Postoperative Consequences of Intraoperative NOL Titration
Phase: PHASE3
Conditions: Anesthesia; Adverse Effect
Sponsor: The Cleveland Clinic

 
 
 
Postoperative Consequences of Intraoperative 
NOL Titration 
 
 
Version 3, 11-03-2020 
NCT04679818 
 
Primary Investigator: 
Kurt Ruetzler, MD 
 
 
Co Investigators: 
Praveen Chahar, MD 
Jacek Cywynski, MD 
Tatyana Kopyeva, MD 
Allen Keebler, DO 
Kamal Maheshwari, MD 
Edward Mascha, PhD 
Alparslan Turan, MD 
 
Lead fellows: 
Mateo Montalvo, MD 
Hani Essber, MD 
Jeevan Shivakumar, MD 
Marc Schmidt, MD 
 
 
Anesthesiology Institute, Department of OUTCOMES RESEARCH and Department of 
General Anesthesiology, Cleveland Clinic, Main Campus, 9500 Euclid Ave — P77, 
Cleveland, OH 44195, Tel: 216 407-4108, email: ruetzlk@ccf.org 

NOL study protocol, Version 3.0, page 2 
 
Background 
Opioid requirements in hospitalized patients varies at least ten-fold depending on 
a host of factors, many of which are unknown to clinicians or poorly characterized in 
medical records. Important factors include genetic sensitivity, alcohol consumption, 
previous opioid use, pain intensity etc. Even within specific categories, say chronic opioid 
users, there is tremendous variation in sensitivity — and thus opioid requirement under 
various conditions. 
In most situations, patients can simply be queried about pain, and their responses 
used to guide analgesic administration. But during anesthesia, patients do not experience 
pain (a conscious response). But patients nonetheless clearly experience and respond to 
nociception even during general anesthesia. Increases in blood pressure and heart rate 
roughly indicate when patients are experiencing nociceptive stress, but neither is reliable. 
No other routine anesthetic monitors provide useful indications of nociceptive intensity. 
Even experienced anesthesiologists cannot reliably predict or estimate opioid 
requirements in individual patients. Consequently, most routinely give small amounts of 
opioid during general anesthesia, and often give a bolus of a slow-onset, long-acting 
opioid such as morphine or hydromorphone at the end of surgery to provide analgesia 
during the initial hours of post-anesthetic recovery. The doses given, while reasonable on 
average, often prove inadequate or excessive for individual patients. Those given too 
much awaken slowly at the end of anesthesia and may breathe poorly; those given 
inadequate doses suffer intense pain upon awaking and it often takes many boluses of 
opioid and considerable time to control their pain. 
There are now several devices that estimate nociception during general 
anesthesia including the Surgical Pleth Index, pupillary reflexes, galvanic skin 
responses, and heart-rate variability.1-4 The best-validated system is the PMD-200 
system from Medasense (Ramat Gan, Israel). It is comprised of a console and 
designated finger probe and a single-use sensor. The PMD-200 acquires 4 signals: 
photoplethysmography, galvanic skin response, accelerometery, and skin temperature. 
Based on a random forest analysis, the device generates the NOL index.5,6 The 
intended use of NOL is to assess nociception input during general anesthesia. 
NOL is a unitless index that extends from 0 to 100, with values exceeding 25 
indicating that patients are experiencing substantial nociceptive input.7 Previous work in 
anesthetized patients has shown that NOL values are low in the absence of nociceptive 
input (e.g., when unstimulated) and progressively increase in response to progressively 
more intense stimuli (e.g., tetanic electrical stimulation, skin incision, and intubation).6 At 

