Train-of-four Monitoring Using the Tetragraph Neuromuscular Transmission Monitor and Comparison to Standard (Visual) Train-of-four Assessment With a Peripheral Nerve Stimulator
Phase: NA
Conditions: Surgery
Sponsor: Joseph D. Tobias

 
Train-of-four Monitoring Using the Tetragraph Neuromuscular Transmission 
Monitor and Comparison to Standard (Visual) Train-of-four Assessment 
With a Peripheral Nerve Stimulator   
 
 
NCT04475250 
 
 
November 7, 2022 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
Page 1 of 12 
HRP-503  v.12.10.18 
PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM 
Neuromuscular Transmission Monitor and comparison to standard (visual) train-of-four 
assessment with a peripheral nerve stimulator 
 
PRINCIPAL INVESTIGATOR: 
Name: Joseph Tobias, MD 
Department/Center: Anesthesiology & Pain Medicine 
Telephone Number: 614-722-4200 
Email Address: Joseph.Tobias@nationwidechildrens.org 
 
VERSION NUMBER/DATE: Version 3 – November 7, 2022 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent Change? 
2 
1/21/2022 
Increasing the number of 
subjects to 200, removing the 
weight stratification and lower 
weight limit, changing the time 
that identifying info will be kept 
to 6 years to meet NCH 
guidelines. 
Yes 
3 
11/7/2022 
Correcting spelling of device 
name. Adding recent FDA 
approval in children.  Adding an 
additional cohort of 50 subjects 
that will have TetraGraph™ 
sensor applied to the arm and 
foot simultaneously. Total 
sample size of 200 unchanged. 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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HRP-503  v.12.10.18 
1.0 
Study Summary 
 
Study Title 
Train-of-four monitoring using the Tetragraph Neuromuscular 
Transmission Monitor and comparison to standard (visual) train-
of-four assessment with a peripheral nerve stimulator 
 
Study Design 
Prospective, non-blinded comparative study 
Primary Objective 
The primary objective of this study is to evaluate the use of the 
Tetragraph Neuromuscular Transmission Monitor in pediatric-
sized patients (≤60 kilograms) and to evaluate its utility 
determining sugammadex dosing 
Secondary Objective(s) 
To compare the difference in sensitivity between the arm 
placement and foot placement. 
Research Intervention(s)/ 
Investigational Agent(s)  
There will be no change in anesthetic management or use of 
investigational pharmacological agents.    
IND/IDE #  
Not applicable 
Study population 
Patients who are scheduled for elective, urgent or emergent 
surgery 
Sample size 
200  
Study duration for 
individual participants 
Duration of the surgical procedure (2-10 hours) 
Study Specific 
Abbreviations/ Definitions  
TOF = train-of-four 
NMBA = neuromuscular blocking agent 
MAP = muscle action potential 
EMG = electromyograpy 
 
2.0 
Objectives 
2.1 
The primary objective of this study is to evaluate the efficacy of TOF 
monitoring using the Tetragraph Neuromuscular Transmission Monitor in 
pediatric sized patients and to determine its utility in determining sugammadex 
dosing. 
2.2 
The secondary objective it to evaluate any difference between placing the 
TetraGraph™ sensor on the arm and hand versus placing it on the ankle and foot. 
 
