External Surface Cooling In huMan endOtoxemia

Experimental animal data and preliminary clinical data suggest that septic
patients with fever may benefit from fever control with external cooling,
presumably via inhibition of excessive inflammation. However, the mechanisms of
this treatment modality remain to be determined in humans. Also, there are
safety concerns regarding fever control in sepsis, as cooling may induce
immunosuppression, coagulopathy, and may impair circulation. In healthy
individuals, lipopolysaccharide (LPS) causes a reversible endotoxemia,
including fever, tachypnea, tachycardia and hypotension. These physiologic and
metabolic changes approximate those in human sepsis, making this model ideal
for an in depth study of mechanisms of external cooling as well as examining
safety. We will use this model to assess the effects of fever control (36°C)
using external cooling on the host immune response, coagulation and
circulation.

To determine the effects of fever control with external cooling during
LPS-induced endotoxemia on:
1. host immune response
2. coagulation processes
3. tissue perfusion and oxygenation
4. neurovascular coupling

Healthy volunteers will be screened (medical history, physical examination,
ECG, blood examination) by a physician. On study day, all subjects (n=24) will
be injected with LPS 2ng/kg i.v., which results in chills at 2 hours and fever
spiking at 3-4 hours. Using external cooling devices, Group 1 (n=6) will be
kept at normothermia (36°C) from start of experiment. 3 hours after LPS
infusion (coinciding with the temperature peak due to LPS), group 2 (n=6) will
be cooled to 36°C. The control group will not be cooled. The study will end 8
hours after LPS infusion. A group will only recieve LPS + medication

Study timeline:
A pilot study will be performed with 1 subject (group 1). If the study design
is deemed feasible, we will continue with groups 1 + 3. After which, an interim
analysis will be performed on our primary endpoint (IL-6) and hemodynamic
parameters such as blood pressure. If no benefit is seen in the intervention
group, group 2 will not be studied. An additional group will recieve only LPS +
medication

Cooling: Subjects will be cooled using a cooling management system also used
for cardiac arrest patients. This system cools externally using 4 gelpads
located on the back, thorax, abdomen and upper legs. These gelpads are
connected to the machine which in turn keeps the pads a the wanted
temperature. Also, cold NaCl will be given to reach target temperature and if
necessary 1g acetaminophen

Temperature measurement: A rectal temperature probe will be placed to provide
feedback to the external cooling device.

Shivering: To counteract shivering in the cooled group, counter skin warming
will be done of the hands and feet using an adapted Bair Hugger, which flows
warm air over desired area. Also, to counteract shivering, buspirone (30mg),
pethidine (max 600mg) or clonidine (75mcg bolus and max infusion rate
2mcg/kg/h), magensium sulfate (max 9g).
Sampling: Blood will be taken before LPS infusion and at 1,3,6,8 hours for
hematology, parameters of immune host response and coagulation tests.
Hemodynamics will be monitored by arterial catheter, arterial blood gas,
echocardiography, and by imaging of the microcirculation.

Group 1: LPS + medication + external cooling to 36°C from T = 0 hours after LPS
infusion
Group 2: LPS + medication+ external cooling to 36°C from T = 3 hours after LPS
infusion
Group 3: LPS
Group 4: LPS + medication

Benefits: none
A dose of 2ng/kg LPS in healthy volunteers has proven to be safe in previous
studies at this institution. Cooling healthy, awake volunteers has also been
proven to be safe, even to temperatures well below the proposed 36°C in this
study.
Although the combination of external cooling and LPS has not been performed
before, we do not expect this to cause safety issues. Discomfort is expected to
be mainly related to shivering, which will be treated immediately. A (relative)
bradycardia will occur, reduction in cardiac output is variable, but if this
occurs, it will result in normalization of a hyperdynamic circulation.
Electrolyte disorders as seen during hypothermia are not expected.
Pethidine, clonidine, buspirone and magnesium sulfate have been given to
healthy volunteers being cooled to suppress shivering without problems, at
higher doses given than in this study. As the intervention lasts only 8 hours,
there is no risk of toxicity, even though cooling could decrease metabolism.
From a safety perspective subjects will be monitored during the total
experiment and until 2 hours afterwards.