NOL study protocol, Version 3.0, page 3 
 
this point, there are only limited data — largely unpublished — showing that titrating 
intraoperative opioids to NOL improves post-anesthetic recovery. 
Most studies of NOL titration and recovery characteristics were conducted with 
remifentanil infusions, using target-controlled infusion, an opioid-dosing technique that is 
rarely used in the United States and not approved by the Food and Drug Administration.6 
Whether intraoperative titration will improve recovery characteristics will depend critically 
on the choice of opioid(s). Remifentanil is easy to titrate because the drug is potent and 
ultra-short acting. Patients given remifentanil are thus usually given a bolus of long-acting 
opioid such as morphine or hydromorphone near the end of surgery to bridge the 
analgesic gap between remifentanil discontinuation and arrival in the PACU. Thus, PACU 
recovery characteristics are largely determined by the long-acting opioid bolus timing and 
dosage which is given empirically and independent of NOL guidance. 
Fentanyl is probably the ideal intraoperative anesthetic for NOL testing because of 
its intermediate and context-sensitive half-life (effect is proportional to not just dose but 
duration of administration). Fentanyl is initially short acting (typically 15 minutes) and thus 
easy to titrate. Its action is not terminated by metabolism; instead, the lipophilic drug 
redistributes into fat tissue. But after several hours of administration, much of the fat 
reservoir fills, and the drug’s effect then becomes constrained by rate of metabolism, and 
can exceed the duration of morphine effect. Fentanyl is thus initially short acting, when 
titration is necessary, but then becomes long-acting and remains effective at least during 
the initial part of recovery. Patients who have long operations (≥2 hours) who are given 
the “right amount” of intraoperative fentanyl have effective pain control without use of a 
long acting opioid. 
Specific Aims 
Previous work has shown that NOL (Medasense, Ramat Gan, Israel) accurately 
quantifies nociception during general anesthesia.6 Presumably, titrating opioids to NOL 
will therefore provide individual guidance so that patients will be given about the right 
amount. Patient given the right amount will presumably awaken quickly when anesthesia 
is done, and have good initial pain control in the PACU. To the extent that NOL titration 
facilitates optimal opioid dosing, patients are likely to have better PACU experiences — 
which would be an important outcome that clinicians and regulators are likely to take 
seriously. 
Aim of this study: 
Demonstrate that intraoperative NOL-guided titration of fentanyl improves initial 
recovery characteristics. All times below are relative to when sevoflurane anesthesia is 
discontinued. 

NOL study protocol, Version 3.0, page 4 
 
Primary hypothesis. 
Pain scores (0-10 verbal response scale) at 10-minute 
intervals during the initial 60 minutes of recovery are less in 
patient with NOL-guided fentanyl than with routine care, 
with 1 point being considered a clinically meaningful 
difference 
Primary Outcome. 
Pain Scores at 10-minute intervals during the initial 60 
minutes of recovery 
 
Secondary hypothesis.   NOL patients are more likely to have a “good” pain scores, 
defined as < 5 (i.e., 0,1,2,3 or 4) across the measured 
intervals, with a relative 10% or more increase in the 
proportion of good scores being considered clinical 
meaningful. 
Secondary Outcome. 
Whether or not the pain score at any measured interval is 
< 5. 
 
We will also consider several exploratory hypotheses. 
 
Exploratory hypothesis 1.  Fewer analgesic rescue boluses are required in NOL- 
titrated patients during the initial 60 minutes of recovery. 
 
Exploratory hypothesis 2.  NOL-guided patients are no less alert (Ramsay score) 
during the initial 60 minutes of recovery than those given 
fentanyl per routine, based on a clinically meaningful non- 
inferiority delta of 20%. 
Exploratory hypothesis 3.  Emergence  from  anesthesia  (discontinuation  of 
sevoflurane anesthesia to extubation) is faster in NOL- 
guided patients. 
Exploratory hypothesis 4.  Fewer NOL-guided patients experience post-operative 
nausea and/or vomiting (PONV) at least once during the 
initial 60 minutes of recovery. 
Exploratory hypothesis 5.  There are fewer episodes of inadequate analgesia (too 
much or too little) in NOL-guided patients. Inadequate 
analgesia will be defined by systolic pressure ≥140 mmHg, 
heart rate exceeding 90 beats/min, diaphoresis, tearing, or 
movement. Excessive anesthesia will be defined by MAP 
<65mmHg or BIS < 40. All values must return to normal for 
at least 15 minutes for a subsequent deviation to be 

NOL study protocol, Version 3.0, page 5 
 
considered a new episode. The outcome for a patient will 
be 
the 
number 
of 
episodes. 
 
 
Exploratory hypothesis 6. There will be less respiratory depression during the initial 
60  minutes  of  recovery,  defined  as  respiratory  rate 
<8 breaths/min or saturation <90% for at least 1 minute 
while on nasal cannula oxygen at 2 L/min; unplanned 
airway support after PACU admission (nasal trumpet, oral 
airway, PPV, BiPap, or intubation with a laryngeal airway or 
endotracheal    tube);    or    naloxone    use. 
 
 
 
Methods 
The study will be conducted with IRB approval and written informed consent. The 
trial will be registered at ClinicalTrials.gov before the first patient is enrolled. 
Subject selection 
We will enroll patients having laparoscopic major abdominal or pelvic surgery, or 
similarly large operations. Patients who chronically use opioids will not be excluded. Both 
men and women will be recruited, and we will encourage under-represented minorities to 
participate. We will enroll up to a maximum of 144 adult patients. 
Inclusion criteria 
1) Adults having major non-cardiac surgery expected to last ≥2 hours; 
2) American Society of Anesthesiologists physical status 1-3; 
3) Age 21-85 years old; 
4) Planned endotracheal intubation. 
 