3.0 
Background 
3.1 
The neuromuscular junction consists of the nerve terminal, the postsynaptic 
muscle end plate (sarcolemma), and the intervening gap. An action potential 
reaching the end of the neuron triggers the release of acetylcholine from synaptic 
vesicles. Acetylcholine then diffuses across the gap to the postsynaptic end plate, 
where nicotinic acetylcholine receptors are clustered. These receptors convert the 
chemical signal into an electrical impulse, causing depolarization in the 
postsynaptic membrane, release of calcium from the sarcoplasmic reticulum, and 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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HRP-503  v.12.10.18 
muscle contraction. The action of acetylcholine is terminated by its passive 
dissociation from receptors, diffusion away from the end plate, and enzymatic 
degradation by acetylcholinesterase.  
Neuromuscular blocking agents are commonly used during anesthetic care to 
facilitate endotracheal intubation or provide muscle relaxation during surgical 
procedures. These agents (non-depolarizing NMBAs) competitively inhibit the 
binding of acetylcholine to the sarcolemma thereby inhibiting skeletal muscle 
function. During clinical care, when neuromuscular blockade is no longer required, 
these agents are reversed, most commonly with a medication known as 
sugammadex which encapsulates the NMBA, resulting in cessation of its 
pharmacological effects. 
The dosing of these medications is guided by monitoring neuromuscular 
transmission by use a peripheral nerve stimulator.  This monitor stimulates the 
nerve (two impulses per second for two seconds) generating what is known as a 
TOF response.  This monitor is routinely used during anesthetic care when 
NMBAs are in use. The electrodes are placed over a peripheral nerve and the 
number of twitches in the distal innervated muscle groups (hand) are noted when 
the device is activated. The number of twitches (0-4) is based on the receptor 
occupancy ratio of the NMBA. The response (number of twitches of the TOF) is 
used to judge the need for redosing of NMBAs as well as efficacy of reversal when 
sugammadex is administered. In clinical practice, the TOF is viewed by visual 
observation thereby leading to concerns that its use may be relatively inaccurate. 
Additionally, since up to 70-80% of receptors must be occupied before any change 
in the TOF is noted, the device is relatively insensitive.  Although easy to use and 
part of our current clinical care, it has been shown that newer devices may be more 
accurate and useful in clinical care. 
3.2 
The TetraGraphTM provides an electrical stimulation of the peripheral nerve 
in the same way as a standard peripheral nerve stimulator, but instead of relying 
on visual observation of the twitch response, it directly measures the amplitude of 
the evoked response of the muscles (Muscle Action Potential or MAP), thereby 
providing a quantitative and automatic measurement of muscle response to a 
stimulus using electromyography (EMG).  This avoids the visual observation of 
the twitch response and its potential inaccuracy. The device also allows a more 
sensitive measure of the EMG thereby providing information with less receptor 
occupancy than is needed to result in changes in the standard TOF. The device has 
been tested, validated, and approved for use in adults and children greater than 1 
month of age   
3.3 
 Most of the research that has been documented using the TetraGraph™ has 
been done by stimulating the nerves and the muscles in the hand.  New anecdotal 
evidence has shown that it may be feasible to placement the monitor on the foot 
and generate an EMG.  This may provide better EMG readings than using the arm 
in smaller children. 
• Murphy GS. Neuromuscular monitoring in the perioperative 
period. Anesth Analg. 2018;126:464-468. 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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HRP-503  v.12.10.18 
• Naguib M, Brull SJ, Johnson KB. Conceptual and technical 
insights into the basis of neuromuscular monitoring. 
Anaesthesia 2017;72(Suppl. 1):16-37. 
• Brull SJ, Eriksson L. The French Guidelines on muscle 
relaxants and reversal in anaesthesia: The chain is finally 
broken and the soul is freed. Anaesth Crit Care Pain Med 
2020;39:31-33. 
• Biro P, Paul G, Dahan A, Brull SJ. Proposal for a revised 
classification of the depth of neuromuscular block and 
suggestions for further development in neuromuscular 
monitoring. Anesth Analg 2019;128:1361-1363 
 
4.0 
Study Endpoints 
4.1 The primary study endpoint is to evaluate the efficacy and feasibility of using 
the TetraGraph™ monitor in pediatric-sized patients (≤60 kilograms). The 
study will evaluate the ability of the monitor to generate, record, and evaluate 
the EMG. We will compare the new device with standard visual TOF 
monitoring using a peripheral nerve stimulator. 
 
5.0 
Study Intervention/Investigational Agent 
5.1 The only novel intervention is the use of the TetraGraph™ device to monitor 
neuromuscular blockade. No change in the anesthetic technique will be 
required during the study. When NMBAs are administered, standard practice 
includes the use of a peripheral nerve stimulator with visual TOF monitoring. 
The study will include only patients scheduled for a surgical procedure that 
requires uses of NMBAs. The TetraGraph™ will be placed on one extremity 
and the standard peripheral nerve stimulator will be placed on a different 
extremity. 
5.2 In a cohort of 50 subjects, the TetraGraph™ sensor will be placed on both an 
upper and lower extremity and simultaneous measurements will be recorded 
using two monitors. 
 
