml/min per 100 ml mmHg × 10 -3 ; and extracellular/total body water changed from 0.42 ± 0.01 to 0.40 ± 0.01 l/l (all differences not significant). Conclusion Although experimental human endotoxaemia is frequently used as a model to study sepsisassociated pathophysiology, an endotoxin-induced increase in microvascular permeability in vivo could not be detected using three different methods. Endotoxin administration to human volunteers is not suitable as a model in which to study changes in microvascular permeability.

Endotoxemia-induced inflammation and the effect on the human brain

“…Compared with experiments with 0.2 ng/kg, improvement of working memory was shown in a study with 10 healthy volunteers with a dose of 0.8 ng/kg LPS [22]. In these studies, cortisol level and cytokines increased slightly, compared with our results [22,30,31], which is associated with dysfunction of other organs [24,28,45]. Furthermore, a potential problem in the studies with low doses of LPS was that no correction for practice effect was performed while practice effects during CFT are common, especially in situations with short test-retest intervals.…”

Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery

“…With n  = 10, there is an 80 % power to find a difference corresponding to an effect size of one (the difference between paired samples divided by the standard deviation of that difference) using a two-sided test and alpha = 0.05 within each of the studied groups. With a precision in the TER of 2 %/hour as suggested [17], a similar difference of 2 %/hour will be detected by n  = 10. If all three groups are analyzed together ( n  = 30), a power of 80 % is reached to detect an effect size of 0.53, suggesting that a bias of only 1 % will be found significant.…”

Leakage of albumin in major abdominal surgery

“…In contrast, interleukin-6 reaches its peak in plasma at the end of major abdominal surgery and decreases significantly over the following 6 h [ 19 ]. Infusion of endotoxin is insufficient to induce increased vascular permeability in volunteers [ 20 ], whereas sepsis is associated with a greater and more persistent elevation of biomarkers than after major surgery [ 19 ]. The inflammatory response was only assessed by C-reactive protein in our patients.…”