Matt Harmon

102 Chapter five Methods Study Design The ESCIMO-study (External Surface Cooling In huMan endOtoxemia) was a human volunteer open-label non-randomized controlled trial. This study was reviewed and approved by the Amsterdam university medical center Medical Ethical Committee (NL53460.018.15) and performed according to the Declaration of Helsinki, including Good Clinical Practice. We included 12 healthy volunteers, aged 18-35 years with a body mass index (BMI) between 20-25 kg/m 2 . The volunteers were screened before the start of the study and had no abnormalities on physical examinations, routine laboratory tests and electrocardiography. Subjects were excluded if they had a history of drug abuse, medication use on prescription, or had participated in any medical drug study 3 months prior to inclusion or in a previous volunteer studies using LPS. Supplemental table 1 shows the complete in- and exclusion criteria for this study. Volunteers were assigned either to the intervention group receiving LPS and induced normothermia or to a fever group only receiving LPS (n=6 per group). Study model The experiments took place at the Daycare center of an academic teaching hospital in Amsterdam, the Netherlands. An arterial catheter was placed for the monitoring of the blood pressure and taking blood samples, and a rectal temperature probe was inserted to measure core temperature. Other vital parameters were monitored with electrocardiography (ECG) and pulse oximetry. Ambient temperature in the room was set at 21°C. At T=0 hours, all subjects received 2ng/kg Escherichia coli LPS (National Institutes of Health Clinical Center, Bethesda, United States of America). In the intervention group, induced normothermia was initiated at T=1 hour and continued to T=8 hours after LPS infusion using an external surface cooling device (Artic Sun© temperature management system). Cooling pads were applied to the torso and upper legs after which subjects were cooled to a core target temperature between 36.0 - 37.0°C via a closed loop system with feedback provided via the rectal temperature probe. Subjects also received cooled intravenous (IV) fluids for 150 minutes (4°C normal saline). Cooling awake subjects without pharmacological adjuncts can result in increasing shivering with increases in the metabolic rate as well as inducing thermal discomfort. Moreover, cooling the skin can result in a compensatory increase in core temperature due to autonomic temperature defense mechanisms