Conditions: General Surgery
Keywords: Postoperative respiratory depression Neuromuscular Agents
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 260
Healthy volunteers: no

Brief summary:
The study is designed to determine whether patients who receive sugammadex immediately after tracheal extubation will exhibit a decrease in the incidence of postoperative residual paralysis and an associated decrease in the incidence of postoperative respiratory depression.

Detailed description:

Arms:
arm 1: Subjects will have Sugammadex administered after routine reversal of anesthesia is performed and patient is extubated. arm 2: Subjects will have Placebo administered after routine reversal of anesthesia is performed and patient is extubated.

Interventions: intervention 1: Sugammadex intervention 2: Placebo
Intervention descriptions: intervention 1: Sugammadex will be administered intravenously at 2 mg/kg after routine reversal of anesthesia is performed and subject is extubated. intervention 2: Placebo will be administered intravenously at 2 mg/kg after routine reversal of anesthesia is performed and subject is extubated.

Protocol document:
Prot_SAP_000.pdf: 
Randomized Double-­­Blinded, Controlled 
Trial to Compare the Effectiveness of 
Sugammadex vs. Placebo to Prevent 
Residual Neuromuscular Block in the Post-­­
Anesthesia Care Unit as Evaluated with a 
Non-­­Invasive Respiratory Volume Monitor  
  
NCT02728726 
 
6/29/2017 










MISP Template: Protocol 
5 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
B.   Respiratory Volume Monitoring (RVM) Background: 
 
An  non-­­invasive  RVM  (ExSpiron,  Respiratory  Motion,  Inc., Waltham 
MA) based on thoracic electrical impedance been shown to  accurately  
monitor  respiratory  status  in  non-­­intubated patients, providing a 
real-­­time respiratory curve and measurements of minute ventilation 
(MV), tidal volume (TV) and respiratory rate.4,5,6,7,8 The ExSpiron 
system consists of two main components, a monitor and an electrode 
PadSet, which utilizes 3 adhesive electrode patches placed on the 
thorax, similar to ECG monitoring electrodes. 
 
Simultaneous measurements of MV, TV, and RR with the RVM and a 
Wright monitoring spirometer demonstrated a precision error of 
7.2% and 7.1% for MV and TV, and an accuracy error of 9.3% and 
9.0%, respectively. Throughout the range of 4 breaths per minute 
(bpm) to 40 bpm and during erratic breathing, RVM measurements 
were highly correlated with measurements made with a Morgan 
diagnostic spirometer (r = 0.96, 95% CI: 0.93 to 0.99).9 
 
In a recent study at the Massachusetts General Hospital in Boston 
published  in  the  Journal  of  Trauma,10   the  RVM  evaluated  132 
PACU patients following elective joint replacement surgery under 
general or regional anesthesia.  This  work  demonstrated  the effects  
of  opioids  on  RVM  measurements,  and  a  stratification based on 
opioid sensitivity was proposed.  This finding is relevant to the study 
proposed here, because the following categories were defined: “At-­­
Risk”  was defined as patients with a MV <80% of a given  patient’s  
predicted  MV  based  on  a  body  surface  area formula. “Un-­­Safe”  
MV was considered to be <40% of Predicted MV sustained for at 
least 2 minutes. 


MISP Template: Protocol 
6 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
 
 
Figure  1:  A)  MV  measurements  at  various  time  points  in  the  PACU. 
Across  the  entire  patient  population  a distinct  depression  in MV  within  15 
minutes of the first opioid dose in the PACU was seen. The average MV across 
the whole population did not noticeably decrease and recovers to baseline prior 
to discharge. B) MV across the cohort calculated  as percent predicted  by 
BSA. The plot demonstrates MV as Percent Predicted (MVPRED), and allows 
normalization of the opioid response to account for patient size. C) Patients 
designated “At-Risk” The red bars show the course of the 18 of 50 (36%) of 
patients who received an opioid dose when their MV was below 80% MVPRED 
became “Un-Safe”.  D) Patients designated  “Not-at-Risk”  Green bars show 
the course  of the remaining  32/ 50 (64%)  of patients  who  received  opioids 
when   their  MV  was  above   80%   MVPRED    and  had  minimal   respiratory 
depression. 
 