Exclusion criteria 
1) Planned neuraxial or regional block; 
2) Clinician preference for an opioid other than, or in addition to, fentanyl; 
3) Non-sinus heart rhythm; 
4) Neurologic condition that, in the opinion of the investigators, may preclude 
accurate assessment of postoperative pain and nausea; 
5) Lack of English language fluency; 
6) Routine user of psychoactive drugs other than opioids; 
7) Contraindication to sevoflurane, fentanyl, morphine, or ondansetron. 

NOL study protocol, Version 3.0, page 6 
 
8) Intracranial surgery. 
9) BMI > 40 
 
 
 
Protocol 
Patients will be premedicated with 0-2 mg midazolam per preference of the 
attending anesthesiologist. General anesthesia will be induced as preferred by the 
attending anesthesiologist, usually with a combination of lidocaine 1 mg/kg, propofol 1-4 
mg/kg, fentanyl 1-2 µg/kg, and rocuronium 0.6-1.2 mg/kg or succinylcholine 1.5 mg/kg, 
as clinically appropriate. The trachea will be intubated and the lungs will be mechanically 
ventilated per clinical routine. General anesthesia will be maintained with sevoflurane at 
a target concentration of 0.7 %, with the dose being adjusted based on apparent clinical 
need, supplemented with fentanyl. Sevoflurane will be given per clinical routine and 
adjusted as usual in response to vital signs, surgical need, etc. Nitrous oxide will not be 
used for induction or during anesthetic maintenance. Vasopressors, antihypertensives, 
and drugs to control heart rate may be given as clinically indicated. Depth of anesthesia 
will be recorded for all patients using BIS. 
Unless another opioid is clinically indicated, fentanyl will be the only opioid used 
for induction and throughout anesthesia. Long-acting opioids such as morphine will not 
be given. No opioid will be given unless clinically indicated from the end of surgery until 
patients reach the recovery unit. 
Patients will be randomized 1:1, stratified for pre-operative chronic opioid use, with 
random-sized blocking to NOL guided analgesic management or routine care. The 
randomization table will be prepared by trial statisticians, and allocation will be concealed 
until shortly before anesthetic induction with a web-based randomization system. 
1) Routine opioid management. Clinicians will be blinded to NOL monitoring 
and use clinical judgement to determine how much fentanyl should be given, 
and when. Clinical judgement will be according to their standard practice and 
may include interpretation of blood pressure, heart rate, diaphoresis, tearing, 
and pupil size. Boluses of fentanyl 1 µg/kg actual body weight (ABW), up to a 
maximum dose of 100 µg per bolus, can be given per clinical judgement. 
Towards the end of the surgery (approximately 30-45 minutes before end of 
surgery, based on clinical judgment), the boluses of fentanyl will be reduced to 
0.5 µg/kg ABW, up to a maximum of 50 µg per boluses. Boluses will be given 
per clinical judgment. 
2) NOL-guided opioid administration. Clinicians will titrate fentanyl to keep 
NOL under 25 — always using good clinical judgement for individual patients. 

NOL study protocol, Version 3.0, page 7 
 
NOL values exceeding 25 for more than 30 seconds will typically be treated 
with boluses of fentanyl 1µg/kg ABW, up to a maximum of 100 µg per boluses, 
5-minute intervals. Towards the end of the surgery (approximately 30-45 
minutes before end of surgery, based on clinical judgment), the boluses of 
fentanyl will be reduced to 0.5 µg/kg ABW, up to a maximum of 50 µg per 
boluses, 5 minutes intervals. The target of a NOL score below 25 will be 
maintained until surgery ends. 
Approximately 20-30 minutes before end of the surgery, a preemptive bolus of 
hydromorphone will be given intravenously per clinical routine; 
- 
Patients younger than 70 years: 0.4 mg of hydromorphone for patients with an 
ABW <60 kg and 0.6 mg of hydromorphone for patients with an ABW > 60 kg 
- 
Patients aged between 70 and 75 years: 0.4 mg of hydromorphone, 
- 
Patients older than 75 years: 0.2 mg of hydromorphone. 
Near the end of surgery, 4 mg ondansetron will be given intravenously per clinical routine. 
Upon completion of surgery, sevoflurane will be discontinued. Neuromuscular block will 
be reversed with sugammadex per clinician preference. At the end of the surgical 
procedure, patients will be extubated and transferred to the post anesthesia care unit 
(PACU). 
Surgical pain will be treated with boluses of intravenous morphine/ hydromorphone 
per clinical routine by nurses blinded to intraoperative randomization. PCA will be 
activated upon arrival to PACU, per routine care. Generally, rescue boluses are given 
when verbal response pain scores are ≥4/10, but consistent postoperative analgesic 
management will be at the discretion of the postoperative clinical team. Nausea and 
vomiting will be initially treated by intravenous injection of 4mg ondansetron per clinical 
routine. Alternative anti-emetics will be administered as clinically indicated. 
 
