PJ-008200 Measurements on healthy subjects to design a nociception index

Pain is defined by the International Association for the Study of Pain as *an
unpleasant sensory and emotional experience associated with actual or potential
tissue damage, or described in terms of such damage*. Nociception is *the
neural process of encoding noxious stimuli*.

Nociception during surgery can lead to surgically-induced neuropathic pain
(SNPP). SNPP has been estimated to occur in 10-50% of patients. To prevent
SNPP, a perioperative strategy would be to continuously block nociception, and
for this an objective measure of nociception is necessary.
In clinical practice it is seldom possible to completely block activation of
the nociceptive pathways. When spinal or regional anesthesia is not possible,
the one of the opioid drugs is administered to counteract the nociceptive
signals. At present it is very difficult for clinicians to judge when or if the
opioid dose is adequate, and this is a problem because both inadequate and
excessive doses have adverse consequences. In adequate doses of opioids are
associated with sympathetic activation and hemodynamic instability (tachycardia
and hypertension), and possibly an increased risk of SNPP. On the other hand
excessive doses are associated with adverse effects such as bradycardia and
hypotension, post-operative nausea and vomiting, generalized itching and
constipation. Moreover, excessive doses may be associated with opioid tolerance
and opioid-induced hyperalgesia which can lead to increased post-operative
opioid requirements, and eventually a higher incidence of SNPP.

Nociception measurement and management is a quality indicator for hospitals.
Monitoring of nociception in the OR could result in improved patient safety,
higher OR throughput, and better patient outcome.

In current clinical practice, anesthesiologists primarily rely on changes in
heart rate (HR) and arterial blood pressure (ABP) as a measure of the balance
between nociception and anti-nociception (i.e. the dose of analgesic drugs)
during surgery. However, with this approach some nociceptive responses may be
missed.

There is a need for a continuous, objective nociception index especially for
sedated unconscious patients who cannot express their pain levels. There is an
increasing number of new nociception/pain/stress indices in the market using a
combination of vital signs, using galvanic skin conductance or brain signals or
using a combination of different parameters. However, none of these
technologies is currently better than BP and HR in predicting nociceptive
response and there is definitely room for improvement. In our current study, we
aim to use a novel combination of parameters to design a unique nociception
index.

Heart rate variability (HRV) is a widely used measure of alterations in
sympathetic and parasympathetic autonomic nervous system activity. HRV has been
associated with nociceptive stimuli since many years. More recent studies have
underpinned the potential value of HRV in nociception measurement.

Another physiological response to nociceptive events is an increase in blood
pressure. This has been shown for tonic nociceptive stimuli, as well as short
nociceptive stimuli.

Photoplethysmography (PPG) measures local blood volume changes, e.g. at the
fingertip. The pre-processing of a patient monitor removes some of the
information in a PPG waveform, which is why we chose a recording method that
avoids this. The PPG waveform consists of a DC component (i.e. low-frequency
variations) and an AC component (higher frequency variations). The AC component
has been shown to be relevant for measuring nociception. Various parameters can
be derived from the PPG waveform, such as amplitude, area under the curve, and
rising slope.

Galvanic skin response is a measure that is used to measure stress, and has
also been linked to nociception; either on its own, in combination with heart
rate, or in the multi-parameter NoL (nociception level) index.

Nociception can be measured in the brain through electroencephalography (EEG).
Evoked potentials (EP) can be observed in the EEG signal after nociceptive
stimuli. It is known that peaks in the EP correlate with stimulation strength
and subjective experience. The latency of the peaks in the EP are influenced by
the time to conduct the signal between the site of stimulation (the calf of the
leg) and the part of the brain. Comparing the arrival time of the peaks of the
EPs of the different subjects will be influenced by this distance and
conductance velocity. With an average conduction velocity of around 10 m/s
(Adelta fibers and spinothalamic tract) this can differ ~5ms per 5 cm. The
peaks of interests are in the timeframe of 150ms - 400ms with multiple distinct
peaks. Comparing the EP peaks latencies and amplitudes or for group analysis it
is important to be able to take into account the difference in height
(categorical).
Facial expressions have also been studied as a measure of nociception, although
interpersonal differences in expressiveness should be considered. An example of
an implementation of facial detection for pain detection is the PainChek app.
It is currently mostly used in patients with dementia.

With our current study, we can combine all these parameters in a unique dataset
that will be used to design a novel nociception index.

Because all these parameters have never been combined for measuring
nociception, our current study will serve as a pilot study. To ensure that we
have a very well controlled condition for obtaining the data, we will perform
our study on healthy volunteers. A study population balanced in age groups and
gender is needed, because these factors are known to influence nociceptive
response.

When studying nociception in healthy subjects, nociceptive stimuli are given to
the subjects. There are various methods of applying these types of stimuli,
which are well described in the literature. Nociception can be induced by
either phasic or tonic nociceptive stimuli, phasic nociceptive stimuli are
short stimuli of which the stimulation strength is well controllable which
gives the opportunity to administer different stimulus levels (painful or
non-painful). Tonic stimulus is a persistent nociceptive stimulus.

By applying more than one type of stimulus, a more accurate representation of
nociception can be obtained. Electrical stimulation activates the nociceptive
nerve fibers directly surpassing the receptors, and has the advantage of short
and fast pulses making it suitable for studying evoked potentials in the EEG,
see for example. Thermal stimulation pulses are less instantaneous, but do not
bypass the receptors as the electrical stimulation does. Both electrical and
thermal are phasic stimuli giving the opportunity to stimulate at different
stimulations levels making it possible to test the index for both non-painful
as painful levels. For a more gradual nociceptive stimulus, the cold pressor
test is a well-established tonic stimulation method.
Next to relationship between the measured parameters and stimulation modalities
and stimulus strengths also the relationship between these and the subjective
score is of interest. Subjective pain experience can be measured by means of
the so called Numeric Rating Scale (NRS). This is a scale from 0 till 10 with 0
meaning no sensation and 10 the pain tolerance level.

An objective measure of nociception that is to be used during surgery, should
not lose its value when analgesia is used. A commonly used analgesic during
surgery is remifentanil. Remifentanil is also used in the literature to assess
the value of a measure of nociception during analgesia use. Adding remifentanil
to our protocol gives a first, important insight into the value of the new
nociception index during surgery.

The primary objective is to measure the effect of nociceptive stimuli on
features derived from ECG, ABP, PPG, EEG and facial video recordings, to be
used to design an index of nociception. The index of nociception should
correlate well with strength of nociceptive stimulus and subjective NRS score.

The secondary objectives are to:
- Analyse the effect of remifentanil on the correlation between the index of
nociception and the stimulus strengths and related subjective NRS scores
(remifentanil is standard in surgery care, is fast acting, and often used in
other studies that research nociception).
- Evaluate the performance of within Philips Research earlier developed vital
sign based (i.e. HRV, BP) algorithms.
- Benchmark the index of nociception with indices on the market such as ANI
(Analgesia Nociception Index).
- Evaluate the performance of the PainChek facial expressions algorithm for
pain detection

This clinical investigation is designed as an observational pilot study,
because a unique dataset needs to be obtained to design an index of
nociception.

The risks of participation in this study are assessed to be acceptable
(negligible).

The disadvantages of participating in the study can be
- the development of possible side effects;
- Possible inconveniences due to the measurements in the study.
- time consuming of about 5 hours;

There is no clinical benefit for the participating healthy volunteer