Comparison of the ToFscan and TetraGraph During Recovery of Neuromuscular Function in the Post Anesthesia Care Unit
Phase: NA
Conditions: Residual Neuromuscular Blockade
Sponsor: Mayo Clinic

 
 
Comparison of the ToFscan and TetraGraph 
during Recovery of Neuromuscular Function in 
the Post Anesthesia Care Unit 
 
 
 NCT03920670 
 
 
11/Oct/19 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 1 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
 
Comparison of the ToFscan and TetraGraph 
during Recovery of Neuromuscular Function in 
the Post Anesthesia Care Unit 
 
 
Regulatory Sponsor 
Principal Investigator: 
J. Ross Renew, MD 
Funding Sponsor: 
 
Protocol Number:  
Mayo Clinic 
 
18-011298 
Study Product: 
TetraGraph 
List of Participating Centers:  
1. Site Principal Investigator: Béla Fülesdi, MD 
University of Debrecen 
Department of Anesthesiology and Intensive Care 
94 Nagyerdei krt. 
4031 Debrecen, Hungary 
 
2. Site Principal Investigator: Glenn Murphy, MD 
NorthShore University HealthSystem 
Department of Anesthesia, Critical Care, and & Pain Medicine 
2650 Ridge Ave 
Evanston, IL 60201 
 
 
Initial version: [07Nov2018] Version (1.0)  
Revision: [20Nov2018] Version (1.1) 
Revision: [08Jan2019] Version (1.2) 
Revision: [26Apr2019] Version (2.0) 
Revision: [6Jun2019] Version (2.1) 
Revision: [11Oct2019] Version (3.0) 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 2 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
Table of Contents 
 
 
PROTOCOL APPROVAL FORM ........................................................................................................ 4 
1
 
LIST OF ABBREVIATIONS ................................................................................................................ 5 
2
 
STUDY SUMMARY ............................................................................................................................. 6 
3
 
INTRODUCTION ................................................................................................................................. 7 
4
4.1 
ABSTRACT .......................................................................................................................................... 7 
4.2 
BACKGROUND .................................................................................................................................... 7 
4.3 
RISKS AND BENEFITS ......................................................................................................................... 10 
 
STUDY OBJECTIVES ........................................................................................................................ 10 
5
 
STUDY DESIGN ................................................................................................................................. 10 
6
6.1 
GENERAL DESCRIPTION ..................................................................................................................... 10 
6.2 
NUMBER OF SUBJECTS ....................................................................................................................... 10 
6.3 
DURATION OF PARTICIPATION ............................................................................................................ 10 
6.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 11 
6.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 11 
6.6 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 11 
 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 12 
7
7.1 
INCLUSION CRITERIA ......................................................................................................................... 12 
7.2 
EXCLUSION CRITERIA ........................................................................................................................ 12 
7.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 12 
7.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 12 
7.4.1 
When and How to Withdraw Subjects ........................................................................................ 12 
7.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 13 
 
STUDY DEVICE ................................................................................................................................ 13 
8
8.1 
DESCRIPTION .................................................................................................................................... 13 
8.2 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 13 
8.3 
MASKING/BLINDING OF STUDY........................................................................................................... 13 
 
STUDY PROCEDURES ...................................................................................................................... 13 
9
9.1 
VISIT 1 (SCREENING AND ENROLLMENT UP TO THE DAY OF SURGERY) .................................................... 14 
9.2 
VISIT 2 (RANDOMIZATION AND TREATMENT – DAY OF SURGERY) ........................................................... 14 
9.3 
SCHEDULE OF EVENTS ....................................................................................................................... 15 
 
STATISTICAL PLAN ......................................................................................................................... 15 
10
10.1 
SAMPLE SIZE DETERMINATION ....................................................................................................... 15 
10.2 
STATISTICAL METHODS ................................................................................................................. 16 
10.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 16 
 
SAFETY AND ADVERSE EVENTS ................................................................................................... 17 
11
11.1 
DEFINITIONS ................................................................................................................................ 17 
11.1.1 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) ...................... 17 
11.1.2 
Adverse Event ................................................................................................................... 17 
11.1.3 
Serious Adverse Event ..................................................................................................... 17 
11.1.4 
Adverse Event Reporting Period ....................................................................................... 18 
11.1.5 
Preexisting Condition ........................................................................................................ 18 
11.1.6 
Post-study Adverse Event ................................................................................................. 18 
11.1.7 
Hospitalization, Prolonged Hospitalization or Surgery ...................................................... 18 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 3 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
11.2 
RECORDING OF ADVERSE EVENTS .................................................................................................. 18 
11.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ...................................... 19 
11.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ......................................................... 19 
11.4 
MEDICAL MONITORING ................................................................................................................. 20 
 
DATA HANDLING AND RECORD KEEPING .................................................................................. 21 
12
12.1 
CONFIDENTIALITY ........................................................................................................................ 21 
12.2 
SOURCE DOCUMENTS .................................................................................................................... 21 
12.3 
CASE REPORT FORMS .................................................................................................................... 21 
12.4 
DATA MANAGEMENT .................................................................................................................... 21 
12.5 
DATA PROCESSING ........................................................................................................................ 22 
12.6 
DATA SECURITY AND CONFIDENTIALITY ......................................................................................... 22 
12.7 
DATA QUALITY ASSURANCE .......................................................................................................... 22 
12.8 
DATA CLARIFICATION PROCESS ..................................................................................................... 22 
12.9 
RECORDS RETENTION .................................................................................................................... 23 
 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 23 
13
13.1 
STUDY MONITORING PLAN ............................................................................................................ 23 
13.2 
AUDITING AND INSPECTING ........................................................................................................... 23 
 