 
 
C.   Train-­­of-­­Four Monitoring Background: 
 
Train-­­of-­­Four (TOF) is used as an indicator of the depth of 
neuromuscular block and adequacy of reversal. A normal TOF = 
1.0, meaning that there is no fade (no decrease in the amplitude of the 
fourth response, T4, compared to the first response, T1).11 
With increasing levels of neuromuscular block, the TOF decreases 
from 1.0 to 0, at which point the degree of block correlates with 
80-­­85% neuromuscular receptor occupancy. This degree of block 
is sufficient for non--­intracavitary surgeries. For abdominal, thoracic, 
intracranial surgeries, and for robotic, laparoscopic and bariatric 
surgery, all 4 of the TOF responses need to be blocked, 
corresponding to 95-­­100% receptor blockade. While facilitating 
surgery, this extreme degree of block is very difficult to reverse with 
traditional anticholinesterase drugs like neostigmine. In the vast  
majority  of  patients,  reversal  with  neostigmine  from  this deep 
block may require 90-­­120 minutes, markedly increasing the surgical 
duration. Additionally, up to 40% or ALL patients who receive 
intraoperative NMBAs have been shown to exhibit significant residual 
neuromuscular block (TOF<0.9), and 0.8% of 






MISP Template: Protocol 
9 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
 
D. Risk/Benefit Assessment: 
 
Sugammadex. Sugammadex has been FDA approved for clinical 
use in the US and it has been used worldwide since 2008. We 
plan 
to 
administer the 
smallest dose of 
sugammadex 
recommended for shallow neuromuscular block (2 mg/kg of 
actual body weight), a dose that has not been reported to cause 
allergic or any other side effects. The use of sugammadex may 
lead to complete reversal of residual neuromuscular block, and 
avoidance of the respiratory complications (CREs) associated 
with incomplete reversal after neostigmine. 
 
TOF Measurement. This involves delivery of small electrical 
impulses from a nerve stimulator via surface ECG electrodes to a 
peripheral nerve (usually the ulnar nerve at the wrist) and 
measuring the muscle contraction in the innervated muscle 
(usually the adductor pollicis muscle or the thumb. This testing is 
used routinely in many centers in awakening patients in the 
PACU, and it is not associated with any adverse effects or patient 
discomfort. In fact, routine monitoring has been advocated 
routinely for decades, as it both decreases the incidence of 
CREs and other postoperative complications and increases 
patient satisfaction.11,12 
 
ExSpiron Respiratory Volume Monitoring (RVM).  The RVM 
device has been FDA cleared and is currently in clinical use. It is 
considered a “non-­­significant risk device”. The device requires 
the application of monitoring PadSets to the patient’s skin 
similar to EKG electrodes and, as such, poses minimal risk. It is 
possible that the  electrodes  may  irritate  the  skin.     The  
presence  of  skin irritation will be monitored and treated 
appropriately, and further subject participation with cease if it 
is significant. Collected data up to that point will be used for the 
study, unless the subject requests otherwise. Direct physical 
harm is extremely unlikely. Any adverse events will be 
documented and forwarded to the IRB as per adverse event (AE) 
reporting requirements. 
 
There is always a risk for breach of confidentiality despite best 
efforts. 
 
Categories of Risk: 
 
1) Physical Risk: Sugammadex administration may result in 
temporary changes in taste sensation (disgeusia); allergic 
reactions  have  been  reported  exceedingly  rarely  at  the dose we 
plan to administer (2 mg/kg).   Rare allergic reactions have been 
reported in patients receiving the highest dose indicated, 16 
mg/kg, which is 8 times higher than the dose we plan to 






MISP Template: Protocol 
12 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
which may decrease the incidence of residual neuromuscular block.) 
1)  The ExSpiron will be placed on the patients’ chest prior 
to extubation. ExSpiron data will be collected starting 
prior to tracheal extubation,  during  transport  from  OR  
to  PACU,  and  in PACU. 
2)  Patient care staff will be blinded to the ExSpiron 
numerical and trending data for MV, TV and RR, but the 
respiratory trace will be displayed to demonstrate that the 
ExSpiron is functioning. Of note, the gain on the trace is 
variable so the size of the breath visualized on the screen 
is not correlated to the volume of the breath. This will 
maintain blinding of the patient care staff. 
3)  TOF Monitoring with an objective monitor (TOF--Watch or 
StimPod) will be used in all patients once the decision 
to extubate the patients’ trachea is made. The monitoring 
will continue in the PACU until full recovery (TOF=1.0) is 
documented. Monitoring will be performed as per usual 
clinical routine via surface ECG electrodes. In the PACU, 
the current amplitude will be decreased to 30-­­40 mA, 
current intensities that are used routinely for patient care 
in other centers and that do not result in patient 
discomfort. 
4) Patient care staff will be blinded to TOF data. Only the 
investigator assigned to the PACU data retrieval will know 
the results of TOF Monitoring. 
5)  Patient care should follow standard hospital protocol. 
6)  Physiologic monitoring and clinical assessment data will be 
recorded as per standard protocol in the PACU. 
7)  All  other  therapies  and  medications  including  oxygen, 
CPAP,  opioids  and  sedatives  will  be  delivered  in 
accordance with standard of care. 
8)  Doses  and  times  of  all  medications  (such  as  opioids, 
sedatives, etc.) or respiratory interventions (such as 
albuterol, respiratory treatment, suctioning, high flow 
oxygen, CPAP, BiPAP, etc.) will be recorded throughout the 
entire perioperative period (pre-­­op, OR, PACU). 
9)  Pain scores based on a standard analog scale (1-­­10) will be 
recorded. These will be obtained per standard clinical 
practice. 
10)Arterial or venous blood gas values and Chest x-­­rays taken 
in the OR or PACU will be recorded when obtained as part 
of standard care. 
B. Study Procedures 
1)  Screening and Recruitment: 
Study   personnel  will   review  the   surgery  schedule  
to identify appropriate and eligible patients.  Eligible  


