The effects of depth of anaesthesia and blood pressure on motor evoked potentials inspinal surgery.

For complex and high risk spinal surgery, intraoperative neurophysiological
monitoring (IONM) is used in the University Medical Centre Groningen (UMCG),
with the aim to reduce intraoperative neurological injury. However anaesthesia
has its effects on the reliability of IONM. This research proposal wants to
examine the effects of anaesthesia on IONM.
IONM can be used to monitor both the sensory and the motor tracts. Monitoring
of the motor tracts, using motor evoked potentials (MEPs), is considered the
most reliable method for detecting and preventing neurological damage. MEPs can
be measured using electrodes at different levels: electrodes on the spinal cord
can record direct waves (D-waves) and electrodes over the limb muscles can
record transcranial muscle MEPs (Tc-MEPs).
In order to obtain reliable Tc-MEPs, the voltage threshold (the minimum voltage
required to generate a Tc-MEP) should be low and the recorded amplitude of the
muscle contraction should be high. When reliable Tc-MEPs are obtained the risk
of surgery-induced neurological damage decreases. Many factors can alter the
voltage threshold and the amplitude, including: anaesthesia, blood pressure,
body temperature, blood oxygen levels, and nerve or motor tract compression and
traction.
It is known that for maintenance of general anaesthesia a combination of
propofol and an opioid provides more optimal Tc-MEPs than other anaesthetics.
Nonetheless Tc-MEPs are still very sensitive to the effects of propofol
anaesthesia. The effect of *depth of anaesthesia*, quantified by a processed
electroencephalogram (pEEG), on MEPs has never been rigorously investigated.
Another major factor influencing Tc-MEP amplitudes is spinal cord perfusion.
The latter cannot be measured directly, and blood pressure is used as a
surrogate. Only few studies have investigated the effects of blood pressure on
Tc-MEP. Although anaesthesiologists commonly administer vasopressors to elevate
the blood pressure, it is not known whether this improves or impairs spinal
cord perfusion and thus Tc-MEPs amplitudes.
However, pEEG and blood pressure are influenced by blood loss, pain and
manipulation/movements of the patient. Therefore, in order to examin the
effects of different blood pressures defined by the mean arterial pressure
(MAP) and different depths of anaesthesia defined by pEEG, on Tc-MEP
measurements, with as few as possible confounding parameters, measurements
should be performed after anaesthetic induction and before surgical incision.
In conclusion, the aim of this research proposal is to investigate the effects
of depth of anaesthesia and blood pressure on Tc-MEP measurements. By knowing
the effects of depth of anaesthesia and blood pressure on Tc-MEPs we can obtain
more reliable Tc-MEP measurements causing a higher specificity when a Tc-MEP
decrease occurs and less false positive findings, and therefore preventing more
surgically induced neurological damage.

Part 1:
To determine the effect of depth of anaesthesia, as quantified by pEEG, on the
quality of Tc-MEP measurements during spinal surgery.
Hypothesis: lower depth of anaesthesia, defined by higher values of pEEG will:
a. Decrease the threshold voltage required to evoke a Tc-MEP.
b. Increase the Tc-MEP amplitude and the Tc-MEP area under the curve
(AUC).
Part 2:
To determine the effects of elevating the MAP with a vasopressor infusion on
the quality of Tc-MEP measurements during spinal surgery.
Hypothesis: a higher MAP will:
a. Reduce the threshold voltage required to evoke a Tc-MEP
b. Increase the Tc-MEP amplitude and the Tc-MEP AUC.
*

