Bilirubin kinetic modeling for quantification of extracorporeal liver support.
ABSTRACT To provide a measure of treatment dose for extracorporeal liver support (ELS).
The kinetics of conjugated bilirubin were described by a two-compartment model (Vc, Vp) with central elimination (K) and constant generation rate (G). The transfer of solute between compartments was modeled by intercompartmental clearance (Kpc). The central compartment (Vc) was assumed as a constant fraction of total volume (Vc = 0.3*Vt).
Eight patients were studied during 35 treatments lasting 6 h each. The average K, Vt, Kpc, G, and mass of conjugated bilirubin removed were 18.6 +/- 3.9 ml/min, 9.1 +/- 3.8 liters, 103 +/- 108 ml/min, 0.33 +/- 0.15 mg/min, and 641 +/- 275 mg, respectively. The reduction ratio (48 +/- 10%) measured as the change in post- to pre-treatment concentrations underestimated the modeled fraction of bilirubin mass removed (54 +/- 13%) essentially because of significant conjugated bilirubin appearance during treatments.
Kinetic analysis provides an improved measure of treatment dose as generation, distribution, and elimination of conjugated bilirubin are jointly considered.
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ABSTRACT: This report describes studies of bilirubin kinetics in 13 healthy young adults. The plasma content of unconjugated bilirubin-(14)C was determined at frequent intervals for 24-30 hr after the intravenous injection of a tracer dose of unconjugated isotopic bilirubin. Fecal and urinary radioactivity were measured for 7 days. During this time cumulative recovery averaged 96% of the injected dose. The plasma curves were processed by digital computer. For the 30 hr experimental period, a sum of three exponentials, with average half-times of 18, 81, and 578 min, was required to describe the data. Using the plasma curve integral method, the hepatic bilirubin clearance (47 +/-10 ml/min, mean +/-SD), the bilirubin production rate (3.8 +/-0.6 mg/kg per day), and the mean red blood cell life span (101 +/-13 days) were calculated directly from the parameters of this function. To gain further insight into the metabolism of unconjugated bilirubin, the data were also used to determine the parameters of a multicompartmental model. In the model proposed, plasma unconjugated bilirubin exchanges with two additional pools one of which is thought to represent extrahepatic extravascular, and the other intrahepatic unconjugated bilirubin. Bilirubin is eliminated from the system via the proposed intrahepatic pool. From the data and the model, pool sizes and exchange rates between compartments were calculated, and the liver: plasma concentration gradient estimated. These studies provide a detailed analysis of the kinetics of unconjugated bilirubin in a healthy normal population and are intended to serve as a reference point for studies of abnormal states.Journal of Clinical Investigation 12/1969; 48(11):2176-90. · 12.81 Impact Factor
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ABSTRACT: We have previously reported the clearance of protein-bound and water-soluble hepatic toxins, in vitro and in an animal model, using albumin dialysis as an extracorporeal hepatic support (ECHS) device. The objective of this study was to evaluate albumin dialysis through a phase I clinical trial. We hypothesized that albumin dialysis would (1) decrease elevated levels of hepatic toxins, (2) increase the Fischer ratio, and (3) decrease hepatic encephalopathy (HES) and intracranial pressure (ICP), while (4) maintaining stable hemodynamics. Patients with acute liver failure were treated with an ECHS device utilizing continuous hemodiafiltration with continuous albumin dialysis. Mean arterial blood pressure (MAP), heart rate (HR), systemic