Study of a New Clinical Device for Reducing Body Core Temperature

Introduction:

The ability to manipulate body core temperatures quickly and effectively would impact a
number of fields, with truly transformative potential. By far the best way to effect a
change in body temperature is perfusion with cooled or warmed blood because the vasculature
of the human body equilibrates magnificently well with the body and especially the body core
tissues due to the diffuse microcirculation. This process is quite invasive, however, and
noninvasive techniques to date have mostly revolved around various surface heat transfer
mechanisms that ultimately rely on relatively inferior conduction heat transfer.

Grahn, et al., at Stanford University have identified a new technique to increase the rate
of heat transfer between the skin and the body core by up to a factor of ten by harnessing
the convective power of the circulatory system in a completely noninvasive way [1, 2]. Our
system is derivative of the Stanford device, but different in many significant ways.

A well-understood and thus modifiable system capable of rapid artificial heat transfer has
almost limitless potential applications, including treatment of acute brain trauma (where
the single greatest challenge to treatment is inducing immediate hypothermia), athletic
performance enhancement, military operations, and enhancement of industries in which workers
are subject to extreme thermal stress.

Description of the Technology/Device:

The technology works as a two-step process, consisting of first stimulating the blood flow
to the AVAs and second cooling the glabrous skin through which blood is flowing.
Accordingly, the device consists of two components: first a blood flow stimulation source,
and second a surface heat exchanger to chill the glabrous skin and thereby the blood flowing
through it that subsequently flows back to the body core, where it cools those tissues.

Two separate means of stimulation will be tested in the trial:

- Transcutaneous Electrical Nerve Stimulation (TENS) - An FDA-approved TENS unit sends a
current via surface electrodes through the skin to stimulate the nerves that control
the state of AVA vasoconstriction. This stimulation will create a vasodilation effect
in the AVAs, allowing an increase in blood flow.

- Mild thermal stimulation along the skin overlying the cervical spine to send a control
signal to vasodilate the AVAs and provide an increased blood flow to glabrous skin. An
FDA-approved electric heating pad is used for this purpose at a temperature of 42°C or
lower.

Cooling will be accomplished by applying water perfusion bladders to the hands and feet. The
water will recirculate through the bladders to a holding tank with an internal pump, and a
thermoelectric cooler regulates the water temperature. The water temperature will be at 20°C
or higher.

Research Incentive:

The AVA structures in glabrous (non-hairy) skin are one component of the body's natural
thermoregulatory system. The anatomy and morphology of AVAs have been described to a great
extent in the literature, e.g. Sherman [6]. Putative pre-AVA sphincters are thought to be
the primary controllers of perfusion through AVAs, regardless of the level of AVA
vasodilation. If the AVAs are completely dilated, but the sphincters closed, blood will pool
in the dilated AVAs, but the flow of blood, which is essential for heat exchange with the
core, will be minimal. In contrast to perfusion of capillaries, which is largely regulated
by local conditions, flow through AVAs appears to be mostly centrally mediated, controlled
primarily by the vasoconstrictor tone imparted by rich sympathetic innervation [7-10]. The
sympathetic vasoconstrictor tone, which appears to oscillate in a characteristic manner over
time, is controlled by the central nervous system's homeostatic centers that respond to
various centrally located core temperature receptors. The complete inner workings of this
control system and its effector mechanisms are not completely understood or quantified, and
other factors influence AVA blood flow to some degree, such as local skin temperatures, the
presence of vasoactive metabolites, level of exercise, and stimulation of various peripheral
thermal sites. Recent work in the Diller lab has indicated the potential inherent in the
latter. The lab has identified regions of the skin that may be non-energetically thermally
stimulated (heating over a small area so as not to warm a significant volume) to induce AVA
vasodilation. We hypothesize these sites contain important thermoafferent sensors that
impact the central component (hypothalamic) of the governing controller.

The ability to induce mild hypothermia from a normothermic state represents the application
of greatest interest to our research group. If optimally developed, a device capable of
inducing only a 2-4°C decrease in body core temperature could have a huge impact in
treatment of various medical disease states and/or emergencies, including cardiac arrest,
severe brain injury, and stroke. It is well known that tissue death due to traumatic
physical injury and/or ischemia can be decreased with therapeutic hypothermia because of the
temperature dependence of cellular metabolism and the complex, destructive biochemical
processes that occur in damaged tissues [12].

Therapeutic hypothermia has been shown to have a great effect in various animal models;
however, translation of these results to the clinical domain has been very difficult. Aside
from any possible interspecies physiological differences, researchers are able to produce
injury and cool the core of the research animals in a very controlled manner, and most
importantly, cooling is induced very soon after injury. From these experiments, it has been
suggested that a "window of opportunity" exists of about 90 minutes post injury, after which
little to no therapeutic effect occurs from mild hypothermia. Moreover, this 90-minute
threshold may itself be a stretch, and cooling within a 60-minute window may be most
appropriate. Clinically, cooling within the former and surely the latter windows has almost
never been achieved. There are a number of reasons for this: the time between injury and
mobilization of the patient, transportation to an emergency care facility, initial
assessment of the patient in the hospital setting, and most importantly for physiological
science, a lack of fast and effective methods to cool the body core. Due to simple size and
geometry, the human body is much more difficult to heat or cool than, for example, the rat
model. This is especially true for conductive heat transfer mechanisms (which is what most
current noninvasive therapeutic hypothermia implementations are based on) because of the
relatively small ratio of surface area to thermal mass volume [3].

We hope that the problem of rapid core temperature manipulation can be drastically improved
upon, specifically by utilizing convective heat transfer through AVAs of glabrous skin. In
these experiments, we believe an optimized combinatorial protocol utilizing large coverage
of glabrous regions (both palms plus soles of the feet), manipulation of mean skin
temperature, and especially optimized stimulation of peripheral thermoafferent sensors
located in regions of the body such as along the spine, can allow for mild hypothermia
induction in spite of the conflict with the thermoregulatory controller. We especially hope
that manipulation of important thermoafferents will allow us to "trick" the controller and
bypass its effective vasoconstrictive signal.

Inclusion Criteria:

- Age ≥ 18 years

- Admitted to UMCB ICU

- Sedated, intubated and or mechanically ventilated

- At least one core temperature measurement device in place (rectal, bladder, pulmonary
artery) as standard of care

- Medical/surgical condition is stable enough to permit uninterrupted testing and
observation for at least 24 hours

- No medical/surgical procedures are anticipated as necessary or scheduled during
testing and observation period that would be affected by this protocol

- Vital signs and other parameters have been stable for at least 12 hours and there are
no imminent indications of instability

- LAR available and willing to provide informed consent

Exclusion Criteria:

- Condition is too unstable to permit uninterrupted testing and observation

- Pregnant and breast feeding patients

- Patients that might worsen with TH, including coagulopathy (INR>1.5),
thrombocytopenia (platelet count <100,000)

- Patients on antiplatelet therapy other than aspirin

- Patients on anticoagulants other than prophylactic low molecular weight heparin

- Patients on pressors to maintain blood pressure

- Patients with injuries to extremities that could preclude application of cooling
mittens or socks to at least three extremities

- Patients on TH treatment for any other condition