This research protocol contains 2 prospective observational pilot studies. In
part 1 we want to examin the effects of depth of anaesthesia, quantified by
pEEG, on Tc-MEP characteristics. In part 2 we want to examin the effects of
blood pressure, quantified by the MAP, on Tc-MEP characteristics.
Patients that will undergo spinal surgery with the use of Tc-MEPs are eligible
for these studies. Patients will either participate in part 1 or part 2. This
will not be randomised.
See flowchart 1 for the study design of part 1, and flowchart 2 for the study
design of part 2 in the research protocol.
Part 1: Effects of depth of anaesthesia on Tc-MEP characteristics during spinal
surgery
After induction of anaesthesia, and before the onset of the spinal surgery, the
anaesthesiologist will adjust effect-site (brain) propofol concentrations to
achieve pEEG values according to flowchart 1.
Although models exist to predict the time course of clinical effects of
propofol through its interaction with the GABAA receptor, there remain
uncertainty over the accuracy of these models, and of the likelihood of longer
term structural changes following propofol interactions with the receptor. If
there are longer term effects, then path-dependent differences may exist. We
therefore plan 2 groups. One group will start with propofol concentrations
decreasing and one group will start with propofol concentrations increasing
resulting into the pEEG values as can be observed in flowchart 1 in the
research protocol. These predefined pEEG values are not in conflict with the
standard use of care since pEEG ranging from 30-60 are common values during
spinal surgery. Once a stable pEEG level has been reached, which on average
lasts about 15 minutes to obtain a stable pEEG level, Tc-MEPs will be
registered for three minutes and the following will be determined: voltage
threshold to evoke Tc-MEPs, 3 Tc-MEP amplitudes and 3 Tc-MEPs AUCs in the
tibialis anterior muscle left and right, the gastrocnemius muscle left and
right and the abductor hallucis muscle left and right. Throughout the
recordings and subsequent surgery, as per standard clinical protocols,
vasopressor infusions will be used to maintain the mean arterial pressure (MAP)
at 70 - 90 mmHg, and the ventilation adjusted to maintain normocarbia
(end-tidal CO2 4 - 5.0 kPa; or PaCO2 4.5 - 5.5 kPa) to avoid the confounding
influences of hypotension and hypocarbia on Tc-MEPs.
In order to determine if a combination of pEEG and propofol concentration
(estimated effect-site concentration, or measured plasma concentrations) and/or
actual MAP during Tc-MEP registrations, better predict Tc-MEP characteristics
than the pEEG on its own, in total three blood samples will be taken (10 ml per
blood sample) immediately after each of the series of Tc-MEP recordings to
measure the propofol plasma concentrations. Propofol Ce values and MAP values
will be collected directly after each Tc-MEP measurement as well.
For investigating the incidence and severity of neurological deficits pre- and
post-operative neurological examination will be performed. When assuming
sufficient numbers of patients with postoperative neurological deficits we want
to determine the sensitivity and specificity of different thresholds of changes
in Tc-MEP amplitudes and to determine the influence of pEEG and MAP on the
sensitivity of decreased Tc-MEP amplitudes. During surgery, Tc-MEPs will be
performed, according to the standard use of care. Significant Tc-MEP amplitude
decreases, defined as a 50% decrease [4], and the pEEG and MAP values at
exactly the same time as the significant Tc-MEP amplitude decrease occurred,
will be collected.

Part 2: Effects of blood pressure on Tc-MEP characteristics during spinal
surgery
After induction of anaesthesia, and before the start of spinal surgery, the
anaesthesiologist will target a pEEG value of 40. A corresponding low MAP at
around 60 mmHg will hereby be accomplished. Slow infusion rates of
noradrenaline will slowly increase the MAP. At every 2 minutes, while
increasing the infusion rates, Tc-MEPs characteristics will be measured in the
tibialis anterior muscle left and right, the gastrocnemius muscle left and
right and the abductor hallucis muscle left and right. MAPs will be measured
continuously using an invasive arterial cannula. Throughout the recordings and
subsequent surgery, as per standard clinical protocols, propofol infusion rates
will be adjusted to maintain the pEEG between 40 and 60, and the ventilation
adjusted to maintain normocarbia (end-tidal CO2 4 - 5.0 kPa; or PaCO2 4.5 - 5.5
kPa) to avoid the confounding influences of excessive anaesthesia and
hypocarbia on Tc-MEPs.
In order to determine if a combination of MAP, with pEEG and/or propofol
concentration (estimated effect-site concentration, or estimated or measured
plasma concentrations) better predict Tc-MEP characteristics than the MAP on
its own, in total three blood samples will be taken (10 ml per blood sample) at
MAP values of approximately 60, 80 and 100 mmHg, to measure the propofol plasma
concentrations. Propofol Ce values and pEEG values will be collected directly
after each Tc-MEP measurement as well.
For investigating the incidence and severity of neurological deficits pre- and
post-operative neurological examination will be performed. When assuming
sufficient numbers of patients with postoperative neurological deficits we want
to determine the sensitivity and specificity of different thresholds of changes
in Tc-MEP amplitudes and to determine the influence of pEEG and MAP on the
sensitivity of decreased Tc-MEP amplitudes.
During surgery, Tc-MEPs will be performed, according to the standard use of
care. Significant Tc-MEP amplitude decreases, defined as a 50% decrease [4],
and the pEEG and MAP values at exactly the same time as the significant Tc-MEP
amplitude decrease occurred, will be collected.
*

Prolonged total anaesthesia time
Due to the study protocol the total anaesthesia time will be prolonged for
approximately 30 - 60 minutes. With a medium duration of major neurosurgical
and orthopaedic procedures of 4 - 7 hours this prolongation is not substantial.
There is no evidence that the duration of general anaesthesia will affect
outcome parameters such as pain, nausea and vomiting.