 
Measurements 
Demographic and morphometric characteristics will be recorded, including sex, 
age, race, height, weight and opioid use in the last month (estimated morphine 
equivalents). Anesthesia clinicians cannot be blinded since they will need to titrate opioid 
administration to NOL. However, all postoperative care and evaluations will be fully 
blinded to randomization, thus preventing measurement bias. There will thus be separate 
teams of investigators for the intraoperative and postoperative portions of the trial. 
All routine anesthetic monitoring will be used, and the results recorded 
electronically. Blood pressure will be evaluated continuously with an arterial catheter if 
clinically indicated; otherwise, blood pressure will be evaluated oscillometrically at 3- 

NOL study protocol, Version 3.0, page 8 
 
minute intervals. Anesthetic drugs including end-tidal sevoflurane concentration, type and 
duration of surgery will also be recorded electronically at one-minute intervals. Inadequate 
analgesia will be defined by systolic pressure ≥140 mmHg, heart rate exceeding 
90 beats/min, MAP<65 mmHg. Vasoactive drugs and episodes and duration of 
hypotension (mean arterial pressure <65 mmHg, occurrences of MAP <60 & MAP <55) 
will be recorded. Muscle-relaxant administration will be recorded as well. 
During surgical stimulation under general anesthesia, a NOL of zero indicates no 
nociceptive response, and NOL of 100 indicates extreme nociceptive response. NOL 
values below 25 represent nociception/anti-nociception balance, suggesting either no 
nociception in the absence of noxious stimuli, or effective analgesia in the presence of 
noxious stimuli. NOL values are recorded by the Medasense monitor at 5-second 
intervals. 
The clock on the NOL monitor will be synchronized to that driving the electronic 
record. Nociception will be continuously evaluated in all participating patients. However, 
values will be blinded to clinicians when patients are assigned to the routine opioid 
management group. 
We will record the time of reversal agent administration wrist, the time at which 
sevoflurane is discontinued, along with the end of surgery (last stitch), eye opening, and 
extubation. Discontinuation of sevoflurane will be considered the end of anesthesia and 
the beginning of recovery. 
The following will be recorded on the PMD-200 monitor, using the EVENTS button, 
as accurately as possible: 
1. Medications administration: 
a. Fentanyl 
b. Vasoactive drugs 
c. Muscle relaxants 
d. Reversal agents 
2. Events: 
a. Induction 
b. Intubation 
c. Foley catheter placement 
d. Incision 
e. Insufflation 
f. Trocar insertion 
g. Discontinuation of sevoflurane 
h. Extubation 

NOL study protocol, Version 3.0, page 9 
 
In recovery, patients will be asked to rate their pain at rest on a 0-10 verbal 
response scale. Measurements will be taken at 10-minute intervals from awakening until 
60 minutes has elapsed. Somnolent patients will be given a score of “S” for queries to 
which they are unable to respond. Patients will simultaneously be asked to rate nausea 
on a 0-10 scale. Sedation will be evaluated with the Ramsay score, also at 10-minute 
intervals. 
Episodes of vomiting during the initial 60 minutes of recovery will be recorded. The 
time and dose of any administered postoperative analgesics or anti-emetics will be 
recorded. 
The trial will end after 60 minutes of recovery and all subsequent management will 
be per clinical routine. 
 
 
Data Analysis 
Randomized groups will be assessed for balance on baseline characteristics using 
the standardized differences, defined as the difference in means or proportions divided 
by the pooled standard deviation. An absolute standardized differences > 0.10 will be 
considered as imbalanced. We will use modified intent-to-treat such that all randomized 
patients receiving any of the study intervention (either one, even if the incorrect treatment 
was applied) will be included in the primary analyses. 
Primary outcome. We will assess the treatment effect of NOL guided analgesic 
management versus routine care on mean pain score with the first 60 minutes of the 
recovery period using a linear mixed effects model adjusting for within-patient correlation 
across the 7 time points, and fixed effects for intervention, time (as categorical) and the 
stratification variable of pre-operative chronic opioid use. 8 We will also asses the 
treatment-by-time interaction. We will decide on the most appropriate correlation 
structure empirically, using the AIC criterion, and considering either AR(1), exchangeable, 
or other correlation. 
Sensitivity analysis. As a sensitivity analysis we will assess the treatment effect on pain 
score using a mixed effects proportional odds model in which we consider patient as a 
random effect while estimating the proportional odds ratio for patients having a better 
outcome on NOL than standard care, again adjusting for the stratification variable. 
Secondary outcome. We will assess the treatment effect of NOL versus routine care 
on the proportion of patients with pain score less than 5 (i.e., 0-4) across the 7 time points 
using a generalized linear mixed effects model with a binary outcome (<5 or ≥5), log link 