ETHICAL CONSIDERATIONS ......................................................................................................... 23 
14
 
STUDY FINANCES ............................................................................................................................ 24 
15
15.1 
FUNDING SOURCE ......................................................................................................................... 24 
15.2 
CONFLICT OF INTEREST ................................................................................................................. 24 
15.3 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 24 
 
PUBLICATION PLAN ....................................................................................................................... 24 
16
 
REFERENCES ................................................................................................................................... 24 
17
 
LIST OF IN-TEXT TABLES .............................................................................................................. 26 
18
18.1 
SCHEDULE OF EVENTS ................................................................................................................... 26 
18.2 
INTRAOPERATIVE DATA ................................................................................................................. 26 
18.3 
PACU DATA ................................................................................................................................. 27 
 
LIST OF IN-TEXT FIGURES............................................................................................................. 29 
19
19.1 
TETRAGRAPH ............................................................................................................................... 29 
19.2 
TOFSCAN ..................................................................................................................................... 29 
19.3 
VNRS ......................................................................................................................................... 30 
 
 
 
 
 
 
 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 5 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
 List of Abbreviations 
2
 
 
AE 
Adverse Event/Adverse Experience 
AMG 
Acceleromyography 
CE 
Conformite Europeene 
CFR 
Code of Federal Regulations 
cMAPs 
Compound Muscle Action Potentials 
CRF 
Case Report Form 
CTSA 
Center for Translational Science Activities 
DSMB 
Data and Safety Monitoring Board 
EMG 
Electromyography 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HER 
Electronic Health Record 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
KMG 
Kinemyography 
MMG 
Mechanomyography 
NMBA 
Neuromuscular Blocking Agent 
Non-UPIRTSO 
Non-Unanticipated Problems Involving Risk to Subjects or 
Others 
PACU 
Post Anesthesia Care Unit 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
TOF 
Train-of-four 
UPIRTSO 
Unanticipated Problems Involving Risk to Subjects or Others 
VNRS 
Verbal Numeric Rating Scale 
 
 
 
 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 6 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 Study Summary 
3
Title 
Comparison of the ToFscan and TetraGraph during Recovery of 
Neuromuscular Function in the Post Anesthesia Care Unit 
Running Title 
ToFscan vs TetraGraph 
Phase 
N/A 
Methodology 
Randomized, Open-Label 
 
Overall Study 
Duration 
6 months 
Subject Participation 
Duration 
Less than 1 hour 
Single or Multi-Site  
Multicenter International  
Objectives 
The primary aim of this study is to assess the agreement and 
repeatability between TOF values obtained from ToFscan and 
TetraGraph 
Number of Subjects 
120 (40 per site) 
Diagnosis and Main 
Inclusion Criteria 
Patients undergoing an elective surgery and requiring administration of 
NMBA intraoperatively 
Study Device 
TetraGraph 
 
Duration of 
Administration 
Single stimulation of ulnar nerve repeated at specific intervals as 
outlined in the Study Procedures (Section 6.2) 
Reference therapy 
ToFscan 
Statistical 
Methodology 
This pilot study is meant to be descriptive and it aims to collect basic 
data for future larger study 
 
 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 7 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 Introduction 
4
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
 
4.1 
Abstract 
 
Residual neuromuscular blockade is a common occurrence in the post-anesthesia care unit 
(PACU) when neuromuscular blocking agents (NMBAs) have been used in the operating room.  
The only method of reliably detecting residual neuromuscular blockade is through the use of 
quantitative neuromuscular monitors.   Unfortunately, several barriers exist that have prevented 
the widespread application of these devices.  For instance, there is a paucity of quantitative 
neuromuscular monitors commercially available.  Also, two modalities of quantitative 
monitoring, kinemyography and acceleromyography, rely on movement of the muscles of 
interest, a characteristic frequently compromised during patient positioning for surgical 
procedures or in uncooperative awake patients in the PACU.  Additionally, many clinicians are 
unfamiliar with these quantitative monitors, and incorporating them into their practice can 
represent an undesirable educational burden.  The aim of this investigation is to compare the 
performance of two quantitative monitors utilized on post-anesthesia recovering patients.  The 
ToFscan (Draeger Medical Inc., Telford, PA) represents one of the few standalone 
acceleromyography (AMG)-based quantitative monitors available for routine clinical use in the 
United States.  The TetraGraph (Senzime AB, Uppsala, Sweden) is a standalone 
electromyography (EMG)-based quantitative monitor that recently received Conformité 
Européene (CE) approval.  While both of these quantitative monitors can be utilized to guide 
intraoperative NMBA re-dosing and confirm recovery, they provide their objective data via 
drastically different techniques.  AMG, based on Newton’s Second law which describes force 
being proportional to acceleration, measures acceleration of the thumb and requires its 
unobstructed movement.  As such, performing AMG in awake, uncooperative patients can yield 
inaccurate results because of unwanted patient movement.  Alternatively, EMG measures 
electrical activity within the muscle following peripheral nerve stimulation, and is unaffected by 
involuntary patient motion.  We plan to compare measurements with these two devices 
throughout various stages of neuromuscular recovery in the PACU end compare the usefulness 
of these devices in this vulnerable patient population. 
 
