Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli.

BACKGROUND: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios. METHODS: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant. RESULTS: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETX-cytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release. CONCLUSION: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.

A minimal model to describe short-term haemodynamic changes of the cardiovascular system.

AIMS: Current pharmacokinetic-pharmacodynamic models describing the haemodynamic changes often do not include necessary feedback mechanisms. These models provide adequate description of current data but may fail to adequately extrapolate to additional scenarios. This study aims to develop a minimal model to describe the short-term changes of haemodynamics that can be used as the basis for model development by future researchers. METHODS: A minimal haemodynamic model was developed to describe the influence of drugs on blood pressure components. The model structure was defined based on known mechanisms and previously published models. The model was evaluated under 2 different simulation settings. The model parameters were calibrated to describe (without estimation) the haemodynamics of 2 antihypertensive drugs with data extracted from the literature. Structural identifiability analysis was done using various combinations of the observed variable. RESULTS: The proposed model structure includes mean arterial pressure, heart rate and stroke volume and is composed of 4 states described by differential equations. Model evaluation showed flexibility in describing the haemodynamics at different target perturbations. Overlay plots of model predictions and literature data showed a good description without data fitting. The structural identifiability analysis revealed all model parameters and initial conditions were identifiable only when heart rate, mean arterial pressure and cardiac output were measured together. CONCLUSIONS: A minimal model of the haemodynamic system was developed and evaluated. The model accounted for short-term haemodynamic feedback processes. We propose that this model can be used as the basis for future pharmacometric analyses of drugs acting on the haemodynamic system.

Clinical Pharmacist-Provided Services In Iron-Overloaded Beta-Thalassaemia Major Children: A New Insight Into Patient Care.

Iron-overloaded ß-thalassaemia major (BTM) children have high risk of delayed sexual/physical maturation, liver/heart diseases and reduced life expectancy. The lifelong need to use iron chelators, their unpleasant administration, side effects and lack of awareness regarding iron overload risks all hamper BTM patient compliance to iron chelators. This study evaluated the impact of clinical pharmacist-provided services on the outcome of iron-overloaded BTM children. Forty-eight BTM children were randomly assigned to either control group, who received standard medical care, or intervention group, who received standard medical care plus clinical pharmacist-provided services. Services included detection of drug-related problems (DRPs) and their management, patient education regarding disease nature and iron chelators, as well as providing patient-tailored medication charts. After six months of study implementation, there was a highly significant difference between the control and intervention groups in serum ferritin (SF) (mean: 3871 versus 2362, µg/l, p = 0.0042), patient healthcare satisfaction (median: 24.47 versus 90.29, p < 0.0001) and quality of life (QoL) (median: 49.84 versus 63.51, p = 0.0049). The intervention group showed a decline from baseline to the end of study in DRPs (64-4), the number of non-compliant patients (24-3) and mean SF levels (3949-2362 µg/l, p < 0.0001). Clinical pharmacist-provided services can positively impact the outcome of BTM children.