Effect of Reversal of Neuromuscular Blockade on the Amplitude of Motor Evoked Potentials: A Randomized Controlled Crossover Study Comparing Sugammadex and Placebo
Phase: PHASE4
Conditions: Posterior Cervical Decompression and Fusion
Sponsor: University Health Network, Toronto

 
 
 
 
 
 
Effect of reversal of neuromuscular blockade 
on the amplitude of motor evoked potentials:   
A randomised controlled cross-over study 
comparing sugammadex and placebo 
 
 
 
Protocol Version: 1.0 
Protocol Date: 20 April 2018 
ClinicalTrials.gov ID: NCT03087513 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ClinicalTrials.gov ID: NCT03087513 
Motor Evoked Potentials RCT Version 1.0 20 April 2018 
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Effect of reversal of neuromuscular blockade on the amplitude of 
motor evoked potentials: A randomised controlled cross-over study 
comparing sugammadex and placebo 
 
Investigators 
 
 
1. Nathan Royan MBBS FANZCA. Department of Anaesthesia, 
Toronto Western Hospital, University of Toronto 
 
2. Lashmi Venkatraghavan MD, FRCPC. Department of 
Anaesthesia, Toronto Western Hospital, University of Toronto  
 
3. Atul Prabhu FRCA, FRCPC. Department of Anaesthesia, Toronto 
Western Hospital, University of Toronto 
 
4. Pirjo Manninen MD, FRCPC, Department of Anaesthesia MD, 
Toronto Western Hospital, University of Toronto 
 
5. Gina Bastaldo MSc CNIM. Department of Surgery and 
Anaesthesia, Toronto Western Hospital, University of Toronto  
 
6. Roger Sarjeant MSc CNIM, Department of Surgery and 
Anaesthesia, Toronto Western Hospital, University of Toronto  
 
7. Eric Massicotte MD, MSc, FRCS (C), Division of Neurosurgery, 
Toronto Western Hospital, University of Toronto 
 
 
1. Project Summary 
 
Intraoperative monitoring of the motor evoked potentials has been 
shown to be both a sensitive and specific indicator for detecting 
intraoperative neurologic injuries during spine surger y.(Fehlings, 
Brodke et al. 2010) It is utilised whenever there is risk for injury of 
nerve roots or the spinal cord during the procedure.  
 
Anaesthetic agents, especially the inhaled volatile anaesthetics and 
muscle relaxants, are confounders for motor evoked potential 
monitoring as they have deleterious effects on the amplitude of motor 
evoked potentials.(Sekimoto, Nishikawa et al. 2006) Hence, total 
intravenous anaesthesia with no intraoperative muscle relaxants, are 
the standard anaesthetic technique for these surgeries.  
 
Muscle relaxants are usually required during the induction of 
anaesthesia and endotracheal intubation of larynx. Current practice is 
to wait for the resolution of residual neuromuscular blockade before 
the motor evoked potential recordings (MEPs) are initiated and this 
makes it difficult to assess if there was any neurological injury 
associated with positioning of the patient. A previous case series has 

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shown that reversal of muscle relaxant can improve the amplitude of 
MEPs.(Batistaki, Papadopoulos et al. 2012)  
 
The aim of this study is to perform a randomised controlled t rial to 
study the changes in motor evoked potential amplitudes comparing 
sugammadex and placebo. 
 
2. Background 
 
Intraoperative monitoring (IONM) is most frequently employed in 
patients where the spinal cord or nerves are considered at risk. This 
may be evident through patient symptoms, pathological process or 
appearance on imaging.  
 
Trained neurophysiologists that work in concert with the surgeon and 
anaesthesiologist perform the intraoperative monitoring. The 
monitoring commences once the patient has received general 
anaesthesia. Small electrodes are placed under the skin of the scalp and 
peripheries and different electrical stimuli are delivered to evoke a 
measured response. The neurophysiologist is able to monitor different 
potentials (motor evoked potentials, somatosensory evoked potentials, 
electromyography) and assess for a significant change.  
 