4.2 
Background 
 
Postoperative residual weakness from neuromuscular blockade continues to be a common 
problem in the post-anesthesia care unit (PACU). Despite the routine use of reversal agents, a 
significant number of patients continue to arrive in the PACU with objective evidence of residual 
neuromuscular blockade (Naguib, Kopman, and Ensor 2007; Cammu et al. 2006).  While not 
every patient with residual weakness develops a postoperative complication, many can develop 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 8 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
avoidable critical respiratory events (Murphy et al. 2008; Berg et al. 1997).  Furthermore, special 
populations such as the elderly, are at particular risk for developing complications related to 
postoperative residual weakness (Murphy et al. 2015).  The use of quantitative monitoring has 
been demonstrated to reliably reduce the incidence of postoperative residual weakness and the 
ensuing complications (Todd, Hindman, and King 2014; Todd and Hindman 2015; Murphy et al. 
2011).  With an abundance of literature supporting the use of objective neuromuscular monitors, 
a panel of experts recently recommended the universal adoption of such devices whenever 
NMBA are utilized (Naguib et al. 2018).   
Quantitative neuromuscular monitoring devices objectively measure residual weakness and 
display the results numerically.  This is traditionally accomplished by performing a train-of-four 
(TOF) stimulation at the ulnar nerve and measuring the response of the adductor pollicis muscle.  
The degree of muscle weakness is determined by calculating the TOF ratio, which consists of the 
ratio of the fourth muscle contraction to the first.  Adequate recovery that excludes clinically 
significant weakness from neuromuscular blockade is defined as a TOF ratio ≥ 0.9, a 
measurement that can be determined reliably only with a quantitative monitor (Sundman et al. 
2000; Eriksson et al. 1997).  Although evidence strongly suggests objective monitors should be 
used perioperatively whenever NMBAs are administered, these devices can be expensive and 
require additional training.  Many clinicians default to the antiquated practice of utilizing 
qualitative (subjective) neuromuscular stimulating units such as a peripheral nerve stimulator 
(PNS) (Grayling and Sweeney 2007; Naguib et al. 2010). 
There are several types of quantitative neuromuscular monitors.  These devices can be 
incorporated into the anesthesia workstation, allowing data to be seamlessly integrated into the 
electronic medical record.  Unfortunately, this setup can preclude using these monitors in the 
PACU as portability is sacrificed.  In contrast, other monitors exist as standalone, portable (hand-
held) units.   
Aside from portability, objective monitors can further be categorized based on the modality 
utilized to measure responses. Mechanomyography (MMG) measures the force of contraction of 
the adductor pollicis (thumb) muscle following ulnar nerve stimulation and has served as the 
traditional “gold-standard”.  Mechanomyographic responses are precise and reproducible, 
however the setup is cumbersome and the lack of commercially available devices has relegated 
MMG to strictly research purposes. Acceleromyography (AMG) measures acceleration of a 
muscle group (typically the thumb) in response to stimulation (typically the ulnar nerve). This 
technique is similar to MMG, but instead of measuring the force of muscle contraction, an 
accelerometer fixed to the thumb measures the acceleration of the thumb in response to ulnar 
nerve stimulation.  Based on Newton’s Second law that states force is proportional to 
acceleration, the measured acceleration is correlated with the force of contraction in the clinical 
setting.  There are currently two standalone AMG-based monitors available for clinical use: the 
STIMPOD (Xavant Technologies, Pretoria, South Africa) and the ToFscan (Draeger Medical 
Inc., Telford, PA).  These devices represent improvements in AMG technology over its 
predecessor, the TOF-Watch (Schering-Plough Corp., Kenilworth, NJ, USA) as they utilize three 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 9 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
dimensional transducers that can better quantify the complex motion of the thumb.  Despite these 
advances, the use of AMG can be limited due to patient positioning that precludes free motion of 
the thumb, as well instances of awakening patients moving their thumb during measurements.  
Kinemyography (KMG) is based on similar principles to AMG, and relies on the thumb being 
able to move freely.  Upon neurostimulation, KMG utilizes a piezoelectric motion sensor that is 
bent between the thumb and index fingers following muscle contraction.  The degree of this 
bending is quantified and used to determine a TOF ratio.  While Datex-Ohmeda (Helsinki, 
Finland) manufactures a KMG device that can be incorporated into the anesthesia work station, 
there are no currently available standalone KMG devices.  Electromyography (EMG) devices 
measure electrical activity, termed compound muscle action potentials (cMAPs) following nerve 
stimulation (typically at the adductor pollicis muscle after ulnar nerve stimulation).  As EMG 
measures cMAPs and does not require freely moving thumbs for accurate measurements, many 
experts have referred to this monitoring modality as the “new gold standard”. TetraGraph 
(Senzime AB, Uppsala, Sweden) is a standalone EMG-based device that recently received 
Conformité Européene (CE) approval.    We have previously investigated this device and 
presented our findings at several annual meetings such as International Anesthesia Research 
Society (May 2018, May 2017, May 2013), the Society for Technology in Anesthesia (January 
2018), and the American Society of Anesthesiologists (Octotober 2017, October 2012), 
European Society of Anaesthesiology (June 2018, June 2015).  Furthermore, we have recently 
submitted abstracts to the PostGraduate Assembly in Anesthesiology in December 2018 as well 
as a manuscript describing a multi-center, volunteer study investigating TetraGraph versus 
AMG-based monitors.  Our work thus far has found this device to be easy to apply, reliable, and 
able to provide comparable measurements to other quantitative monitors.   
Utilizing recommendations from the Good Clinical Practice (GCP) Guidelines for monitoring of 
neuromuscular function (Fuchs-Buder et al. 2007), we will investigate the performance of the 
TetraGraph in patients recovering from anesthesia in the PACU.  The postoperative setting is 
particularly important, as several previous studies performed in awakening patients have reported 
discordant TOF ratios: accelerographic TOF ratios were not an accurate representation of the 
neuromuscular status (recovery) of the patients (Baillard et al. 2004). We plan to compare two 
portable quantitative monitors, the EMG-based TetraGraph and the AMG-based ToFscan.  
ToFscan has recently been described as an acceptable surrogate for research purposes to the 
frequently used TOF-Watch (Murphy et al. 2018).  The TOF-Watch monitor, however, is no 
longer manufactured, while the ToFscan is commercially available and approved by the United 
States Food and Drug Administration (FDA).  While the ToFscan has a three-dimensional sensor 
that can measure acceleration in multiple planes, it still has the same limitations associated with 
muscle movement inherent to AMG-based quantitative monitors.  This is of particular 
importance in the recovery room when patients may not be fully cooperative when quantitative 
monitoring is warranted to exclude postoperative residual weakness as a cause of patient distress. 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 10 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
4.3 
Risks and Benefits 
 
