2012, Recknagel, P., Gonnert, F.A., Westermann, M., Lambeck, S., Lupp, A., Rudiger, A., Dyson, A., Carré, J.E., Kortgen, A., Krafft, C., Popp, J., Sponholz, C., Fuhrmann, V., Hilger, I., Claus, R.A., Riedemann, N.C., Wetzker, R., Singer, M., Trauner, M., Bauer, M.

Background: Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings: In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions: Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary.

2023, Diebold, Steffen M.

The objectives of the present study were (1) to investigate gastrointestinal hydrodynamics of Labradors as a model for human midgut (2) to examine various attributes of intestinal fluids in vivo and (3) to study the influence of hydrodynamics on the dissolution and absorption of a poorly soluble drug from various suspensions. Gastrointestinal flow rates were determined volumetrically using an aspiration method. Isotonic saline and 20 % glucose solutions were used to alter gastrointestinal hydrodynamics. Felodipine, a BCS class II substance, was suspended in these fluids. Osmolality, pH, bile acid concentration and drug solubility in various chyme samples were determined. Blood plasma levels of felodipine were recorded while gastrointestinal dissolution was ongoing. Fluid recovery at midgut fistula was significantly higher (>100 %) for glucose 20 % than for isotonic saline solutions (70 %). After administration of 200 ml glucose 20 % the (overall) grand median of differential gastrointestinal flow rates (DFR) was 8.3 ml/min.. Individual spike flow ranged from 20 up to 60 ml/min. Corresponding flow rates after administration of 200 ml isotonic saline were 35.0 ml/min. for the grand median including individual spike flows beyond 100 ml/min.. Within and between-dog variability in flow rate data was similar. In general, glucose solutions released more evenly. Following oral administration of glucose solution 20 % osmolality of intestinal fluids decreased within 40 min. from about 1000 mOsm. towards more physiological values of about 350 mOsm.. Saturation solubility of felodipine (Cs) in jejunal chyme after administration of either solution (saline or glucose) was determined to be about 10 (µg/ml) on average (median), exposing high variability with time! The intestinal solubility varied greatly within the course of an experiment. However, a strong correlation was observed between the aspirated fluid volume and the dissolved amount of felodipine confirming the well known relationship of Noyes, Whitney, Nernst and Brunner in-vivo. Grand median of pH in jejunal chyme of labradors was determined to be 6.68. Median values range from 4.38-7.62. The pharmacokinetic data showed a slight trend to differences based on particle size and on fluid administered.