MISP Template: Protocol 
13 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
patients will be informed about the study and the study 
will be explained to them.  They will be able to ask 
questions.  If they would like to participate, written 
informed consent will be obtained. Recruitment at Mayo 
Clinic site will be conducted by Investigators on the day of 
surgery. Patients will be identified and approached before 
they are taken to the preoperative area. A private room 
located near the surgical area will be used for consenting 
of prospective participants. Family and/or friends will be 
allowed to remain with a patient during the consenting 
process. Patients usually arrive approximately 2 hours 
prior to their scheduled surgery time, which will be 
adequate time to discuss the study and allow patients to 
make an informed decision whether or not to participate 
in this research study. 
2)  Randomization: 
Patients   will   be   randomized   to   one   of   two   groups: 
administration   of    sugammadex    (n=150)   vs.    placebo 
(n=150) prior to tracheal extubation in the OR. 
3)  Prior to Procedure (in the OR or preoperative area): 
i. 
For RVM monitoring, ExSpiron PadSet will be placed 
on   the   patient’s   thorax   (see   Appendix   A   for 
placement instructions). Deviations from standard 
placement will be documented. Once in the OR the 
ExSpiron will be connected and the ExSpiron will be 
synchronized to the ventilator. 
 
ii. 
For  TOF  monitoring,  skin  ECG  electrodes  will  be 
placed along the ulnar nerve on the volar forearm, 
as per routine clinical protocol. Visual or tactile 
intraoperative monitoring of neuromuscular block 
level will be performed according to the clinicians’ 
usual routine. At the end of surgery, once the 
clinician 
has 
determined 
that 
recovery 
of 
neuromuscular 
block 
is 
adequate 
(after 
administration of standard of care reversal agents) 
for maintenance of spontaneous   ventilation,    the    
TOF    will    be determined  objectively  (it  will  be  
measured with the currently available monitor, 
TOF-­­Watch or StimPod), and then the patient’s 
trachea will be extubated, as per usual clinical 
routine. In 150 of the 
300 patients, a dose of sugammadex (2 mg/kg) will 
be 
administered, 
and 
then 
routine 
TOF 
measurements will be made in the PACU. 
4)   Operating Room (OR): 
a.   Record all medications (dose, route, time) 


MISP Template: Protocol 
14 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
b.   Record surgery start and end times 
c. Record position changes 
d.   Record intubation and extubation times 
5)  Recovery Room (PACU): 
a.   Record PACU arrival and check device function. 
b.   Record all medications (dose, route, time) 
c. Record form and dose of administered oxygen & all 
changes in administered oxygen or respiratory 
treatments of any kind 
d.   Record PACU discharge time 
e.   MV, TV & RR numerical data will be hidden and not  
 


MISP Template: Protocol 
15 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
available for patient care decisions, but the 
continuous respiratory trace will be displayed. 
Patient care providers should not use this trace for 
clinical decision-­­making. If the trace is absent or 
grossly abnormal, this should be recorded and study 
staff notified to ensure proper device function. 
f. TOF  data  will  be  hidden  and  not  available  for 
patient care decisions 
6) Final Discharge Parameters: Record the patients’ final 
discharge date and time (LOS) from the PACU. 
7)  De-­­identification:   All study data will be de-­­identified  and 
identifying information will be linked to a code only 
accessible to the study staff. The code will be destroyed 
following final data analysis. 
8) Assessment of Subject Safety and Data Safety Monitoring 
Plan: All patients will be followed by one of the study 
investigators to ensure there are no complications 
associated with sugammadex administration (flushing, 
tachycardia, hypotension, etc). There are no expected 
complications of RVM monitoring. There are no expected 
complications associated with TOF monitoring, and in fact, 
such monitoring has been shown to improve patient safety 
by 
decreasing      postoperative      CREs      and      other 
complications.11,12 External monitoring will not be 
provided; however, Principal Investigator will review all 
data for accuracy to ensure adherence to the approved 
protocol. Data will be recorded by the study coordinator 
and all electronic study-related files will be stored on a 
secured Mayo Clinic server. Drug accountability and 
dispension will be handled by pharmacy. Any potential 
adverse events will be assessed by the principal 
investigator for severity and relevance to the study drug. 
9)   Subject Participation: 
 
