http://repub.eur.nl/res/aut/19789/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/24157/ 2009-04-01T00:00:00Z Purpose: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). Methods: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg-124 h-1) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. Results: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. Conclusions: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis. http://repub.eur.nl/res/pub/16470/ 2009-02-01T00:00:00Z BACKGROUND: Hyperlactatemia and its reduction after admission in the intensive care unit (ICU) have been related to survival. Because it is unknown whether this equally applies to different groups of critically ill patients, we compared the prognostic value of repeated lactate levels (a) in septic patients versus patients with hemorrhage or other conditions generally associated with low-oxygen transport (LT) (b) in hemodynamically stable versus unstable patients. METHODS: In this prospective observational two-center study (n = 394 patients), blood lactate levels at admission to the ICU (Lac(T0)) and the reduction of lactate levels from T = 0 to T = 12 hours (DeltaLac(T0-12)) and from T = 12 to T = 24 hours (DeltaLac(T12-24)), were related to in-hospital mortality. RESULTS: Reduction of lactate was associated with a lower mortality only in the sepsis group (DeltaLac(T0-12): hazard ratio [HR] 0.34, p = 0.004 and DeltaLac(T12-24): HR 0.24, p = 0.003), but not in the LT group (DeltaLac(T0-12); HR 0.78, p = 0.52 and DeltaLac(T12-24); HR 1.30, p = 0.61). The prognostic values of Lac(T0), DeltaLac(T0-12), and DeltaLac(T12-24) were similar in hemodynamically stable and unstable patients (p = 0.43). CONCLUSIONS: Regardless of the hemodynamic status, lactate reduction during the first 24 hours of ICU stay is associated with improved outcome only in septic patients, but not in patients with hemorrhage or other conditions generally associated with LT. We hypothesize that in this particular group a reduction in lactate is not associated with improved outcome due to irreversible damage at ICU admission.