NOL study protocol, Version 3.0, page 10 
 
(to be able to estimate relative risk), patient as random effect and modeling the within- 
subject serial correlation using an R matrix (considering autoregressive AR(1), 
exchangeable and unstructured correlation structures), with treatment group and the 
stratification variable as fixed effects. We will also asses the treatment-by-time 
interaction. Results will be reported as the relative risk (95% CI) of having a “good” pain 
score over time in NOL versus routine care. 
Exploratory outcome 1. We will assess the treatment effect on the first exploratory 
outcome of number of analgesic rescue boluses using either a negative binomial 
regression (for count data), or else a proportional odds logistic regression if the negative 
binomial distribution is not a good fit to the data. In either case we will again adjust for the 
stratification variable. 
Exploratory Outcome 2. We will assess the treatment effect on the Ramsey score 
measured at 10 minute intervals for during the first 60 minutes using a mixed effects 
proportional odds model to adjust for the within-patient correlation in the same manner 
as described for the sensitivity analysis for the primary outcome. We will test whether 
NOL is noninferior to routine care on the Ransey score using a noninferiority delta of 1.2 
for the proportional odds ratio, such that NOL will be deemed noninferior if the upper 
confidence limit for the odds ratio is less than 1.2. This will be accompanied by a 1- 
sided statistical test for noninferiority using the method described in Mascha and 
Sessler (2011), 9 in which we use the parameter estimate and standard error of the 
treatment effect from the mixed effects model as well as the noninferiority delta in the 
test statistic, as 
ˆ −  
TNI =  1 
 , where ˆ 
SEˆ1 
is the estimated log-odds ratio, SEˆ1 is the estimated standard error, and  is 
, 
the log (delta), or log (1.2). 
 
 
Exploratory Outcome 3. We will assess the treatment effect (in form of a hazard ratio) 
on the time to emergence from anesthesia using a Cox proportional hazards regression 
model adjusting for the stratification variable. We will check the proportional hazards 
assumption graphically and with the treatment-by-log (time) interaction. In presence if 
an interaction the treatment effect will be assessed using the log-rank test from a Kaplan- 
Meier analysis. 
Sample size justification. 
 
Pilot patients: N=21 pilot patients were enrolled prior to the start of the study to 
familiarize the study team with the protocol and identify any systematic issues that might 
result in protocol modifications. In the below sample size calculations we used data on 
these patients to help estimate the standard deviation of the primary outcome (pain score) 
and the within-subject correlation on the pain score across the 7 measurement times. 
1 

NOL study protocol, Version 3.0, page 11 
 
Required Sample Size. We plan the study to have 90% power at the 0.05 significance 
level to detect a difference in mean pain score of 1.25 or more between groups when 
measured over 10 minutes intervals during the first 60 minutes in the recovery period and 
analyzed using a linear mixed effects regression model. Based on our pilot study data 
(N=21) and previous work (SOLAR study report, Figure 1) we estimate the standard 
deviation of the pain score to be about 2.5 and the within-subject correlation to be 
approximately 0.60 when assumed to be exchangeable across measurements. Making 
these assumptions we would need a total of 116 patients before accounting for interim 
analyses, and a maximum of 144 after adjusting for planned interim analyses at each 1/4 
of the maximum sample size. We therefore plan to randomize and enroll a maximum of 
144 patients under these assumptions. 
Interim analyses. We will conduct interim analyses for efficacy and futility at each 1/4 of 
the maximum sample size using a group sequential design and conservative gamma 
spending function parameters of -2 for efficacy and 0 (more aggressive) for futility. If the 
alternative hypothesis effect size (1.25 point difference) is true in the population sampled 
from, with the planned sample size we will cross an efficacy or futility boundary at each 
of the 4 looks with respective cumulative probabilities of 0.16, 0.50, 0.78 and 1.0. 
Z-statistic boundaries for efficacy (futility) will be > 2.80 (≤ 0.156), > 2.58 (≤ 0.667), > 2.34 
(≤ 1.42), and > 2.09 (≤ 2.09). The average total sample size across many simulations, 
assuming the alternative hypothesis is true (a true difference of 1), is N=64. 
 