Motor evoked potential monitoring is a well-established and safe 
intervention to assist in prevention of intraoperative injury during 
spine surgery.(Schwartz, Sestokas et al. 2011) There is no current 
consensus for criteria for change in amplitude for trans -cranial motor 
evoked potential monitoring. The peak-peak amplitude of the baseline 
motor evoked potential is utilised as a monitoring tool during surgery.  
The smaller the change in amplitude that is utilised as alarm criterion 
the more false positives that will be conveyed to the surgeons.  (Legatt, 
Emerson 2016) Our neurophysiologists use a decrease in the amplitude 
by more than 50% or loss of the signal as a trigger to warn the surgeon 
of potential development of a neurological insult or injury.  
 
The usual anaesthetic practice at our institution for patients undergoing 
posterior cervical spine surgery is to administer muscle relaxation to 
aid intubation at the start of the case and occasionally small doses of 
rocuronium (10-20mg) prior to turning the patient prone. The 
neuromuscular blockade is then allowed to wear off and the 
neurophysiologist will attempt to record their baseline motor evoked 
potentials during or just prior to surgical exposure.  
 
A peripheral nerve monitor may be used to monitor the degree of 
residual neuromuscular blockade. This is standard anaesthetic 
equipment with the most common mode to assess residual blockade 
used being a train of four count. This involves adhesive dots applied 
over the ulna nerve and a current applied (approximately 70 -80mA) in 
a train of four impulses 0.5 seconds apart with a pulse width of 250 
microseconds. It is a safe method of assessing the occupancy of 

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acetylcholine receptors at the neuromuscular junction by observing the 
number of twitches displayed in the peripheral muscle (e.g thumb 
movement). 
 
Number of twitches 
 
0- 100% receptors blocked 
1- 90% receptors blocked 
2- 75-80% receptors blocked 
3- 75% receptors blocked 
4- 0% receptors blocked 
 
For the purposes of our study we plan to continuously monitor the train 
of four count and ratio using a peripheral nerve stimulator  module that 
is built into the anesthesia machine (GE Datex Ohmeda) . The train of 
four count on both measuring tools will be delivered as a train of four 
impulses 0.5 seconds apart (2Hz) at 70-80mA with a pulse width of 250 
microseconds. 
 
Our current approach does not involve routine measurement of the 
degree of residual neuromuscular blockade with a peripheral  nerve 
stimulator. This is a safe approach as monitoring is achievable with 
partial blockade but may not necessarily be most beneficial in patients 
with existing neurological impairment as complete reversal of 
neuromuscular blockade is not ensured.(Li, Song et al. 2010)  
 
The issues with this current technique are;  
 
a) Patients cannot be monitored for neurological changes during 
their transfer into the prone position 
b)  There is likely residual neuromuscular blockade decreasing the 
amplitude of motor evoked potentials 
 
A cases series of 10 patients in healthy subjects undergoing lumbar 
spine surgery demonstrated a 74% increase in mean amplitude of the 
MEPs with reversal of neuromuscular blockade with sugammadex 
2mg/kg.(Batistaki, Papadopoulos et al. 2012) 
 
We plan to perform a randomised controlled cross over trial comparing 
the change in MEP amplitudes with administration of sugammadex or 
placebo. This will be performed on at risk patients (e.g. cervical 
myelopathy) undergoing posterior cervical spine surgery where MEPs 
can be more difficult to attain but of higher utility. (Kombos, Kopetsch 
et al. 2003) 
 
The crossover arm of the trial is to enable patients to function as their 
own control group. During surgical closure patient will remain on a 
total intravenous anaesthesia (propofol and remifentanil). When the 
patient returns to a train of four count of 2 or more on peripheral nerve 
monitor repeat motor evoked potentials will then be recorded and 

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patients will receive the alternate drug to the one received in the initial 
arm of the trial.  
 
The purpose of this study is to determine the increase in amplitude of 
the motor evoked potentials when residual neuromuscular blockade is 
reversed with sugammadex or placebo.  
 
4. Hypothesis 
 
We hypothesize that reversal of neuromuscular blockade by 
sugammadex will increase the amplitude of motor evoked potentials 
compared with placebo.  
 