6.0 
Procedures Involved* 
6.1 This is a prospective study that will evaluate the feasibility of using 
the TetraGraph™ in smaller pediatric patients (≤60 kilograms).  
6.2 The study cohorts will include patients requiring anesthetic care and 
use of neuromuscular blockade. The device, which is FDA-approved 
for use in adults and children, will be attached to an extremity and data 
recorded by the device as it stimulates the nerve and generates the 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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EMG from the muscle. Data is recorded every 20 seconds by the 
TetraGraph™ based on its normal functioning parameters.  
6.3 We will also compare data from the standard peripheral nerve 
stimulator and the TetraGraph™. Specifically, we will compare the 
visual TOF ratio obtained from the peripheral nerve stimulator and the 
one recorded from the Tetragraph at 5-15 minute intervals and at the 
time that reversal of neuromuscular blockade is required 
(administration of sugammadex). 
6.4 The additional cohort of 50 subjects will allow placement of two 
TetraGraph™ sensors so that the efficacy can be compared between these 
two monitoring sites. 
6.5 Exclusion criteria: 
• Patients with history of a peripheral neurologic or 
neuropathic disorder 
• Patients in whom the upper extremity cannot be used for 
TOF monitoring 
• Patients undergoing a surgical procedure in which 
neuromuscular blockade is not required 
• Edematous patients 
6.6 There are no foreseeable risks associated with the use of 
TetraGraph™ device.  
6.7 The data (EMG readings) will be downloaded from the 
TetraGraph™ device in the operating room. This is standard for this 
monitor and does not require additional software or any change in 
standard practice when using this device. The research team will 
transmit the data to the password-secured server and store it as an 
MP4 file and JPEG file. The data will then be deleted from the 
TetraGraph™ device. 
 
7.0 
Data and Specimen Banking* 
N/A 
 
8.0 
Sharing of Results with Subjects* 
8.1 Results will not be shared with subjects. 
 
9.0 
Study Timelines* 
9.1 An individual study subject’s participation in the study should last 2-
8 hours depending on the duration of the surgical procedure. 
 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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9.2  All study subjects should be enrolled within 18 months of the start of 
the study. 
 
9.3 The study data will be analyzed, a manuscript written, and the study 
completed within 24 months of the start of the study. 
 
10.0 Inclusion and Exclusion Criteria* 
10.1 Potential subjects will be identified by reviewing the surgery 
schedule in Epic and will be recruited from the main OR pre-
operative area the day of their surgery. 
10.2 Inclusion criteria: ASA 1-4 patients, weighing ≤60 kg undergoing a 
surgical procedure with general anesthesia and requiring the 
administration of a NMBA. 
10.3 Exclusion criteria: 
• Patients with history of a peripheral neurologic or 
neuropathic disorder 
• Patients in whom the upper extremity cannot be used for 
TOF monitoring 
• Patients undergoing a surgical procedure in which 
neuromuscular blockade is not required 
• Edematous patients 
 
11.0 Vulnerable Populations* 
11.1 We will include children, and will not include pregnant women, and 
prisoners as they are not part of our usual patient population. 
11.2 This study presents no more than minimal risk as it only requires use of a 
novel device for monitoring the TOF (TetraGraph™) which is non-invasive 
and poses no foreseeable risks and certainly none greater than standard TOF 
monitoring with a peripheral nerve stimulator 
11.3 Study staff will discuss the study with the parents and children together, 
review the consent form with them, answer any questions, and obtain 
parental permission and assent from those children able to provide it. 
 
12.0 Local Number of Subjects 
12.1 200  
 
13.0 Recruitment Methods 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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13.1 Potential subjects will be recruited in the surgical preoperative area 
on the day of the surgery. The research team will contact the adult 
patient or guardian/parents and obtain written consent/parental 
permission.  Assent will also be obtained from age appropriate 
patients. 
13.2 The patients to be recruited are those who are scheduled for surgery 
under general anesthesia in the NCH operating rooms. 
13.3 Using Epic, the research team will check the patients scheduled for 
planned surgery in the NCH operating rooms. 
 
