Regulation of interleukin 12 p40 and p70 production by blood and alveolar phagocytes during severe sepsis.

Paradoxically, the host response to severe sepsis may lead to immunosuppression, thereby favoring nosocomial infections. We examined the role of the two IL-12 isoforms, bioactive IL-12p70 and regulatory IL-12p40, in 16 patients with severe sepsis. We compared the capacity of purified blood and alveolar phagocytes [polymorphonuclear neutrophils (PMN) and monocytes/macrophages] to secrete each isoform. Blood monocytes had normal basal secretions. In contrast, a marked imbalance was observed after ex vivo stimulation by lipopolysaccharide plus IFN-gamma, with significantly lower IL-12p70 production and higher IL-12p40 production. Conversely, stimulated IL-12p40 production by the patients' blood PMN tended to be impaired, as was their cell-surface beta2 integrin and L-selectin expression, known as markers of cell activation. In the patient's bronchoalveolar lavage fluid, the production of both IL-12 isoforms after ex vivo stimulation was significantly lower with alveolar macrophages than with autologous blood monocytes and significantly higher with alveolar PMN than with autologous blood PMN. This sheds new light on the potential role of PMN in local modulation of inflammation, via secretion of the anti-inflammatory IL-12 p40 subunit. The imbalance between the bioactive and regulatory IL-12 isoforms, which is probably designed to control excessive inflammation, may also make septic patients more susceptible to nosocomial infection.

Pharmacokinetics of long-term sufentanil infusion for sedation in ICU patients.

OBJECTIVE: To determine the pharmacokinetics of long-term infusion of sufentanil in ICU patients. DESIGN AND SETTING: Open-label study in a surgical intensive care unit. PATIENTS: Ten consecutive patients without renal or hepatic failure requiring mechanical ventilation for at least 6 days. INTERVENTIONS: Patients received sufentanil (initial bolus 0.5 micro g/kg and continuous infusion rate of 0.5 micro g/kg per hour) and midazolam (initial bolus 0.08 mg/kg and continuous infusion 0.05 mg/kg per hour). Sedation was adjusted according to the Ramsay scale (score >3). Blood samples were taken during and up to 72 h after the infusion, and plasma concentrations were measured using a sensitive radioimmunoassay method. MEASUREMENTS AND RESULTS: Plasma concentration-time profiles of sufentanil and pharmacokinetic parameters such as initial postinfusion half-life (t(1/2alpha)), elimination half-life (t(1/2beta)), total clearance (Cl), volume of distribution (Vdbeta), and time required to obtain a 50% decrease in plasma concentration (tcp(0/2)). The mean duration of sedation was 12+/-7 days. The initial half-life t(1/2alpha) was 1.33+/-1.15 h. The observed prolonged elimination half-life (t(1/2beta)=25.5+/-9.4 h) was related to the large volume of distribution (Vdbeta=22.6+/-9.4 l/kg). The mean total clearance was 13.4+/-7.0 ml/kg per minute. The mean time required to obtain a 50% decrease in plasma concentration was short (tcp(0/2=)4.7+/-3.7 h). CONCLUSIONS: The pharmacokinetic analysis of sufentanil for ICU sedation revealed increased volume of distribution and elimination half-life. Nevertheless the rapid distribution and elimination processes suggest that the rapid reversibility of sedation with sufentanil is maintained after long duration of infusion. Further studies should be carried out to evaluate the clinical relevance of these results.