5. Significance of the study 
 
Facilitating increased amplitudes of MEPS via reversal of residual 
neuromuscular blockade will enable increased accuracy of monitoring. 
 
Providing the option of reversal of neuromuscular blockade will allow 
MEPs to be monitored during patient positioning to prevent placing 
them in a neurologically compromising position.  
 
6. Methods 
 
6.1 Research Design 
 
This is a prospective, single centre, triple blinded randomised 
controlled cross-over trial. Patients who are scheduled for an elective 
posterior cervical spine procedure in prone position and require motor 
evoked potential monitoring (MEPs) will be included. Patients will be 
randomised to assign to one of the following treatment sequences: 
sugammadex followed by placebo, or vice versa. The primary outcome 
is the change of MEP amplitude of the first dorsal interossei from 
baseline 3 minutes after administration of the allocated intervention. 
The patients, anesthesiologists and neurophysiologists (outcome 
assessor) will be blinded for the allocated intervention group.  
 
The first study intervention will be performed after the patients are 
positioned in prone with a train of four count of 2 and satisfactory 
baseline motor evoked potentials have been recorded. This will likely 
occur during or just prior to surgical exposure.  
 
The second study intervention will be performed during surgical 
closure. This will be once the surgeons have completed their use of 
motor evoked potentials and the patient remains on total intravenous 
anaesthesia (propofol and remifentanil). A minimum washout period of 
100 min after the last bolus dose of rocuronium (equivalent to 5 half 
lives) is required and the completeness of washout will be confirmed 
with no residual tetanus fade, fade on train of four (or fading in double 
burst stimulation) on a peripheral nerve stimulator. The operative time 

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of posterior cervical spine procedure is usually around 3 hours and 
should allow complete washout of rocuronium. After the preconditions 
are achieved on peripheral nerve stimulator or the direct train of four 
monitor, the second intervention (either sugammadex or placebo) will 
be administered. 
 
On each occasion the increase in amplitude of the motor evoked 
potential of both upper and lower limbs will be assessed at 3,6,9,12 
and 15 minutes post intervention. 
 
6.2 Trial Population 
 
The study participants will be recruited from patients admitted to 
Toronto Western Hospital for elective posterior cervical spine surgery 
requiring motor evoked potential monitoring as per the admitting 
surgeon. 
 
Inclusion criteria 
 
- 
All adult patients aged 18-80 years with ASA class I-III 
undergoing cervical spine surgery in the prone position with 
motor evoked potential monitoring.  
- 
Operation time greater than 3 hours 
 
Exclusion criteria 
 
- 
Allergy to propofol or documented egg allergy 
- 
Known allergy to sugammadex 
- 
Severe renal dysfunction (EGFR<30) 
- 
British Research Medical Council (BRMC) motor grading <3 in 
any peripheral muscle group pre-operatively. This is inability to 
move the muscle group against gravity.  
- 
Surgical requirement of strict muscle relaxation for surgical 
exposure  
- 
Lack of informed consent 
- 
Pregnancy 
- 
Loss of MEPs signals during washout period (or intraoperative 
spinal cord injury resulting in irreversible loss of MEP)  
 
6.3 Recruitment 
 
All patients who are admitted to Toronto Western Hospital and satisfy 
the above criteria will be considered for enrolment into the study. 
Informed consent will be sought as detailed in section 12. A record 
will be kept of all eligible patients who are not enrolled and reasons 
for non-enrolment. 
 
6.4 Randomisation Method 
 

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Enrolled patients will be randomised according to a computer based, 
permuted block randomisation method, with a 1:1 allocation ratio and a 
variable block size of 4-6. 
 
6.5 Allocation Concealment 
 
Sequentially numbered, opaque, sealed envelopes will be used for 
allocation schedules and individual assignments. The study envelope 
will be opened at the beginning of each case by a trained research 
assistant and the reversal drugs will be prepared. 
 
6.6 Blinding 
 
This is a randomised blinded study where the administering 
anaesthetist, surgeon and neurophysiologists will be blinded to the 
intervention. The study patients will receive a 10ml syringe containing 
either sugammadex or placebo (saline 0.9%) to be administered in a 
1mls per 10kg basis (up to 100kg).  
Further, a blinded research assistant will perform assessment, data 
collection, and analysis of neurophysiology data attained.  
 