14.0 Withdrawal of Subjects* 
14.1 Patients may withdraw from the study at any time.  
14.2 There are no anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
 
15.0 Risks to Subjects* 
15.1 Although not likely, there may be a potential risk for breach of patient 
health information. There is no study related physical risk to study 
subjects associated with this study. All study related procedures are 
non-invasive.  All patients will receive our current standard of care 
with visual assessment of the TOF using a standard peripheral nerve 
stimulator. The only change in standard clinical practice is that 
additional placement of the TetraGraph™ device. 
15.2 Subject information will not be given to any other investigators. 
Subjects and their information will be closely monitored and guarded 
by study staff; there will be limited access to patients and their 
information by trained study staff; and subject information will only 
be shared and discussed between study staff specific to this study. 
Subject PHI will be stored in a locked cabinet, and will be stored and 
maintained in password protected computer files. 
 
16.0 Potential Benefits to Subjects* 
16.1 There are no specific immediate benefits to the patient. 
16.2 We hope what we learn from this study will benefit other pediatric 
surgical patients requiring train-of-four monitoring in the future. 
 
17.0 Data Management* and Confidentiality 
17.1 Statistical analysis and data presentation will be a descriptive 
analysis of the feasibility of using the device in patients of various 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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weight ranges. Feasibility, for the purpose of using this monitor 
intraoperatively, will defined as the generation of appropriate EMG 
for monitoring with ≥ 75% of the nerve stimulations.  This will 
depend on the ability of the device to stimulate a peripheral nerve 
and generate the EMG of the muscle.  We will compare the TOF 
from the TetraGraph™ with that from the standard peripheral nerve 
stimulator. 
17.2 De-identified data will be shared with the manufacturer of the 
monitor, Senzime.  They will be assisting with data analysis, as well 
as, using the data for approval in pediatrics. 
 
17.3 Research records will be stored in a locked cabinet and password 
protected computer.  Only certified research personnel will be given 
access to identifiable subject information 
 
17.4 Following publication of study results, research records will be 
stored for a period of 6 years and then will be destroyed by placing 
in a secure shredding bin. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
18.1  The study will only be monitored by the study investigators. 
 
19.0 Provisions to Protect the Privacy Interests of Subjects 
19.1 Subject information will not be given to any other investigators. 
Subjects and their information will be closely monitored and guarded 
by study staff; there will be limited access to patients and their 
information by trained study staff; and subject information will only 
be shared and discussed between study staff specific to this study.  
 
20.0 Compensation for Research-Related Injury 
20.1  Not applicable 
 
21.0 Economic Burden to Subjects 
21.1  None 
 
22.0 Consent Process 
22.1 The consent process will begin in the preoperative surgery unit on the day of 
surgery, by PI, Sub­Investigators, Study Coordinators, and/or trained 
research staff. 

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Transmission Monitor 
 
 
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22.2 The study will be thoroughly explained to the patient and their family. There 
will be ample time allotted for questions and answers. An explanation of 
voluntary participation will take place, and the family will be asked if they 
are interested in participating in the study. If the patient and their parent(s), 
or legal guardian agrees to participate they will be asked to sign consent and 
assent form. The patient will then be enrolled in the study with the 
understanding that they can elect to stop the study and be withdrawn from 
the study at any time.  
 
23.0 Process to Document Consent in Writing 
23.1 We will be following “SOP: Written Documentation of Consent (HRP-
091).”  
 
24.0 Setting 
24.1 Research procedures will be performed in the operating room during 
anesthetic care. 
 
25.0 Resources Available 
25.1 We will need approximately 20 minutes per patient to explain the 
research protocol, obtain consent, and enroll patients. The Department 
of Anesthesiology & Pain Medicine has 2 research coordinators/RNs 
and 4 research associates who will be enrolling subjects for this study.  
All study staff will be trained regarding the study procedures. Before 
the study starts, the involved personnel will be informed by e-mail and 
during a pre-study meeting about the study protocol, the research 
procedures, research member’s duties, and functions. 
 
26.0 Multi-Site Research* 
Not applicable 
 
27.0  Protected Health Information Recording 
1.0 
Indicate which subject identifiers will be recorded for this research. 
☒  Name 
☐  Complete Address 
☐  Telephone or Fax Number 
☐  Social Security Number (do not check if only used for ClinCard) 
☒  Dates (treatment dates, birth date, date of death) 
☐  Email address, IP address or url 
☒  Medical Record Number or other account number 
☐  Health Plan Beneficiary Identification Number 

PROTOCOL TITLE: Train-of-four monitoring using the TetraGraphTM Neuromuscular 
Transmission Monitor 
 