• The benefits of using neuromuscular blockade monitoring devices:  
Early detection of residual neuromuscular blockade 
• The risks of using neuromuscular blockade monitoring devices: 
Slight discomfort when electrical stimulation is administered 
 Study Objectives 
5
 
Primary Objective 
To assess the agreement and repeatability between TOF values obtained from the ToFscan and 
TetraGraph during recovery from neuromuscular blockade as measured upon arrival to the 
PACU, and then  5 (+5 min) and 10 (+10 min)) minutes later. 
 
Secondary Objective 
Determine the incidence of postoperative residual weakness in the PACU (defined as TOFR 
<0.90). 
Assess patient discomfort associated with each neurostimulation utilizing a verbal numeric rating 
scale (VNRS) from 0-10.   
 
 Study Design 
6
 
6.1 
General Description 
 
This unblinded, multicenter international, prospective, randomized, observational study will 
involve 120 patients undergoing surgical procedure that involved administration of 
neuromuscular blockade agents intraoperatively.  
 
6.2 
Number of Subjects 
 
One hundred twenty ( forty per site). 
 
6.3 
Duration of Participation 
 
10 minutes in PACU 
 
 
 
 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 12 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 Subject Selection Enrollment and Withdrawal 
7
7.1 
Inclusion Criteria 
 
• Age > or = 18 years old 
• Patients willing to participate and provide an informed consent 
• Patients undergoing an elective surgical procedure that requires use of non-depolarizing 
NMBA agents administered intraoperatively. 
7.2 
Exclusion Criteria 
 
• Patients with unilateral disorders, such as stroke, carpal tunnel syndrome, broken wrist 
with nerve damage, Dupuytren contracture, or any similar wrist injury.  
• Patients with systemic neuromuscular diseases such as myasthenia gravis 
• Patients with significant organ dysfunction that can significantly affect pharmacokinetics 
of neuromuscular blocking and reversal agents, i.e., severe renal impairment or end-stage 
liver disease. 
 
7.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be enrolled from the Departments of Anesthesiology at the Mayo Clinic in Florida, 
NorthShore University Health System, and University of Debrecen. The study has an accrual 
target of 120 patients. On a daily basis, there are over 20 elective surgical cases performed at 
Mayo Clinic in Florida and thus no difficulties in accrual based on historical volumes are 
anticipated. Each participating center reviewed the feasibility and determined that approximately 
3 participants per week will be completed for this study. The initial accrual period will last at 
least 3 months. Patients will be provided with a Research Participant Consent and Privacy 
Authorization Form describing the study devices, protocol, inclusion and exclusion criteria, as 
well as risks and benefits of participation.  
7.4 
Early Withdrawal of Subjects 
7.4.1 When and How to Withdraw Subjects 
 
Patients are free to withdraw at any time and for whatever reason. If patient withdraws consent 
prior to arrival to PACU, the study data will not be collected. If patient withdraws consent after 
study data was already completed, the participant will need to provide instructions to the study 
team to remove his/her data from the data set.  Pre-specified reasons for discontinuing include, 
but are not limited to, the following:  
• Patient Request: Patient decided that he/she did not want to continue (for any reason) 
• Adverse Event: Patient experienced a related or unrelated event that would interfere with 
the study objectives/evaluation  

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 13 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
• Inclusion/Exclusion Discrepancy/Violation: Patient should not have been enrolled 
• Other: Any other reason 
 
7.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a Participant withdraws from the study, no additional attempts will be made to contact the 
Participant. 
 Study Device  
8
8.1 
Description 
 
ToFscan is a nerve stimulator module used for the measurement of neuromuscular transmission 
via accelerometry. ToFscan was developed by Drager Technologies, Canada, and it uses a three-
dimensional piezoelectric sensor that attaches to the thumb via a hand adapter to measure 
acceleration in multiple planes (Murphy et al, 2018).  
 
TetraGraph device is a neuromuscular transmission monitor capable of estimating the depth of 
neuromuscular block in anesthetized patients who received neuromuscular blocking agents. 
TetraGraph uses EMG to measure the muscle action potentials that are generated in response to 
percutaneous electrical neurostimulation.  
 
8.2 
Method for Assigning Subjects to Treatment Groups 
 
This is an open-label pilot investigation and all study participants are assigned to both standard 
of care and investigational device use in PACU. The randomization involves the use of dominant 
vs non-dominant arm. 
 
The randomization will be performed utilizing REDCap and assigned anesthesia clinical care 
team will be informed of patients’ assigned to guide them with the selection of the assigned 
treatment option. 
 
8.3 
Masking/Blinding of Study  
 
This is an open-label pilot investigation. Masking and blinding procedures are not applicable.   
 
 Study Procedures 
9
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 14 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
9.1 
Visit 1 (Screening and Enrollment up to the day of surgery) 
 
• Review of medical record 
• Informed Consent - Patients will be identified during their preoperative appointment and 
introduced to a study; they will be provided with a copy of the consent document and 
information about the study. The consenting will take place after additional discussion on 
the day of surgery.  
 