venous oxygen saturation (Svo(2)), ICP, and HES were recorded. Blood samples were evaluated for hepatic toxins and factor VII levels. Nine patients were enrolled (status I, n = 5; status IIA, n = 4). There was no significant change in MAP, HR, or Svo(2) (MAP: Pre = 81 +/- 5.6 mm Hg, Post = 79 +/- 5.9 mm Hg, P =.70; HR: Pre = 104 +/- 5.2 bpm, Post = 107 +/- 6.2 bpm, P =.62; Svo(2): Pre = 72 +/- 3.5, Post = 71 +/- 1.7, P =.77). There was a decrease in the ammonia and total bilirubin levels (NH(3): Pre = 129.8 +/- 23.8 mg/dL, Post = 63.9 +/- 16.1 mg/dL, P =.01; total bilirubin: Pre = 20.3 +/- 2.5 mg/dL, Post = 17.6 +/- 2.7 mg/dL, P =.4). There was a significant increase of the Fischer ratio and factor VII levels (Fischer ratio: Pre = 0.98 +/- 0.2, Post = 2.17 +/- 0.5, P =.038; factor VII: Pre = 13.9 +/- 4.9, Post = 23.2 +/- 4.8, P =.015). There was a significant decrease in the HES and ICP (HES: Pre = 3.8 +/- 0.1, Post = 2 +/- 0.7, P =.02; ICP: Pre = 37 +/- 3.9, Post = 13.3 +/- 2.8, P =.048). Of 5 status I patients, 1 recovered native hepatic function and 3 were bridged to transplantation. This phase I study suggests that albumin dialysis as a liver support device is safe and effective in clearing hepatic toxins, with an associated decrease in the HES and ICP. This encouraging efficacy data warrant further investigation with a phase II/III trial.Surgery 09/2001; 130(2):354-62. · 3.37 Impact Factor
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ABSTRACT: Extracorporeal liver support therapies have been used for several decades as a bridging therapy prior to liver transplantation or as an addendum to standard medical therapy. The Prometheus system represents a cell-free, extracorporeal, liver assist method for the removal of both albumin-bound and water-soluble endogenous toxins. The aim of the present study was to evaluate the removal capacity and selectivity of the different inbuilt dialyzers and adsorption columns during a single 6-hour treatment. Nine patients with acute on chronic liver failure were included (6 females, age 49+/- 4 years). Levels of endogenous toxins (urea nitrogen [UN, mg/dl], creatinine [Cr, mg/dl], total bilirubin [tB, mg/dl], and bile acids [BA, mumol/l]) and albumin [Alb, g/l] were monitored in blood sampled at different sites (arterial line, venous line and between the absorbers and the high-flux dialyzer) and at various time points (time 0, 30, 60, 120, 240, and 360 min). A significant decrease of the serum level of all toxins was observed (UN 108.7+/- 23.2 vs. 38.1+/- 14.9, Cr 2.4+/- 0.7 vs. 1.2+/- 0.3, tB 31.1+/- 4.1 vs. 17.0+/- 1.6, BA 155.7+/- 32.5 vs. 66.0+/- 15.4; mean+/- SEM, time 0 vs. time 360, signed rank rest, all p< 0.005). The reduction rate of UN, Cr, tB and BA amounted to 68.1+/- 5.1, 45.9+/- 6.2, 41.2+/- 5.1, and 58.2+/- 5.0%, respectively. Blood clearances [Cl, ml/min] of all, but especially of the protein-bound toxins declined over time (Cl UN 171.5+/- 4.3 vs. 142.9+/- 16.8; Cl Cr 135.7+/- 10.0 vs. 111.8+/- 9.1; Cl tB 29.3+/- 5.1 vs. 13.7+/- 3.7; Cl BA 84.9+/- 4.8 vs. 45.1+/- 13.3; time 30 vs. time 360; linear mixed models, all p< 0.005). Serum albumin levels decreased by 2.9+/- 0.9 g/l (signed rank test, p=0.055). Not unexpectedly, tB was almost uniquely cleared by the adsorbers (UN 0.2+/-1.1, Cr 6.9+/- 5.7, tB 92.3+/- 4.2, BA 62.9+/- 3.9% of total Cl). Both albumin-bound and water-soluble toxins are adequately removed by the Prometheus system. Our data suggest that the rate and efficacy of removal of albumin-bound toxins is related to both the strength of the albumin binding and the saturation of the adsorption columns. Limited losses of albumin occur during treatment with the Prometheus system.Blood Purification 01/2005; 23(5):349-58. · 2.06 Impact Factor