a.   Recruitment: Subjects will be recruited in the pre-­­ 
procedure  holding  areas  by  the  study  team 
members prior to their surgery. 
 
b.   Screening   Interview:   Subject   screening   will   be 
based on study personnel examining the surgery 
schedule of the next or same day to identify 
appropriate procedures scheduled and patient’s 
eligibility. 
 
c. Informed consent process and timing of obtaining of 
consent: Informed consent will be obtained by the 
study staff prior to surgery in the preoperative 
holding area, in patients requiring surgery and 


MISP Template: Protocol 
16 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
general anesthesia and  planned  extubation  in  the 
OR.  After a thorough review of the study. Sufficient 
time will be given to the patients, parents, guardians 
or legal representative to ask questions and decide 
on participation. 
 
d.   Location where study will be performed: University  
 


MISP Template: Protocol 
17 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
of Texas, UTHealth at Houston and Mayo Clinic, 
Jacksonville, Florida 
operating holding 
areas, 
operating and recovery rooms, and intensive care 
units as applicable. 
e.   Personnel who will conduct the study include PI and 
research team members. 
 
10) Subject fees: There are no fees for this study. 
11) Procedures to  protect subject confidentiality:   A  unique 
study  ID  number  will  be  assigned  to  each  subject  as  a 
means to de-­­identify the study data. A code will be kept 
separately with the PI. Study files will be kept in a locked 
office  in  a  locked  cabinet  or  a  password-­­protected 
computer with encrypted study files. The location will be 
the PI office with restricted access. The code will be locked 
separately from study files in the PI office. 
 
a. 
Certificate of Confidentiality: N/A 
 
b.  
How data will be coded, recorded, and stored to 
protect confidentiality: All data will be de-­­ 
identified.  All data will be linked to the subject 
study ID by a code. 
 
c.  
Data     will     be     analyzed     by     institutional 
biostatisticians at UTHealth at Houston. 
 
d.  
Parties   who   will   have   access   to   the   data, 
including the key to the identity code: only Jaideep 
Mehta,  MD  and  J. Ross Renew,  MD  and  primary 
study staff will have access to the master study 
log/key.  Other investigators and the clinical and 
engineering staff at Respiratory Motion, Inc. will 
only have access to de-­­identified data. 
 
e.  
Parties   who   will   have   access   to   research 
records: Investigators on the study, Respiratory 
Motion, Inc. will have access only to de-­­identified 
records. 
 
f.  
Collaboration:   This   study   is   performed   in 
collaboration with Respiratory Motion, Inc. 
 
g.  
Alternatives: The alternative to participating in 
this study is not participating. 
 
h.  
How new information will be conveyed to the 
study subject and how it will be documented: Other 
than the initial explanation of the purpose and plan 
for the study, we don’t expect new information to  






MISP Template: Protocol 
20 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
B. Statistical Analysis: 
 
a.   Using Fisher exact test, we will compare across the two 
groups the incidence of: 
 
i.   Sustained MV<80%MVPRED for at least 1 minute in the 
first 15-30 minutes after arrival in PACU 
ii.   Sustained MV<40% MVPRED for more than 10 
contiguous minutes of the last 30 minutes prior to PACU 
discharge 
iii.. Sustained MV<40%MVPRED for at least 2 
minutes after opioid administration (amongst 
patients receiving opioids in the PACU) 
iv.   Sustained MV<40%MVPRED for at least 2 minutes in 
the absence of opioids (amongst patients w/o opioids in 
the PACU 
v. Sustained MV<40%MVPRED for at least 2 
minutes after opioid administration (amongst 
patients receiving opioids in the PACU) when 
corrected for PACU LOS 
vi.   Sustained MV<40%MVPRED for at least 2 minutes in 
the absence of opioids (amongst patients w/o opioids in 
the PACU when corrected for PACU LOS 
vii.   Adverse events, including: 
 