9.2 
Visit 2 (Randomization and Treatment – day of surgery) 
 
• Elective surgical procedure as per standard of care 
• Intraoperative neuromuscular blockade, management, and neuromuscular antagonism 
will be at the discretion of the attending anesthesiologist.  
• Upon arrival to the PACU, consenting patients will be randomized to have the 
TetraGraph placed on either their dominant or non-dominant arm TetraGraph uses 
proprietary, single-use surface electrodes (TetraSensTM, Senzime AB, Uppsala, Sweden) 
with stimulating electrodes placed over the ulnar nerve, a reference electrode placed on 
the adductor pollicis (1st digit) (Figure 16.1).  The skin will be prepped with careful 
abrasion and cleansing of the skin in the usual fashion prior to electrode placement. 
• ToFscan will be placed on the patient’s opposite arm.  Stimulating electrodes (Red Dot 
ECG electrodes, 3M, St. Paul, MN) will be placed over the ulnar nerve with the negative 
electrode near the wrist crease and positive electrode placed 3-4 cm proximally.  The skin 
will be prepped with careful abrasion and cleansing of the skin in the usual fashion prior 
to electrode placement. The ToFscan utilizes a thumb splint with the encased transducer 
secured to the hand (Figure 16.2).  
• To obtain measurements with TetraGraph, TOF stimulation will be performed at 50mA 
and the measurement recorded. This measurement will be repeated twice, 20 seconds 
apart.  If the two measurements differ by >10%, a third measurement will be recorded, 
with the closest two readings kept and the outlier discarded.  If TetraGraph yields a train-
of-four count but not a ratio with any measurement, this will be recorded.  
• To obtain ToFscan measurements, TOF stimulation will be performed and the 
measurement recorded.  According to the manufacturer, the ToFscan does not require 
calibration, and the default stimulating current is 50 mA.  The TOF measurement will be 
repeated twice, 20 seconds apart. If the measurements differ by >10%, a third 
measurement will be repeated, with the closest two readings kept and the outlier 
discarded.  If TetraGraph yields a train-of-four count but not a ratio with any 
measurement, this will be recorded.  
• Each neurostimulation with the TetraGraph and ToFscan will be conducted 
simultaneously with two observers. Patients will be queried as to the level of discomfort 
associated with obtaining measurements (Figure 16.3).  We have previously utilized this 
scoring system for a large, multi-center volunteer trial (manuscript submitted). If patients 
are unable to quantify their discomfort, this will be documented. 
• The above described process will be repeated for both monitors upon arrival to PACU 
and after 5 minutes and 10 minutes into the PACU stay.  

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 15 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
• ToFscan is an FDA approved monitor, while TetraGraph is CE marked, but not FDA 
approved yet. If TOF ratios below 0.9 are obtained with the ToFscan at any point during 
this study, the attending anesthesiologist will be notified, as per usual clinical routine.  
Possible actions include continued monitoring and supportive care, additional reversal 
agent administration, or, in extreme cases of weakness, ventilatory support with bilevel 
positive airway pressure (BiPAP) or tracheal re-intubation. 
• Following measurements obtained with both devices at these specified time intervals and 
assuming TOF ratio is >0.9, the devices will be removed and the patient will proceed 
along the standard recovery pathway. 
• If at any point the patient describes the discomfort associated with neurostimulation as a 
verbal numeric score of 7 or higher, the patient will be given the option to discontinue the 
study.  
• Prior to discharge from PACU, patients will be asked to recall if they had a 
neurostimulation. If they do recall it, we will again query the level of discomfort 
associated with obtaining measurements (Figure 16.3). 
 
9.3 
Schedule of Events 
 
 
Schedule of Events 
Study Activity 
Visit  1 
Visit 2 
ToFscan and 
Tetragraph 
 
X 
Informed consent 
X 
 
Review of Medical 
Record 
X 
 
Adverse event 
evaluation 
 
X 
 
 Statistical Plan 
10
10.1 Sample Size Determination 
 
Based on paired t-test, 23 enrolled patients will give 90% power to detect a difference in TOF 
ratios with a significance level of 0.05 (JMP Pro Software version 13.0.0 [August 23, 2018]; 
SAS Institute Inc., Cary, NC). We utilized a standard deviation of  0.07 that was determined 
during our multi-center volunteer study comparing another AMG device and TetraGraph.  
However, we will enroll 40 patients at 3 sites for a total of 120 patients to account for dropout 
during the study and to provide further insight into the incidence of postoperative residual 
weakness and three large centers.  The other centers that might be submitting similar studies and 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 16 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
sharing de-identified data for the purposes of data analysis and publication are as follows: 
NorthShore University HealthSystem, Evanston, IL, USA 
 
 and University of Debrecen, Debrecen, 
Hungary 
. Each 
site will complete separate applications for their IRB or Ethics committee approval; Mayo Clinic 
in Florida will serve as the lead site and will provide oversight to ensure compliance with the 
protocol at each site. .  
 
10.2 Statistical Methods 
 
Descriptive Statistics 
 
Analysis of agreement between the devices will be assessed using the method described by 
Bland and Altman (Olofsen et al. 2015).  The bias is defined as the mean difference of repeated 
measurements from the ToFscan and the TetraGraph obtained at the same time intervals. The 
limits of agreement are defined as bias ± 2 SD, where SD denotes the standard deviations of the 
differences.  Limits of agreement are interpreted as the reference range within which 95% of the 
differences will lie.  The bias and the limits of agreements surrounding the bias (± 2 SD) will be 
calculated with 95% confidence intervals.  Repeatability between the two devices at the various 
time intervals will also be assessed with significance defined as a p-value <0.05.  
 
