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Objective: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis.Design: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial.Setting: Six medical and surgical intensive care units located in Germany and the Netherlands.Patients: Forty patients with severe sepsis.Interventions: IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day I followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included.Measurements and Main Results: The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 mug/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group.Conclusions: Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.

Purpose of review The outcomes of intervention studies implementing intensive insulin therapy aimed at tight glucose control (TGC) are yet not conclusive. There is concern about an increasing incidence of hypoglycemic episodes. Normoglycemia is not easy to obtain in a 'real-life' ICU setting. To facilitate the implementation of TGC, we review its practical aspects. Recent findings Point-of-care blood gas/glucose analyzers currently present the best trade-off between accuracy and speed. A nurse-driven dynamic scale protocol leads to the most efficacious and safe implementation of TGC. Paper protocols have been published and computerized protocols are a new development. Closed-loop systems are not yet available for clinical use. Summary, Clinicians should take care in selecting both the patient group and target blood glucose level. As long as doubts remain about the potential benefits, it is important to perform TGC in a safe way. This can be done with a nurse-driven protocol, using arterial blood samples measured on a point-of-care blood gas analyzer. Insulin administration should be continuous, and guided by a dynamic scale protocol either on paper or on the computer. Periodical monitoring of performance and incremental modification of the protocol leads to best results.