The effects of anesthesia on motor evoked potentials

Rationale:
For complex and high risk spinal surgery, intraoperative neurophysiological monitoring (IONM) is used in the University Medical Center Groningen (UMCG), with the aim to reduce intraoperative neurological injury. However anesthesia has its effects on the reliability of IONM. This research proposal wants to examine the effects of anesthesia 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 electrical stimulation MEPs (TES-MEPs).
In order to obtain reliable TES-MEPs, the TES-MEP threshold (the minimum voltage required to generate a TES-MEP) should be low and the recorded amplitude of the muscle contraction should be high. When reliable TES-MEPs are obtained the risk of surgery-induced neurological damage might decrease. Besides surgery-induced neurological damage, many other factors can also alter the TES-MEP threshold and the amplitude, including: anesthesia, blood pressure, body temperature and blood oxygen levels
It is known that for maintenance of general anesthesia a combination of propofol and an opioid provides more optimal TES-MEPs than other anesthetics. Nonetheless TES-MEPs are still very sensitive to the effects of propofol anesthesia. The effect of “depth of anesthesia”, quantified by a processed electroencephalogram (pEEG), on TES-MEPs has never been rigorously investigated.
Another major factor influencing TES-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 TES-MEP. Although anesthesiologists commonly administer vasopressors to elevate the blood pressure, it is not known whether these drugs improve or impair spinal cord perfusion and thus TES-MEPs amplitudes.
However, TES-MEPs are also influenced by blood loss, pain and manipulation/movements of the patient. Therefore, in order to examine the effects of different blood pressures defined by the mean arterial pressure (MAP) and different depths of anesthesia defined by pEEG, on TES-MEP measurements, with as few as possible confounding parameters, measurements should be performed after anesthetic induction and before surgical incision.
In conclusion, the aim of this research proposal is to investigate the effects of depth of anesthesia (part 1) and blood pressure (part 2) on TES-MEP measurements. By knowing the effects of depth of anesthesia and blood pressure on TES-MEPs we can obtain more reliable TES-MEP measurements causing a higher specificity when a TES-MEP decrease occurs and less false positive findings. Therefore surgically induced neurological damage can be detected and prevented more reliable.

Main objectives:
Part 1:
To determine the effect of depth of anesthesia, quantified by pEEG, on the characteristics of TES-MEP measurements in spinal surgery.
Hypothesis: lower depth of anesthesia, defined by higher values of pEEG will:
a. Decrease the threshold required to evoke a TES-MEP.
b. Increase the TES-MEP amplitude and the TES-MEP area under the curve (AUC).
Part 2:
To determine the effects of elevating the MAP with a vasopressor infusion on the characteristics of TES-MEP measurements in spinal surgery.
Hypothesis: a higher MAP will:
a. Reduce the threshold required to evoke a TES-MEP
b. Increase the TES-MEP amplitude and the TES-MEP AUC.

Study design:
A prospective observational pilot study. Patients will either participate in part 1 or part 2 of this study.
Study population:
All patients undergoing spinal surgery with the use of TES-MEP will be included in this study.

Main study parameters/endpoints:
Part 1:
The main study parameters of part 1 are TES-MEP thresholds, TES-MEP amplitudes and TES-MEP AUC of the leg muscles, associated with different depths of anesthesia, defined by different pEEG values (30, 40 and 50).
Part 2:
The main study parameters of part 2 TES-MEP thresholds, TES-MEP amplitude and TES-MEP AUC of the leg muscles, this time associated with different blood pressures, while the MAP is elevated from 60 to 100 with a vasopressor infusion.