Handling of Missing Data 
 
This is a prospective study and therefore we do not anticipate any missing data.  In the event of 
any unexpected missing data, no attempt to impute this missing data will be made; missing data 
will simply be treated as missing in the statistical analysis. 
 
10.3 Subject Population(s) for Analysis 
 
Each participant who goes through the recovery processes in the PACU and completes 
monitoring of residual neuromuscular blockade will be included in the primary analysis 
regardless of study withdrawal for any reason. In the event of any study withdrawals, in 
secondary analysis we will examine the sensitivity of our results to the exclusion of patients who 
withdrew. 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 17 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 Safety and Adverse Events 
11
11.1 Definitions 
11.1.1 Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, or not part of an underlying 
disease. A problem or event is "unanticipated" when it was unforeseeable at the time of its 
occurrence. A problem or event is "unanticipated" when it occurs at an increased 
frequency or at an increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
 
11.1.2 Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
11.1.3 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 18 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
11.1.4 Adverse Event Reporting Period 
 
For this study, the follow-up period is defined as 10 minutes following the arrival in the PACU. 
 
11.1.5 Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
 
11.1.6 Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
 
11.1.7 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
11.2 Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the electronic case report form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic, laboratory or procedure results should recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 19 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
11.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
 
11.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB  
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. Each participating site will report SAEs to 
their respective IRB or Ethics Committee with copy of submission and review provided to the 
leading site. Should there be any SAEs at any of the participating sites; the study team at that site 
will notify the primary site (Mayo Clinic in Florida) within 24 hours of learning of the event.  
 
Any serious adverse event (SAE) which the Principal Investigator has determined to be a 
UPIRTSO will be reported to the Mayo IRB as soon as possible but no later than 5 working days 
after the investigator first learns of the problem/event. 
 
The following information will be collected on the adverse event worksheet (and entered in the 
research database):  
• Study ID 
• Disease  
• The date the adverse event occurred 
• Description of the adverse event 
• Relationship of the adverse event to the research device* 
• Determination if the adverse event was expected  
• The severity of the adverse event (severity scale described below**) 
• If any intervention was necessary 
• Resolution (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution 
 
The sponsor-investigator will review all adverse event reports to determine if specific reports 
need to be made to the IRB.  The sponsor-investigator will sign and date the adverse event report 
when it is reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will be reported to 
the IRB. 
 
 
* Relationship Index 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 20 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
The relationship of an AE to the Investigational Device is a clinical decision by the sponsor-
investigator (PI) based on all available information at the time of the completion of the eCRF and 
is graded as follows: 
 
1. Not related: a reaction for which sufficient information exists to indicate that the etiology is 
unrelated to the use and proper application of study device. 
 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship 
to use of the study device which makes a causal relationship improbable and in which use of 
other devices, chemicals, or underlying disease provide plausible explanations. 
 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to use of the study device but which could also be explained by concurrent disease or 
use of other devices or chemicals. 
 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable time 
sequence to use of the study device, unlikely to be attributed to concurrent disease or use of other 
devices or chemicals. 
 
5. Definite: a reaction that follows a reasonable temporal sequence from the use of the study 
device. 
 
 
** Severity Scale 
 
The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded in details as indicated on the CRF. If the intensity of an AE changes over a 
number of days, then separate entries should be made having distinct onset dates.  
 
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 
3. Severe: AEs interrupt a patient's usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
 
11.4 Medical Monitoring 
It is the responsibility of the Principal Investigator (at each participating site) to oversee the 
safety of the study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 10  “Study Monitoring, 
Auditing, and Inspecting”).  Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 21 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
 Data Handling and Record Keeping 
12
12.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
12.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records and any forms completed specifically for this study.  
12.3 Case Report Forms 
 
All data necessary for this study will be obtained from EHR or at the time devices are being used 
and recorded on the electronic Case Report Forms (CRFs) created in REDCap. All missing data 
will be explained.  
 
12.4 Data Management 
 
Study data to be collected and managed using EHR and study-generated source documents and 
transcribed into electronic CRFs in REDCap, electronic data capture software, hosted by CTSA 
at Mayo Clinic.  REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; and 
4) procedures for importing data from external sources. 
 
Each center will enter data into Mayo Clinic developed REDCap database. The administrator for 
REDCap added external users with their unique username and Data Access Groups (DAGs) were 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 22 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
created to ensure centers were only able to access their own data. Mayo Clinic Florida will have 
access to the entire de-identified data set.  
 
Each center is designated a site number and the following naming convention for the records will 
be used: 
01-XXX – First two digits for site number and last three digits sequential subject files (starting at 
001). Mayo Clinic Florida will use the following format for their subject files: 01-001, 01-002, 
etc. 
See Table with the list of participating centers and site number to identify correct naming 
conventions for the subject files. 
 
12.5 Data Processing 
 
All study date will be stored and analyzed at Mayo Clinic in Florida using the REDCap 
electronic data capture tool. De-identified data will be shared with investigators conducting 
similar study at their institution for the purposes of combined data analysis and publication. 
 
Study center at NorthShore will not be entering any PHI in REDCap, specifically the date of 
birth and date of surgery will not be entered by this center into REDCap. A free-text to enter age 
will be the designated field for the NorthShore center to enter. 
 
12.6 Data Security and Confidentiality 
 
All source documents including clinical findings, observations or other activities will be stored in 
a REDCap database that will be designed by an Investigator.  Access to the REDCap database 
will be limited to the Principal Investigator, Investigators, Study Team members, and 
Statistician. 
 
