Thesis supervisor: Professor Joel Starkopf, dr.med. (UT Department of Anesthesiology and Intensive Care) and Visiting Professor Hartmut Kern, dr. med. (UT Department of Anesthesiology and Intensive Care).
Opponent: Professor Jan J. De Waele, MD, PhD (Dept. of Critical Care Medicine, Ghent University Hospital, Belgium).
Sepsis – a systemic, deleterious host response to infection – and its most complicated forms, severe sepsis and septic shock remain a major healthcare problem. The key issues in the treatment of sepsis are adequate antibacterial therapy, rapid source control and handling of the systemic inflammatory reaction. Nonselective extracorporeal removal of mediators by a specific method of renal replacement therapy - high volume haemodiafiltration (HVHDF) has been used to control systemic inflammation. While potentially effective in inhibiting the systemic reaction, HVHDF may lead to excessive removal of antibiotics and ineffective antibacterial treatment. We aimed to describe the pharmacokinetics of two antibiotics – doripenem and piperacillin/tazobactam during HVHDF in order to define optimal dosing for this method. We also aimed to describe the impact of HVHDF on the patients’ circulation and inflammatory mediator profile. After a single dose of doripenem and piperacillin/tazobactam 12 blood samples were collected from severe sepsis and septic shock patients with renal failure. Before and after a 10 hour HVHDF session the patients’ haemodynamic variables and serum inflammatory mediator concentrations were measured. We found high interpatient variability in the serum concentrations of both antibiotics after administering the same dose to everyone. The mean clearance of both antibiotics from the body was about twice slower than in healthy volunteers. Doses recommended by the manufacturer for patients with normal renal function could be used during HVHDF to treat severe sepsis and septic shock in patients with renal failure. Due to high interpatient variability monitoring the concentrations of both antibiotics during treatment would allow more precise dosing. While the patients’ circulation improved during HVHDF, the improvement was not caused by decrease of inflammatory mediator concentrations.