 
Simulations with Effect Size Larger Than Planned. With the given design and 
corresponding stopping rules, if the true effect size (difference of 1.25 in mean pain score) 
is large than planned, the probability of crossing an efficacy boundary earlier in the trial 
will be proportionately increased. For example, if the true difference is 1.5, the cumulative 
probability of crossing a boundary (either efficacy or futility) in the 1st through 4th looks will 
be approximately 0.21, 0.62, 0.91 and 1.0, with average total sample size across many 
simulations was 81 patients. 
Internal Pilot Study to Reassess Standard Deviation and Within-Patient Correlation. 
At the second interim analysis we will conduct an internal pilot study to reassess the 
standard deviation and within-patient correlation using the observed data for the primary 
outcome. Without considering the observed treatment effect, in a blinded fashion, we will 
use the observed within-patient correlation from the linear mixed effects model and the 
standard deviation at each time point to reassess the maximum required N to have 90% 
power at the 0.05 significance level the detect a difference of 1.25 or more in pain score. 
If the required sample size is at least 10% higher than initially planned, the Executive 
Committee will decide whether to recommend that the maximum sample size be 

NOL study protocol, Version 3.0, page 12 
 
increased to maintain 90% power. There is no statistical penalty for this internal pilot re- 
estimation of the within-patient correlation “nuisance parameter”. 10 
 
 
 
Human Subjects Protection 
The experimental device PMD-200 from Medasense, Ramat-Gan) is CE marked 
and has been sold and used in the European Union for 3 years, and in Canada for 2 
years. However, the NOL device has yet to be submitted for FDA clearance. The 
proposed pilot trial is designed to provide information that will help the investigators, 
Medasense, and the FDA optimally design a Phase 3 multi-center trial that might support 
FDA approval. 
Typical pain scores during the initial phase of post-anesthetic recovery at the 
Cleveland Clinic Main Campus are 7/10, indicating poor pain control. The only aspect of 
our protocol that is non-standard is opioid titration to NOL. Pain scores could hardly be 
worse with NOL guidance, and in all cases, clinical judgement will prevail. Standard vital 
signs monitoring will continue to be used per current routine care. Our experienced 
anesthesia attending will never give patients clearly inadequate or excessive doses. 
An important consideration is that opioid under-dosing and over-dosing is easily 
correctable. Most patients at the Cleveland Clinic and world-wide are under-dosed (as 
indicated by typically high initial pain scores) which is ameliorated simply by giving 
additional opioid. Over-dosing is also not especially serious since opioids can be 
antagonized by administration of small repeated doses naloxone until the right residual 
opioid effect remains. We thus request a non-significant risk device exemption for the 
proposed pilot trial. 
Supplemental material includes sedation and delirium instruments, CE certificates, 
and safety and design documentation. 
The following Adverse Events (AE) will be collected: 
 
• All AEs with an anesthesia-related cause 
• All adverse device effects (ADE) 
• All Serious Adverse Events (SAE) (including sepsis events or related to opioid 
therapy) 
Pre-planned interventions or occurrence of endpoints, including deviations in vital 
signs, specified in the CIP are not considered AEs, if not defined otherwise 
Definitions according to ISO 14155:2011 will be used in this study. 

NOL study protocol, Version 3.0, page 13 
 
Where the definition indicates “device”, it refers to the PMD-100. 
 
Table 1. Definition of Adverse Events and Device Deficiency 
 
Term 
Abbreviation 
ISO Definition 
Adverse Event 
AE 
Any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in 
subjects, users or other persons, whether or not 
related to the investigational medical device. 
NOTE 1: This definition includes events related to the 
investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the 
procedures involved. 
NOTE 3: For users or other persons, this definition is restricted 
to events related to investigational medical devices. 
Adverse Device 
Effect 
ADE 
Adverse event related to the use of an 
investigational medical device. 
NOTE 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, installation, 
operation, or any malfunction of the investigational medical 
device. 
NOTE 2: This definition includes any event resulting from use 
error or from intentional misuse of the investigational medical 
device. 
Serious Adverse 
Device Effect 
SADE 
Adverse device effect that has resulted in any of 
the consequences characteristic of a Serious 
Adverse Event. 
Serious Adverse 
Event 
SAE 
An adverse event that 
a) led to death, 
b) led to serious deterioration in the health of 
the subject, that either resulted in: 
• a life-threatening illness or injury, 
• a  permanent impairment of a body 
structure or a body function, 
• in-patient or prolonged hospitalization, 
• medical or surgical intervention to prevent 
life-threatening illness or injury or 

NOL study protocol, Version 3.0, page 14 
 
Term 
Abbreviation 
ISO Definition 
permanent 
impairment 
to a body 
structure or a body function, 
• led to fetal distress, fetal death or a 
congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event. 
Unanticipated 
Serious Adverse 
Device Effect 
USADE 
Serious adverse device effect which by its 
nature, incidence, severity or outcome has not 
been identified in the current version of the risk 
analysis report. 
Device 
Deficiency 
DD 
Inadequacy of a medical device with respect to 
its identity, quality, durability, reliability, safety or 
performance. 
NOTE: Device deficiencies include malfunctions, use errors, and 
inadequate labelling. 
 