12.7 Data Quality Assurance 
 
Once the study is completed the Principal Investigator will randomly select 3 participants and 
compare the data documented in the EHR with what is entered into the REDCap database.  If 
there is any discrepancy, the Principal Investigator and/or Investigators will cross-reference all 
30 patients to ensure accuracy.  
 
Participating centers will be asked to provide de-identified/redacted source documents for 
selected subjects for verification of data.  
 
12.8 Data Clarification Process 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 23 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
For any data query the Principal Investigator and Investigators will meet to clarify the data 
queried and make corrections based on consensus.  
12.9 Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. Each site’s 
Principal Investigator will maintain regulatory and essential study documents to ensure 
compliance with local and federal policies/guidelines.  
 
The sponsor-investigator will retain the specified records and reports: 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS 669717   
 
 Study Monitoring, Auditing, and Inspecting 
13
13.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the compliance or quality assurance reviewer is given access to all the study-
related documents. 
 
13.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).   
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 Ethical Considerations 
14
This study is to be conducted according to United States and International government 
regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 24 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject and the individual obtaining the informed consent. 
 
 Study Finances 
15
15.1 Funding Source 
 
This investigator initiated study is not funded. Study coordinator’s time is supported by the 
Department of Anesthesiology. 
 
15.2 Conflict of Interest 
 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor-investigator prior to participation in this study. 
 
No financial conflicts of interested are anticipated or have been identified for this study. 
15.3 Subject Stipends or Payments 
 
No payment is given to study participants. 
 
 Publication Plan 
16
 
The primary responsibility for publication of the study results is with the Primary Investigator. 
After the complication of study and prior to publication, the study results will be shared with all 
Investigators. The study will be registered at ClinicalTrials.gov prior to subject recruitment along 
with the posting of the results within 12 months of final data collection for the primary outcome 
measure.  
 
 References 
17
 
 
Baillard, C., S. Bourdiau, P. Le Toumelin, F. Ait Kaci, B. Riou, M. Cupa, and C. M. Samama. 2004. 
'Assessing residual neuromuscular blockade using acceleromyography can be deceptive in 
postoperative awake patients', Anesth Analg, 98: 854-7, table of contents. 
Berg, H., J. Roed, J. Viby-Mogensen, C. R. Mortensen, J. Engbaek, L. T. Skovgaard, and J. J. Krintel. 
1997. 'Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 25 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
prospective, randomised, and blinded study of postoperative pulmonary complications after 
atracurium, vecuronium and pancuronium', Acta Anaesthesiol Scand, 41: 1095-103. 
Cammu, G., J. De Witte, J. De Veylder, G. Byttebier, D. Vandeput, L. Foubert, G. Vandenbroucke, and T. 
Deloof. 2006. 'Postoperative residual paralysis in outpatients versus inpatients', Anesth Analg, 
102: 426-9. 
Elyassi, A. R., and H. H. Rowshan. 2009. 'Perioperative management of the glucose-6-phosphate 
dehydrogenase deficient patient: a review of literature', Anesth Prog, 56: 86-91. 
Eriksson, L. I., E. Sundman, R. Olsson, L. Nilsson, H. Witt, O. Ekberg, and R. Kuylenstierna. 1997. 
'Functional assessment of the pharynx at rest and during swallowing in partially paralyzed 
humans: simultaneous videomanometry and mechanomyography of awake human volunteers', 
Anesthesiology, 87: 1035-43. 
Evora, P. R., L. Alves Junior, C. A. Ferreira, A. C. Menardi, S. Bassetto, A. J. Rodrigues, A. Scorzoni 
Filho, and W. V. Vicente. 2015. 'Twenty years of vasoplegic syndrome treatment in heart surgery. 
Methylene blue revised', Rev Bras Cir Cardiovasc, 30: 84-92. 
Faber, P., A. Ronald, and B. W. Millar. 2005. 'Methylthioninium chloride: pharmacology and clinical 
applications with special emphasis on nitric oxide mediated vasodilatory shock during 
cardiopulmonary bypass', Anaesthesia, 60: 575-87. 
Fuchs-Buder, T., C. Claudius, L. T. Skovgaard, L. I. Eriksson, R. K. Mirakhur, J. Viby-Mogensen, and 
Meeting th International Neuromuscular. 2007. 'Good clinical research practice in 
pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision', Acta 
Anaesthesiol Scand, 51: 789-808. 
Grayling, M., and B. P. Sweeney. 2007. 'Recovery from neuromuscular blockade: a survey of practice', 
Anaesthesia, 62: 806-9. 
Kaisers, U., J. M. Langrehr, M. Haack, A. Mohnhaupt, P. Neuhaus, and R. Rossaint. 1995. 'Hepatic 
venous catheterization in patients undergoing positive end-expiratory pressure ventilation after 
OLT: technique and clinical impact', Clin Transplant, 9: 301-6. 
McCartney, S. L., L. Duce, and K. Ghadimi. 2018. 'Intraoperative vasoplegia: methylene blue to the 
rescue!', Curr Opin Anaesthesiol, 31: 43-49. 
Murphy, G. S., J. W. Szokol, M. J. Avram, S. B. Greenberg, J. H. Marymont, J. S. Vender, J. Gray, E. 
Landry, and D. K. Gupta. 2011. 'Intraoperative acceleromyography monitoring reduces symptoms 
of muscle weakness and improves quality of recovery in the early postoperative period', 
Anesthesiology, 115: 946-54. 
Murphy, G. S., J. W. Szokol, M. J. Avram, S. B. Greenberg, T. D. Shear, M. Deshur, J. Benson, R. L. 
Newmark, and C. E. Maher. 2018. 'Comparison of the TOFscan and the TOF-Watch SX during 
Recovery of Neuromuscular Function', Anesthesiology. 
Murphy, G. S., J. W. Szokol, M. J. Avram, S. B. Greenberg, T. D. Shear, J. S. Vender, K. N. Parikh, S. S. 
Patel, and A. Patel. 2015. 'Residual Neuromuscular Block in the Elderly: Incidence and Clinical 
Implications', Anesthesiology, 123: 1322-36. 
Murphy, G. S., J. W. Szokol, J. H. Marymont, S. B. Greenberg, M. J. Avram, and J. S. Vender. 2008. 
'Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit', 
Anesth Analg, 107: 130-7. 
Naguib, M., S. J. Brull, A. F. Kopman, J. M. Hunter, B. Fulesdi, H. R. Arkes, A. Elstein, M. M. Todd, and 
K. B. Johnson. 2018. 'Consensus Statement on Perioperative Use of Neuromuscular Monitoring', 
Anesth Analg, 127: 71-80. 
Naguib, M., A. F. Kopman, and J. E. Ensor. 2007. 'Neuromuscular monitoring and postoperative residual 
curarisation: a meta-analysis', Br J Anaesth, 98: 302-16. 
Naguib, M., A. F. Kopman, C. A. Lien, J. M. Hunter, A. Lopez, and S. J. Brull. 2010. 'A survey of current 
management of neuromuscular block in the United States and Europe', Anesth Analg, 111: 110-
9. 
Olofsen, E., A. Dahan, G. Borsboom, and G. Drummond. 2015. 'Improvements in the application and 
reporting of advanced Bland-Altman methods of comparison', J Clin Monit Comput, 29: 127-39. 
Sundman, E., H. Witt, R. Olsson, O. Ekberg, R. Kuylenstierna, and L. I. Eriksson. 2000. 'The incidence 
and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: 
pharyngeal videoradiography and simultaneous manometry after atracurium', Anesthesiology, 92: 
977-84. 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 26 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
Todd, M. M., and B. J. Hindman. 2015. 'The Implementation of Quantitative Electromyographic 
Neuromuscular Monitoring in an Academic Anesthesia Department: Follow-Up Observations', 
Anesth Analg, 121: 836-8. 
Todd, M. M., B. J. Hindman, and B. J. King. 2014. 'The implementation of quantitative electromyographic 
neuromuscular monitoring in an academic anesthesia department', Anesth Analg, 119: 323-31. 
Woehlck, H. J., B. T. Boettcher, K. K. Lauer, D. C. Cronin, J. C. Hong, M. A. Zimmerman, J. Kim, and M. 
Selim. 2016. 'Hydroxocobalamin for Vasoplegic Syndrome in Liver Transplantation: Restoration 
of Blood Pressure Without Vasospasm', A A Case Rep, 7: 247-50. 
 