1.   Respiratory complications (O2 desaturation, 
atelectasis, respiratory status requiring 
advanced monitoring, etc.) 
2.   Respiratory interventions (O2 
administration, CPAP, BiPAP, medications, 
etc.) 
3.   ICU or step-­­down unit transfer 
 
viii.   Normal TOF ratio (>0.90) at equivalent time points 
in the PACU (e.g. on arrival, at discharge, etc…) 
 
b.   Using 2-sample t-­­tests we will compare: 
 
i.   Average MV during the 15-30 minutes after arrival at 
the PACU 
ii.   Average MV during the 30 minutes prior to the 
time cleared for PACU discharge  
iii.   Average LOS in the PACU 
iv.   Average pain scores 
v.   Average total opioid dose (morphine equivalents) in 
the PACU 
 
 


MISP Template: Protocol 
21 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
c. Using paired t-­­tests we will compare: 
i.   MV, TV, and RR measurements before and after 
sugammadex administration 
d.   We will perform sensitivity and specificity analysis to 
evaluate the ability of sugammadex to: 
i.   Decrease respiratory complications (O2 
desaturation, atelectasis, respiratory status 
requiring advanced monitoring, etc.) 
ii.   Decrease the need for respiratory interventions (O2 
administration, CPAP, BiPAP, medications, etc.) 
iii.   Decrease transfers to step-­­down or ICU 
iv.   Decrease LOS in PACU 
v.   Increase MV in the PACU at the following time 
points: 
1.   On arrival 
2.   After opioids 
3.   At discharge 
e.   We will perform multi-­­factor Analysis of Variance 
(MFANOVA) with dependent variables: “sustained 
MV<40% MVPRED for at least 2 minutes”, “Adverse event”, 
PACU LOS, etc… as defined in each hypothesis, based on 
demographics to demonstrate group uniformity. 
f. We will use Pearson correlations and linear regressions, 
without regard to treatment group to compare: 
i.   MV measurements and TOF ratios 
ii.   MV measurements and total opioid dose 
iii.   Pain scores and total opioid dose 
iv.   MV measurements and pain scores 
 
C. Multiplicity: 
For the purposes of this work, we will treat Hypothesis A1 as a 
primary objective and A2 as a key secondary.  We will consider 
p<0.05 to be statistically significant for the primary objective and 
this result will be the main outcome of our study. We will test the 
key secondary objective (at p<0.05 significance level) only if we 
have achieved significance with the primary.  
 
We will continue with testing the remaining secondary 
hypotheses only if we have significant results from the primary 
and the key secondary. For each additional secondary 
hypothesis, we will calculate statistical significance both with 
and without Hochberg correction.14 If we discover marginally 
significant effects in any of the remaining hypotheses, we will 
propose additional studies powered and geared towards 
specifically addressing said hypotheses. 
 
 


MISP Template: Protocol 
22 
Final Version: 4/6/2015 
Protocol Version date 6/29/17 
 
 
 
D. Power/Sample Size: 
Considering the study in general, the incidence of residual 
neuromuscular block in the PACU is estimated to be 35%.11 
Based upon a sample size of n=92 patients per group, this 
study has 80% power to detect a 5% difference between groups 
in incidence of residual block; this calculation is based on a 
standard deviation of 12%. We would need 100 patients per 
group in order to be conservative to observe this effect.However, 
more specific calculations related to our primary and key 
secondary hypotheses described below suggest we would need 
150 patients per group to ensure we can adequately power these 
hypotheses. 
 
(1) Low MV on arrival at the PACU. We will be comparing 
absolute measurements of MV as well as incidences of MV<80% 
across the two groups. Since comparisons of incidences usually 
requires more data, we are basing our sample size calculations on 
the incidence comparison. 
 
Previous data suggest that as many as 33% of patients arrive in 
the PACU with MV<80% MVPRED. We anticipate that in a group of 
similar patients receiving sugammadex at the end of surgery, the 
prevalence of MV<80%MVPRED will decrease significantly, by 
approximately 18% (
). To demonstrate this reduction 
with 80% power (
) at a 
 level (
), the 
required sample size (assuming a large patient population) for 
each of the two groups (with and w/o sugammadex) can be 
calculated as follows: 
 
 
 
 
where 
is the average incidence in the two groups and 
is the difference in the incidence of low MV across 
the two groups.  
 
(2) Low MV at discharge from the PACU. Similarly with the PACU 
arrival, at PACU discharge we will compare both MV 
measurements as well as the incidence of Low MV and will 
calculate our sample size  based on the incidence comparison 
 
Previous data suggest that around 22% of patients leave the PACU