Matt Harmon

120 Chapter six Methods Study Design, Setting, and Patient Identification This study is part of a larger study on the mechanisms and safety of fever control in healthy volunteers. In short, the ESCIMO-study (External Surface Cooling In huMan endOtoxemia) was a human volunteer open-label non-randomized controlled trial in which 12 healthy male volunteers aged 18 to 35 were included at the Amsterdam University Medical Centre. Inclusion criteria were an unremarkable medical history and physical examination. This study was reviewed and approved by the Amsterdam university medical centre Medical Ethical Committee (NL53460.018.15) and performed according to the Declaration of Helsinki, including Good Clinical Practice. Study model Every subject received an indwelling arterial catheter for measurement of blood pressure and blood sampling. A rectal temperature probe was inserted to measure core temperature. Other vital parameters were monitored with electrocardiogram and pulse oximetry. Ambient temperature in the room was set at 21°C. In this study, the first 6 participants were designated to the fever group which received LPS. The following 6 participants were included in the normothermia group, which received LPS and were subsequently cooled to normothermia. At T=0 hours, all subjects received 2ng/kg Escherichia coli LPS (National Institutes of Health Clinical Centre, Bethesda, United States of America). In the normothermia group, cooling was initiated at T=1 hour and continued to T=8 hours after LPS-infusion using an external surface cooling device (Arctic Sun© temperature management system), set at a target temperature of 36.0-37.0°C. To minimize shivering, subjects in the normothermia group received buspirone, magnesium sulphate and clonidine. To prevent nausea, ondansetron 4mg was given intravenously. Sample collection and analysis and outcomes Citrated blood samples (BD™ Vacutainer™ Citrate Tubes) were taken from the arterial catheter just before and at 1, 3, 6, and 8 hours after LPS administration. Blood was centrifugated at 1500g and the supernatant was stored at –80°C for later analysis of vWf antigen analysis by Enzyme-linked immunosorbent assay (ELISA) using a homemade assay with antibodies from DAKO (Glostrup, Denmark).