 
Reporting procedures 
AE information will be collected throughout the study and reported to Medasense 
on an AE eCRF, one for each adverse event. It is the responsibility of the investigator to 
identify the occurrence of adverse events to ensure that the information is accurately 
documented in the medical record and on the eCRFs. 
DD information will also be collected throughout the study and reported to 
Medasense on a Device Deficiency eCRF. DDs require immediate reporting if they did 
not lead to an adverse event but could have led to a serious adverse device effect (SADE): 
• if either suitable action had not been taken, 
• if intervention had not been made, or 
• if circumstances had been less fortunate 
 
AE documentation will include the following information at a minimum: 

NOL study protocol, Version 3.0, page 15 
 
• Date of event 
• Time of the event 
• Diagnosis and description 
• Actions taken / treatment (including vital signs, and date and time of rescue 
related actions when applicable) 
• Assessment of seriousness 
• Relatedness to the device 
• Outcome or resolution and date of the resolution 
 
For AEs that require immediate reporting, initial reporting may be done by phone, 
fax, e-mail, or preferably on the eCRF completing as much information as is available. 
The completed AE eCRF must be sent to Medasense as soon as possible. 
In case the investigator requires information from the sponsor in an emergency 
situation, the investigator can contact Medasense team directly. 
The sponsor will ensure timely Adverse Event reporting to meet global regulatory 
requirements. 
 
Table 2. Reporting Requirements for Events 
 
Serious Adverse Device Effects (SADE), including Unanticipated Serious Adverse Device Effect 
(USADE): 
Investigator submit to: 
Medasense 
Immediately after the investigator first learns of the event or of new 
information in relation with an already reported event. 
Regulatory Authority 
As per local reporting requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
Regulatory Authorities 
Reporting timeframe as per local requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Serious Adverse Events (SAE) 
Investigator submit to: 
Medasense 
Immediately after the investigator first learns of the event or of new 
information in relation with an already reported event. 
Regulatory Authority 
As per local reporting requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
Regulatory Authorities 
Reporting timeframe as per local requirement. 

NOL study protocol, Version 3.0, page 16 
 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Adverse Device Effects (ADE) 
Investigator submit to: 
Medasense 
Immediately after the investigator first learns of the event. 
Regulatory Authority 
As per local reporting requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
Regulatory Authorities 
Reporting timeframe as per local requirement 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
All other AEs 
Investigator submit to: 
Medasense 
Submit in a timely manner after the investigator first learns of the event. 
Regulatory Authority 
As per local reporting requirement. 
EC/IRB 
Submit to EC/IRB per local reporting requirement. 
Device Deficiency with SADE potential 
Investigator submit to: 
Medasense 
Immediately after the investigator first learns of the deficiency or of new 
information in relation with an already reported deficiency. 
Regulatory Authorities 
As per local reporting requirement. 
EC/IRB 
As per local reporting requirement. 
Sponsor submit to: 
Regulatory Authorities 
As per local reporting requirement. 
EC/IRB 
As per local reporting requirement. 
All other Device Deficiencies 
Investigator submit to 
Medasense 
Submit in a timely manner after the investigator first learns of the deficiency. 
Regulatory Authorities 
As per local reporting requirement. 
EC/IRB 
As per local reporting requirement. 

NOL study protocol, Version 3.0, page 17 
 
Supplemental Material 
1) Richmond Alertness and Agitation Scale. 
2) 3D Confusion Assessment Method for delirium. 
3) Australian Register of Therapeutic Goods Certificate 
4) EC Certificate 
5) Medical Device License Canada 
6) ISO Certificate 
7) User Manual 
8) Declaration Latex free raw material 
9) Phthalate free declaration 
10) RoHS Declaration 2019 
11) Risk Management Plan 
12) Evaluation of the NOL Index- Clinical Validation Studies 
13)Clinical Evaluation Report 
14)Summative Usability Validation Report 
 
 
 
Funding 
This study project is an investigator-initiated project and is financially supported by 
Medasense Biometric Ltd., Ramat Gan, Israel. 