7. Protocol 
 
7.1 Standard Perioperative Care 
 
Routine standard preparation of the patients will be carried out as per 
our institutional standard for patients undergoing spine surgery. All 
routine physiological monitoring (e.g. ECG, invasive arterial blood 
pressure, Sp02, end tidal C02, temperature and depth of anaesthesia 
monitoring) will be performed. 
 
The induction of anaesthesia will be performed with propofol (2 -5 
mg/kg), fentanyl (2-3mcg/kg) and rocuronium (0.6mg/kg) following 
calibration of the peripheral nerve stimulator. The patient’s trachea 
will be intubated once the peripheral nerve stimulator shows no 
twitches. The time of induction and rocuronium dose must be strictly 
recorded. After tracheal intubation the lungs will be ventilated to 
maintain a PaC02 between 33-35mmHg.  Maintenance of anaesthesia 
will be with desflurane inhalational anaesthesia titrated to entropy 40-
60 until final operative position is achieved. 
 
Hemodynamic management will target a mean arterial pressure (MAP) 
>70 mmHg using standard inotropes and/or vasopressors (e.g. 
phenylephrine and ephedrine) 
 
Prophylactic antibiotics and dexamethasone will be administered as per 
surgical request and institutional practice. Analgesia should be 
administered with fentanyl in additional 25mcg boluses up to the 
completion of surgical exposure and then left to clinical judgement 

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there-onwards. Anti-emetics should be administered as per the 
anaesthesiologist practice. 
 
Patients should undergo peripheral nerve monitoring following the 
induction via a peripheral nerve stimulator and by a direct train of four 
monitor by the neurophysiologists.  
 
On completion of the cross over arm of the trial, the patient may be 
changed to volatile anaesthesia as per institutional practice and 
extubated based on anaesthesiologist clinical judgement. Use of a 
nerve stimulator to assess the train of four count with reversal of 
residual neuromuscular blockade with neostigmine and glycopyrrolate 
if deemed appropriate at the end of the case is recommended.  
 
Post-operative anaesthetic care will occur in the recovery room as per 
standard practice in terms of oxygen therapy, monitoring and 
assessment of neurological status, pain, nausea, vomiting and degree of 
sedation. Fentanyl 25mcg iv will be administered every 5 mins up to a 
maximum of 200mcg to maintain a Numeric Pain Score <4 of 10. 
Morphine or Hydromorphone will be used for additional analgesia after 
fentanyl. Nausea may be managed with dimenhydrinate 25-50mg IV 
and ondansetron 4m IV. 
 
7.2 Study Protocol 
 
Patients should undergo peripheral nerve monitoring following the 
induction via a peripheral nerve stimulator and by a direct train of four 
monitor by the neurophysiologists. The train of four should be assessed 
on peripheral nerve stimulator and on the neurophysiology monitoring 
prior to turning the patient prone. If the patient has two or more 
twitches on either monitoring they should be given 0.1mg/kg 
rocuronium prior to positioning prone.  
 
Once the patient is in their final position for surgery the anaesthetic 
will be changed to a total intravenous anaesthetic (TIVA) with 
propofol and remifentanil titrated to entropy of 40-60. The volatile 
anaesthesia has to be washed out with high flows of 10L/min until end 
tidal desflurane is less than or equal to 0.2. 
 
When the above conditions are met the train of four count (TOFC)  will 
be checked by the anaesthesiologist.  When the TOFC is 2 or more the 
baseline motor evoked potentials (bMEPs) will be performed. 
 
Following the bMEPs the anaesthesiologist will administer the reversal 
drug (either sugammadex 2mg/kg in 10 ml syringe or matching 
placebo). This time must be strictly recorded, as it is the time that has 
elapsed since the induction dose of muscle relaxant. The 
neurophysiologist will perform and record MEPS at 3,6 and 9 minutes 
post reversal dose. The following parameters will continuously be 
monitored during the study period:  TOFC, Entropy, BP, HR, CO2, 

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peak airway pressures, anaesthetic infusion rates, temperature and 
oxygen saturation. If the testing occurs during surgical exposure it is 
important to ask the surgeons to make a very brief pause to allow the 
motor testing to be performed and to check the entropy at the same 
time. 
 
