Ventilator-induced heat shock protein 70 and cytokine mRNA expression in a model of lipopolysaccharide-induced lung inflammation.

OBJECTIVE: To investigate the effect of mechanical ventilation with no PEEP (ZEEP) and 4 cmH(2)O PEEP on heat shock protein 70 (HSP70) and pulmonary inflammatory cytokine expression in a model of lipopolysaccharide (LPS) induced lung inflammation. DESIGN AND SETTING: Prospective, randomized, experimental animal study. SUBJECTS AND INTERVENTIONS: We challenged 42 male Sprague-Dawley rats intratracheally with LPS. After 24 h the rats were randomly assigned to one of the ventilation strategies. Rats received either 4 h of mechanical ventilation with ZEEP or mechanical ventilation with 4 cmH(2)O PEEP. A nonventilated control group received LPS only. Lung pathology after LPS challenge was evaluated by histology to assess baseline lung injury. HSP70 and cytokine mRNA levels were measured in total lung homogenates. RESULTS: PaO(2) levels and lung histology revealed no deterioration after PEEP ventilation and severe deterioration after ZEEP ventilation. There was a significant higher expression of HSP70 and IL-1beta mRNA in the lungs of the ZEEP group than in the PEEP group and nonventilated controls. In the ZEEP group high HSP70 levels were correlated inversely with low IL-1beta mRNA and low IL-6 mRNA. CONCLUSIONS: We propose that HSP70 expression protects the lung against ventilator-induced lung injury by decreasing cytokine transcription in the lung.

Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery.

AIMS: This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients. METHODS: Six mechanically ventilated children aged 1-5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg-1 h-1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale. RESULTS: The data were best described by a two-compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic parameters in the weight-proportional model were clearance (CL) = 35 ml kg-1 min-1, volume of central compartment (V1) = 12 l, intercompartmental clearance (Q) = 0.35 l min-1 and volume of peripheral compartment (V2) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following cardiac surgery and when normalized for body weight, statistically significant differences were observed the parameters CL and V1 (35 vs 29 ml kg-1 min-1 and 0.78 vs 0.26 l kg-1P < 0.05), whereas the values for Q and V2 were similar (23 vs 18 ml kg-1 min-1 and 1.6 vs 1.8 l kg-1, P > 0.05). In children, the percentage of adequately sedated patients was similar compared with adults (50% vs 67%) despite considerably higher propofol concentrations (1.3 +/- 0.10 vs 0.51 +/- 0.035 mg l-1, mean +/- s.e. mean), suggesting a lower pharmacodynamic sensitivity to propofol in children. CONCLUSIONS: In children aged 1-5 years, a pharmacokinetic model for propofol was described using sparse data. In contrast to adults, body weight was a significant covariate for clearance in children. The model may serve as a useful basis to study the role of covariates in the pharmacokinetics and pharmacodynamics of propofol in paediatric patients of different ages.

Mechanical ventilation alters the immune response in children without lung pathology.

OBJECTIVE: This study was undertaken to examine the hypothesis that mechanical ventilation in association with anesthesia would alter the cytokine profile in infants without preexisting lung pathology. DESIGN AND SETTING: Prospective observational study in pediatric intensive care unit in a university hospital. PATIENTS: Twelve infants who were subjected to an uncomplicated diagnostic cardiac catheterization procedure were studied. All subjects were ventilated with a volume control mode, 0.3 FIO(2), 4 cmH(2)O PEEP, and 10 ml/kg tidal volume. Volatile (servoflurane) anesthetics were given. MEASUREMENTS AND RESULTS: Tracheal aspirates and blood samples were obtained before and after 2 h of mechanical ventilation. In tracheal aspirates and in supernatants of stimulated whole-blood cultures cytokine concentrations were measured. In the tracheal aspirates the immune balance was characterized by a proinflammatory response pattern, with a significant increase in TNF-alpha and IL-6 concentrations; concentrations of anti-inflammatory mediators remained very low. The functional capacity of peripheral blood leukocytes to produce INF-gamma, TNF-alpha, and IL-6 in vitro was significantly decreased. This was accompanied by a significant decrease in the killing activity of natural killer cells. CONCLUSIONS: Two hours of servoflurane and mechanical ventilation using a tidal volume of 10 ml/kg is associated with remarkable changes in the immune response in infants without preexisting lung pathology undergoing cardiac catheterization. In the lungs the immune balance favors a proinflammatory response pattern without detectable concentrations of anti-inflammatory mediators. The Th1 immune response by peripheral blood leukocytes was decreased. The observed change in Th1/Th2 balance in favor of Th2 cytokine activity may be a systemic adaptation to the proinflammatory milieu in the lung.