Endotoxin tolerance developed during five consecutive LPS administrations as demonstrated by the attenuated release of proinflammatory cytokines on the fifth day and was associated with less leukocyte and endothelial activation. In contrast to animal and human in vitro data, the attenuated response was not limited to the proinflammatory response, as a similar reduction in the anti-inflammatory cytokines was observed, with the exception of TGF-beta.

Although the gut is often considered the motor of sepsis, the relation between systemic inflammation and intestinal permeability in humans is not clear. We analyzed intestinal permeability during experimental endotoxemia in humans. Before and during experimental endotoxemia (Escherichia coli LPS, 2 ng/kg), using polyethylene glycol (PEG) as a permeability marker, intestinal permeability was analyzed in 14 healthy subjects. Enterocyte damage was determined by intestinal fatty acid binding protein. Endotoxemia induced an inflammatory response. Urinary PEGs 1,500 and 4,000 recovery increased from 38.8 +/- 6.3 to 63.1 +/- 12.5 and from 0.58 +/- 0.31 to 3.11 +/- 0.93 mg, respectively (P < 0.05). Intestinal fatty acid binding protein excretion was not affected by endotoxemia. The peak serum IL-10 concentrations correlated with the increase in PEG 1,500 recovery (r = 0.48, P = 0.027). Systemic inflammation results in an increased intestinal permeability. The increase in intestinal permeability is most likely caused by inflammation-induced paracellular permeability, rather than ischemia-mediated enterocyte damage.

The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.

Purpose: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking. Methods:This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment. Results:In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 ). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes. Conclusions:We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.