 
 List of In-Text Tables 
18
18.1 Schedule of Events 
 
 
Schedule of Events 
Study Activity 
Visit  1 
Visit 2 
ToFscan and 
Tetragraph 
 
X 
Informed consent 
X 
 
Review of Medical 
Record 
X 
 
Adverse event 
evaluation 
 
X 
 
18.2 Intraoperative Data 
 
Study ID: 
 
Examiner 
Initials: 
 
Date (dd / mm / 
yyyy): 
 
 
Muscle relaxant name: 
 
Muscle relaxant total dose (mg): 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 27 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
Time of last muscle relaxant dose (mm : hh): 
                           :                        am  /  pm 
 
Reversal agent name: 
 
Reversal agent dose (mg): 
 
Time of reversal agent administration (mm : hh): 
                       :                   am  /  pm 
 
Time of extubation: 
                               :                               am  /  pm 
 
TOF ratio / TOF count at the time of reversal (if available): 
Monitor used 
during reversal: 
PNS  /  IntelliVue NMT  /  ToFscan  /  None 
Site of monitoring 
during reversal: 
Hand  /  Face  /  Leg 
 
TOF ratio / TOF count at the time of extubation (if available): 
Monitor used at 
extubation: 
PNS  /  IntelliVue NMT  /  ToFscan  /  None 
Site of monitoring: 
Hand  /  Face  /  Leg 
 
18.3 PACU data 
 
Study ID  
 
Date of Surgery (dd / mm / yyyy): 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 28 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
Initials: 
 
Dominant side: L  /  R 
Age (yrs): 
 
Weight (kg): 
 
Height (cm): 
 
BMI: 
 
 
TetraGraph (TG)  
 
 
Arm tested:   dominant / non-dominant 
 
TOFR #1 
TOFR #2 
TOFR #3 
(if needed) 
VNRS  
T0 (on arrival to 
PACU) 
 
 
 
 
T5 (5 min later) 
 
 
 
 
T10 (10 min later)  
 
 
 
Predischarge 
VNRS 
xxx 
xxx 
xxx 
 
 
ToFscan (TS)  
Arm tested:    dominant / non-dominant 
 
TOFR #1 
TOFR #2 
TOFR #3 
(if needed) 
VNRS  
T0 (on arrival to 
PACU) 
 
 
 
 
T5 (5 min later) 
 
 
 
 
T10 (10 min later)  
 
 
 
Predischarge 
VNRS 
xxx 
xxx 
xxx 
 
TG= TetraGraph; TS= ToFscan; TOFR= train-of-four ratio; VNRS= verbal numeric rating scale 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 29 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
 
 List of In-Text Figures 
19
19.1 TetraGraph 
 
 
19.2 ToFscan 
 

ToFscan vs TetraGraph 
 
Version 3.0 
 
 
11/Oct/19 
Page 30 of 30 
J. Ross Renew, MD 
 
CONFIDENTIAL 
19.3 VNRS