Application of the ELFI-TECH monitor for measurement of nociception

Accurate measurement of nociception during anesthesia remains a challenging
task. Nociception, which is defined as the neural process of encoding and
processing noxious stimuli (noxious stimuli are actually or potentially tissue
damaging events), will elicit behavioral, autonomic and hormonal responses in
conscious and unconscious individuals. Detection of behavioral responses during
anesthesia is often difficult due to the use of sedatives and muscle relaxants.
Hence, anesthesiologists rely on autonomic nervous system responses to assess
the nociceptive level of the patient. Most anesthesia health care providers, if
not all, use changes in heart rate and blood pressure as markers of the
occurrence of acute nociceptive events. While these variables may suffice when
intense nociceptive stimuli occur, mild and moderate stimuli are often not
detected or detected too late.

In recent years various indices of nociception have been developed with varying
success in actually detecting nociceptive events. These indices derive a
numerical value from single variables (such as heart rate variability, skin
conductance, skin vasomotor reflex, the electroencephalogram, pupil diameter)
or a combination of signals. There are various new developments, one of which
is the Nociception Level or NoL has recently been studied by us at LUMC
(P13.069). We successfully studied the relationship between nociceptive stimuli
and NoL during anesthesia and surgery. A completely new technology is the
Elfitor device (Elfi-Tech, Rehovot, Israel), which is based on dynamic light
scattering (DLS) and which continuously and non-invasively measures skin blood
flow, skin blood flow variability, heart rate, heart rate variability,
respiration, oxygen saturation, hemoglobin concentration, blood pressure and
cardiac output. Additionally the system allows rheologic measurements from
endothelial red blood cell interaction.

In the current study we will apply the Elfitor and collect its derived
parameters during nociceptive stimulation in healthy volunteers without and
with the administration of a low-dose opioid analgesic. Our study aim is to
assess whether the various parameters derived from the device correlate with
nociceptive stimulation and standard hemodynamic parameters.

The subjects will arrive at 8 AM in the laboratory K5-120 and will receive an
intravenous access line. Next they will be familiarized with the setup, pain
tests, pain scoring and monitoring devices.

After a 30 min rest period the pain tests will be applied. Heat and electrical
pain tests are performed in random order. The duration of the test sequence is
about 2 hours.
Then after another 3 min rest, the opioid remifentanil will be infused using a
target controlled infusion system (Remifusor, Glasgow University). The target
blood concentration is 2 ng/mL. The complete sequence of testing will be
repeated, again with the electrical and heat pain tests randomized in sequence.

Total duration of the study is 5 hours. Subjects will remain in the laboratory
until the effects of remifentanil are completely worn off (this usually takes
about 20 min). Only fit subjects are allowed to leave the laboratory.

The following measurements will be obtained during pain stimulation:

1. Elfitor (positioned on the inside of second digit and outside of the wrist)
ipsilateral from where pain is applied, preferably the non-dominant hand (this
leaves the dominant had for pain scoring). The data will be logged on a laptop
PC and will be analyzed off-line. Most important parameters will be: heart
rate, heart rate variability, blood flow, blood flow variability,
plethysmogram, blood pressure, stroke volume, stroke volume variability, Mayer
waves, and endothelial-red blood cell interaction.

2. Continuous non-invasive cardiac output and blood pressure using the
Nexfin/finger cuff device, positioned on the fourth digit (ring finger) of the
hand at which the Elfitor is placed. The Nexfin estimates finger systolic and
diastolic blood pressure and cardiac output.

3. Pulse oximetry and ECG monitoring will be performed as safety measures.

4. NoL fingerprobe, positioned on the third digit of the non-dominant hand. The
NoL combines information from several physiological parameters which represent
different autonomic pathways. This information includes the photoplethysmogram,
skin conductance level, fluctuations in skin conductance, and their time
derivatives.


Electrical pain stimulation
All participants will be familiarized with the study design, pain tests and
scoring system. Pain intensity is scored using an 11-point numerical rating
score (NRS) ranging from 0 (no pain) to 10 (maximum tolerated pain).

Test 1. Electrical pain is induced by placing electrodes on the tibial surface
of the right leg. Electrical currents are applied using a locally designed and
constructed computer interfaced current stimulator (CICS, Leiden University
Medical Center, Leiden, The Netherlands). A preset increasing current at 0.5
mA/s is delivered and subjects are instructed to score the first time they feel
pain (pain threshold, PTh) and the highest pain sensation they feel during the
stimulation (pain tolerance, PTol) by pushing a button.
This test is performed three times, 5-10 min apart.

Test 2. The values of PTh and PTol are used to construct a linear distribution
of 8 interpolated currents. For example if PTh is 11 mA and PTol 20 mA, the
interpolated temperatures are 12, 13, 14, 15, 16, 17, 18 and 19 mA. These 8
currents are subsequently presented in random order to the participants at 3-5
min intervals. All subjects are blinded to the sequence and intensity of the
stimuli. They will be asked to rate the different stimuli on the 11-point NRS.

Heat pain stimulation.
An electronic Visual Analogue Scale (eVAS) will be used to quantify pain
intensity in response to a noxious thermal stimulus. The thermal stimulus will
be applied on the volar side of the forearm using a thermal probe (a 3 * 3 cm
thermode) of the TSA-II NeuroSensory Analyzer (Medoc Ltd, Ramat Yishai,
Israel). This is a computer-controlled device capable of generating highly
reproducible thermal stimuli. The eVAS will be measured electronically using a
slide potentiometer (length = 10 cm) that can be moved from the left (0 or no
pain) to the right (10 or most intense pain imaginable). Using a hand the
subject can move the slide during the heat stimulator test. The eVAS is
recorded and collected on disk for further analyses. In this study a constant
increase in temperature will be applied, from 32 to 51 oC in 3 min after which
the stimulus will be terminated, or at any time earlier when the eVAS score
equals 10 cm. The test will be performed three times, 5-10 min apart; each time
the thermode will be repositioned to prevent sensitization or adaptation.

Remifentanil infusion (blood target concentration 2 ng/ml)
Pain testing

The burden of the study is mild. Heat and electrical pain testing may give
temporary red coloration of the skin. We have ample experience with both
electrical and heat pain testing, and no other side effects are known to occur
with these experimental pain models.

Remifentanil infusion may give hypotension, nausea and vomiting. However, at
the indicated concentration we expect these side effects to be absent or, if
they occur, of a mild nature. They are relatively easy to treat since
remifentanil has a short plasma half-life of 2-3 minutes. Overall the burden to
the subjects is mild.