Following surgery commencement there will be a surgical grading of 
the relaxation of the surgical field once exposure attained and 
collection of surgeon stated observation of patient movement.  
 
The operative time of posterior cervical spine procedure is usually 
around 3 hours and should allow for complete washout of rocuronium. 
A minimum washout period of 100 min after the last bolus dose of 
rocuronium (equivalent to 5 half-lives) is required and the 
completeness of washout will be confirmed with no residual tetanus 
fade, no fade on train of four (or fading in double burst stimulation) on 
a peripheral nerve stimulator.  
 
The crossover arm of the trial will occur during surgical closure at the 
end of the operation when the surgeons have finalised their use of the 
monitoring and the patients are still receiving total intravenous 
anaesthesia (propofol and remifentanil). If needed, each patient will be 
given 0.1mg /kg rocuronium to facilitate surgical closure. When the 
train of four count is of 2 or more the patients will be administered the 
cross-over drug (placebo if received sugammadex initially and vice 
versa) and the motor evoked potentials and same anaesthetic variables 
as above will be recorded for 3,6 and 9 minutes post cross-over dose. 
 
8. Assessment 
 
8.1 Baseline Measurements 
 
At the time of enrollment, the following data will be collected for all 
participants: patient demographics, preoperative neurological function, 
comorbidities, allergies, baseline physiological variables (blood 
pressure, heart rate, O2 saturations, weight) and procedure details.  
 
8.2 Outcome Measurements 
 
Primary Outcome Measure 
 
The primary outcome measure is the increase in amplitude of the motor 
evoked potential measurements of the first dorsal interosseus muscle at 3 
minutes following reversal of residual muscle relaxation with either 
sugammadex or placebo. 
 
Secondary Outcome Measures 
 
- 
Changes in the amplitude of the MEPs from the baseline in the 
first dorsal interosseous muscle at 6 and 9 minutes  

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- 
Side effects of reversal (hemodynamic changes, respiratory 
changes, surgeon observed patient movement, requirement for 
additional muscle relaxation and the anesthetic agents] 
- 
Grading of relaxation of the surgical field by the surgeons using 
a four-point Likert scale (poor, acceptable, good and optimal) .   
 
9. Data Collection and Management 
 
9.1 Data Collection 
 
The following data will be collected (see attached Data Collection 
Form): 
 
Administrative Data 
 
Screening log- detailing numbers of potential participants screened for 
inclusion and reasons for exclusion and numbers actually recruited.  
 
Demographic data 
 
Age, sex, height, weight, American Society of Anaesthesiologists 
physical class (ASA) 
 
Study Data 
 
Baseline data as detailed in section 8 
Outcome data as defined in section 8 
 
9.2 Data Management 
 
An electronic data management system will be used. All data wil l be 
entered directly on the electronic system. Data will be acquired on a 
Research laptop and also the Monitoring Laptop of the 
neurophysiologist. Following the case, data will be transferred from 
the Neurophysiologist laptop to the Research database wher e it will 
later be analysed. 
Pre specified automated data entry checks will be performed on all 
entered data to prevent the entry of impossible values or the omission 
of key data fields. All study databases will be in the password 
protected UHN server. Any data containing participant identifying 
details will be stored separately and securely from study documents.  
 
10. Sample Size 
 
10.1 Hypotheses 
 
Null Hypothesis- There is no difference between the amplitude of the 
baseline motor evoked potentials before and after reversal with 
sugammadex or placebo. 
 

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Alternative Hypothesis- There is a difference in the amplitude of the 
baseline motor evoked potentials before and after reversal with 
sugammadex or placebo. 
 