 
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☐  Full face photographic images and/or any comparable images (x-rays) 
☐  Account Numbers 
☐  Certificate/License Numbers 
☐  Vehicle Identifiers and Serial Numbers (e.g. VINs, License Plate Numbers) 
☐  Device Identifiers and Serial Numbers 
☐  Biometric identifiers, including finger and voice prints 
☐  Other number, characteristic or code that could be used to identify an 
individual 
☐  None (Complete De-identification Certification Form) 
 
2.0   
Check the appropriate category and attach the required form* on the Local 
Site Documents, #3. Other Documents, page of the application.  (Choose one.) 
☒  Patient Authorization will be obtained. (Include the appropriate HIPAA 
language (see Section 14 of consent template) in the consent form OR attach 
the HRP-900, HIPAA AUTHORIZATION form.) 
☐  Protocol meets the criteria for waiver of authorization. (Attach the HRP-901, 
WAIVER OF HIPAA AUTHORIZATION REQUEST form.) 
☐  Protocol is using de-identified information. (Attach the HRP-902, DE-
IDENTIFICATION CERTIFICATION form.) (Checked "None" in 1.0 above) 
☐  Protocol involves research on decedents. (Attach the HRP-903, RESEARCH 
ON DECEDENTS REQUEST form.) 
☐  Protocol is using a limited data set and data use agreement. (Contact the 
Office of Technology Commercialization to initiate a Limited Data Use 
Agreement. 
 
*Find the HIPAA forms in the IRB Website Library, Templates. 
 
Attach the appropriate HIPAA form on the “Local Site Documents, #3. 
Other Documents”, page of the application. 
 
3.0    How long will identifying information on each participant be maintained? 
Following publication of study results, research records will be stored for a period 
of 6 years and then will be destroyed by placing in a secure shredding bin. 
 
4.0 
Describe any plans to code identifiable information collected about each 
participant. 
Not applicable. 
 
5.0 
Check each box that describes steps that will be taken to safeguard the 
confidentiality of information collected for this research: 
☒ Research records will be stored in a locked cabinet in a secure location 
☒ Research records will be stored in a password-protected computer file 
☐ The list linking the assigned code number to the individual subject will be 
maintained separately from the other research data 

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Transmission Monitor 
 
 
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☒ Only certified research personnel will be given access to identifiable 
subject information 
 
6.0 
Describe the provisions included in the protocol to protect the privacy 
interests of subjects, where "privacy interests" refer to the interest of 
individuals in being left alone, limiting access to them, and limiting access to 
their information. (This is not the same provision to maintain the 
confidentiality of data.)  
Subject information will not be given to any other investigators. Subjects and 
their information will be closely monitored and guarded by study staff; there will 
be limited access to patients and their information by trained study staff; and 
subject information will only be shared and discussed between study staff specific 
to this study. Describe the steps that will be taken to protect subjects’ privacy 
interests. “Privacy interest” refers to a person’s desire to place limits on whom 
they interact or whom they provide personal information. 
 
 
Confidential Health Information 
 
1.0 
Please mark all categories that reflect the nature of health information to be 
accessed and used as part of this research. 
☒  Demographics (age, gender, educational level) 
☒  Diagnosis 
☐  Laboratory reports 
☐  Radiology reports 
☐  Discharge summaries 
☒  Procedures/Treatments received 
☒  Dates related to course of treatment (admission, surgery, discharge) 
☐  Billing information 
☐  Names of drugs and/or devices used as part of treatment 
☐  Location of treatment 
☒  Name of treatment provider 
☐  Surgical reports 
☒  Other information related to course of treatment 
☐  None 
 
2.0 
Please discuss why it is necessary to access and review the health information 
noted in your response above. 
Demographics need to be recorded to describe the patient characteristics of the 
study cohort for publication of these data in scientific journals. Diagnosis and 
procedures need to be assessed for inclusion criteria.  
 
3.0 
Is the health information to be accessed and reviewed the minimal necessary 
to achieve the goals of this research?  ☒ Yes    ☐ No 
 

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4.0 
Will it be necessary to record information of a sensitive nature?  ☐ Yes   ☒ 
No 
 
5.0 
Do you plan to obtain a federally-issued Certificate of Confidentiality as a 
means of protecting the confidentiality of the information collected?  ☐ Yes   
☒ No