Part 1: effect of depth of anesthesia on motor evoked potentials in spinal surgery
Primary Objective:
To determine the effect of depth of anesthesia, quantified by pEEG, on the characteristics of TES-MEP measurements in spinal surgery.
Hypothesis: lower depth of anesthesia, defined by higher values of pEEG will:
a. Decrease the threshold required to evoke a TES-MEP.
b. Increase the TES-MEP amplitude and the TES-MEP area under the curve (AUC).
Secondary Objective 1:
To determine if a combination of pEEG and propofol concentration (estimated effect-site concentration, or measured plasma concentrations) and/or actual MAP during TES-MEP registrations, better enable prediction of TES-MEP characteristics than pEEG alone.
Hypothesis:
a. pEEG values alone enable better prediction of TES-MEP characteristics than propofol concentrations alone.
b. pEEG alone is as good as a more complex model involving pEEG, propofol concentrations and MAP, at enabling prediction of TES-MEP characteristics.
Secondary objective 2:
a. To formally quantify the incidence and severity of neurological deficits among the patients included in the study.
b. Assuming sufficient numbers of patients with postoperative neurological deficits, a secondary objective will be to determine the sensitivity and specificity of different thresholds of changes in TES-MEP amplitudes for prediction of outcome.
c. Assuming sufficient numbers of patients with postoperative neurological deficits, a further secondary objective will be to determine the influence of pEEG and MAP values on the sensitivity and specificity of decreased TES-MEP amplitude for prediction of outcome. The specific research question is whether reduced TES-MEP amplitudes are more predictive of adverse outcome when pEEG and MAP are within the currently defined optimal ranges (pEEG 40 – 60, and MAP 70 – 90 mmHg).
Hypothesis: Higher pEEG and MAP values result in a higher proportion of post-operative worsened neurological outcome after a significant TES-MEP amplitude decrease.
Secondary objective 3:
To determine the effects of depth of anesthesia, as quantified by pEEG, on the characteristics of SSEPs.
Hypothesis: lower depth of anesthesia, defined by higher values of the pEEG will not affect SSEP amplitude and/or latency.

Part 2: effect of elevating blood pressure on motor evoked potentials in spinal surgery
Primary Objective:
To determine the effects of elevating the MAP with a vasopressor infusion on the characteristics of TES-MEP measurements in spinal surgery.
Hypothesis: a higher MAP will:
a. Reduce the threshold required to evoke a TES-MEP
b. Increase the TES-MEP amplitude and the TES-MEP AUC.
Secondary Objective 1:
To determine if a combination of MAP, with pEEG and/or propofol concentration (estimated effect-site concentration, or estimated or measured plasma concentrations) better enables prediction of TES-MEP characteristics than the MAP on its own.
Hypothesis:
a. Within the specified range of pEEG (40 – 60), MAP has a greater effect than depth of anesthesia (pEEG) on TES-MEP characteristics.
b. MAP is as good as a more complex model involving MAP, propofol concentrations and pEEG, at predicting TES-MEP characteristics.
Secondary objective 2:
a. To formally quantify the incidence and severity of neurological deficits among the patients included in the study.
b. Assuming sufficient numbers of patients with postoperative neurological deficits, a secondary objective will be to determine the sensitivity and specificity of different thresholds of changes in TES-MEP amplitudes for prediction of outcome.
c. Assuming sufficient numbers of patients with postoperative neurological deficits, a further secondary objective will be to determine the influence of pEEG and MAP values on the sensitivity and specificity of decreased TES-MEP amplitude for prediction of outcome. The specific research question is whether reduced TES-MEP amplitudes are more predictive of adverse outcome when the pEEG and MAP are within the currently defined optimal ranges (pEEG 40 – 60, and MAP 70 – 90 mmHg).
Hypothesis: Higher pEEG and MAP values result in a higher proportion of post-operative worsened neurological outcome after a significant TES-MEP amplitude decrease.
Secondary objective 3:
To determine the effects of blood pressure, as quantified by the MAP, on the characteristics of SSEPs.
Hypothesis: Higher MAP values will not affect SSEP amplitude and/or latency

- Before hospital admission, patients will be informed about either part 1 or part 2 of the study.
- One day before surgery patients will sign the informed consent and get included in either part 1 or part 2 of the study. Pre-operative neurological examination will be performed, consisting of motor and sensory tests, pain scores and the cranial nerves will be tested.
- After anesthetic induction but before surgical incision TES-MEP measurements at different pEEG or MAP values will be performed. This will take 30-45 minutes.
- At every predefined pEEG value (30, 40, 50) or MAP value (60, 80, 100), blood samples will be taken to measure the propofol blood concentrations.
- After surgical incision and during surgery, data of propofol Ce, MAP and pEEG values immediately after TES-MEP measurements will be collected.
- If a significant TES-MEP amplitude decrease occurs, the pEEG and MAP values will be collected from exactly the moment of the significant amplitude decrease.
- 2-5 days postoperatively, neurological examination will be performed.

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