10.2 Sample size 
 
A previous observational study reported sugammadex increased the 
amplitude of MEP by 74% (Batistaki, Papadopoulos et al. 2012). The 
normal upper limb MEP amplitude (first dorsal interosseus) is 2000 +/- 
1600 microV from a previous published cross-over study in MEP 
(Chong, Manninen et al. 2014). Based on the assumption that the 
within-patient standard deviation of the MEP amplitude is 1600 microV 
and a power of 80%, a total of 30 patients is required in this two-
intervention crossover study for detecting a treatment difference of 
1200 microV (60% increment) at a two-sided 0.05 significance level. 
The sample size will be increased to 40 patients (20 patients per group) 
to cater for a potential 15-25% drop-out rate during the study. 
 
11. Analysis 
 
Statistical analysis will be performed using SPSS statistical software 
(version 14). The data distributions will be tested for normality with 
the Kolmogorov–Smirnov test. Descriptive statistics will be 
summarised as mean (± SD), median [Interquartile range (IQR)] or 
number (%) as indicated. The Mann-Whitney U test will be performed 
to compare the amplitude values of the two groups. TOF count, grades 
of surgical relaxation will be compared using the Chi-square test or 
Fisher’s exact test according to the expected counts.  In all cases, a P -
value of 0.05 will be considered statistically significant. 
 
12. Ethical aspects 
 
12.1 Regulatory approval 
 
Regulatory approval will be sought from the local research ethics board 
and the study will not commence until it is obtained. 
 
12.2 Informed consent 
 
Prior to enrolment potential participants will receive written and verbal 
information regarding the nature and purpose of the study, what 
participation involves and potentials benefits and risks. They will  be 
given time to ask questions and it will be emphasised that participation 
is voluntary, that they are free to withdraw from the study at any time 
and that any decision to do so will not affect any treatment they would 
otherwise receive. Where the participant understands and accepts these 
terms, they will be asked to sign the consent form. 
 
12.3 Privacy and Confidentiality 
 

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The laptop and all data transferred to the research database used in the 
study will contain only de-identified data and it will be encrypted as 
per UHN policy 1.40.006 Storage, Transport and Destruction of 
Confidential Information. 
 
References 
 
Batistaki, C., et al. (2012). Sugammadex to reverse rocuronium and facilitate 
intraoperative motor evoked potentials monitoring during spinal surgery. Anaesth 
Intensive Care 40(6): 1073-1074. 
 
 
Chong, C. T., et al. (2014). Direct Comparison of the Effect of Desflurane and 
Sevoflurane on Intraoperative Motor-evoked Potentials Monitoring. Journal of 
Neurosurgical Anesthesiology 26(4): 306-312. 
 
 
Fehlings, M. G., et al. (2010). The evidence for intraoperative neurophysiological 
monitoring in spine surgery: does it make a difference? Spine (Phila Pa 1976) 35(9 
Suppl): S37-46. 
 
 
Kombos, T., et al. (2003). Does preoperative paresis influence intraoperative 
monitoring of the motor cortex? J Clin Neurophysiol 20(2): 129-134. 
 
 
Li, C. X., et al. (2010). Effect of the degree of muscle relaxation on motor-evoked 
potential elicited by transcranial electrical stimulation in spine surgery. Nan Fang Yi 
Ke Da Xue Xue Bao 30(12): 2686-2688. 
 
 
Plummer-Roberts, A. L., et al. (2016). Residual Neuromuscular Blockade. Aana j 
84(1): 57-65. 
 
 
Schwartz, D. M., et al. (2011). Transcranial electric motor evoked potential 
monitoring during spine surgery: is it safe? Spine (Phila Pa 1976) 36(13): 1046-1049. 
 
 
Sekimoto, K., et al. (2006). The effects of volatile anesthetics on intraoperative 
monitoring of myogenic motor-evoked potentials to transcranial electrical stimulation 
and on partial neuromuscular blockade during propofol/fentanyl/nitrous oxide 
anesthesia in humans. Journal of Neurosurgical Anesthesiology 18(2): 106-111. 
 
Alan D. Legatt, Ronald G. Emerson, Charles M. Epstein, David B. MacDonald, 
Vedran Deletis, k Ricardo J. Bravo, and Jaime R. López A (2016). CNS Guideline: 
Transcranial Electrical Stimulation Motor Evoked Potential Monitoring J Clin 
Neurophysiol 33: 42–50.