NOL study protocol, Version 3.0, page 18 
 
References 
1. 
Bonhomme V, Uutela K, Hans G, Maquoi I, Born JD, Brichant JF, Lamy M, Hans 
P: Comparison of the surgical Pleth Index with haemodynamic variables to assess 
nociception-anti-nociception balance during general anaesthesia. Br J Anaesth 2011; 
106: 101-11 
2. 
Boselli E, Daniela-Ionescu M, Begou G, Bouvet L, Dabouz R, Magnin C, 
Allaouchiche B: Prospective observational study of the non-invasive assessment of 
immediate postoperative pain using the analgesia/nociception index (ANI). Br J Anaesth 
2013; 111: 453-9 
3. 
Shimoda O, Ikuta Y, Sakamoto M, Terasaki H: Skin vasomotor reflex predicts 
circulatory responses to laryngoscopy and intubation. Anesthesiology 1998; 88: 297-304 
4. 
Storm H: Changes in skin conductance as a tool to monitor nociceptive stimulation 
and pain. Curr Opin Anaesthesiol 2008; 21: 796-804 
5. 
Martini CH, Boon M, Broens SJ, Hekkelman EF, Oudhoff LA, Buddeke AW, Dahan 
A: Ability of the nociception level, a multiparameter composite of autonomic signals, to 
detect noxious stimuli during propofol-remifentanil anesthesia. Anesthesiology 2015; 123: 
524-34 
6. 
Meijer FS, Martini CH, Broens S, Boon M, Niesters M, Aarts L, Olofsen E, van 
Velzen M, Dahan A: Nociception-guided versus Standard Care during Remifentanil- 
Propofol Anesthesia: A Randomized Controlled Trial. Anesthesiology 2019; 130: 745-755 
7. 
Ben-Israel N, Kliger M, Zuckerman G, Katz Y, Edry R: Monitoring the nociception 
level: a multi-parameter approach. J Clin Monit Comput 2013; 27: 659-68 
8. 
Kahan BC, Morris TP: Reporting and analysis of trials using stratified 
randomisation in leading medical journals: review and reanalysis. BMJ : British Medical 
Journal 2012; 345: e5840 
9. 
Mascha EJ, Sessler DI: Equivalence and noninferiority testing in regression 
models and repeated-measures designs. Anesth Analg 2011; 112: 678-87 
10. 
Kieser M, Friede T: Re-calculating the sample size in internal pilot study designs 
with control of the type I error rate, Statistics in Medicine 
2000, pp 901-911 

NOL study protocol, Version 3.0, page 19 
 
List of changes to the study protocol: 
 
Version 2 (03-29-2020) 
 
• Inclusion criteria: we now specify, that all patients receive a Morphine PCA as 
clinical standard postoperatively. 
• Exclusion criteria: BMI > 40 kg/m2 was added. 
• Protocol: we now specified that sevoflurane concentration will be maintained at a 
target concentration of 0.7%, consistent with good clinical judgement. 
• Protocol: we now specify for the NOL-guided opioid administration group, that NOL 
values above 25 exceed 60 or more seconds, before a fentanyl bolus should be 
given. 
• Protocol: we now specify, that all patients will receive a morphine PCA, which will 
be activated upon arrival to PACU, per routine care. 
• Measurements: we now define inadequate analgesia: inadequate analgesia will be 
defined by systolic pressure ≥140 mmHg, heart rate exceeding 90 beats/min, 
MAP<65 mmHg. Vasoactive drugs and episodes and duration of hypotension 
(mean arterial pressure <65 mmHg, occurrences of MAP <60 & MAP <55) will be 
recorded. Muscle-relaxant administration will be recorded as well. 
• Measurements: we now define documented medications and measurements in 
more details: The following will be recorded on the PMD-200 monitor, using the 
EVENTS button, as accurately as possible: Medications administration: Fentanyl, 
Vasoactive drugs, Muscle relaxants, Reversal agents; Events: Induction, 
Intubation, Foley catheter placement, Incision, Insufflation, Trocar insertion, 
Discontinuation of sevoflurane, Extubation. 
• We added two paragraphs about Adverse Events and Reporting procedures. 

NOL study protocol, Version 3.0, page 20 
 
Version 3 (11/03/2020) 
 
• Title: “benefits” was replaced by “consequences” 
• Several Co-investigators have been added. 
• Aims and hypothesis have been revised. 
• Methods: subject selection. “We will enroll up to 144 adult patients.” (replaced 30 
cases) 
• Inclusion criteria: “Morphine PCA as clinical standard postoperatively” was 
removed and is now considered optional 
• Number of pilot patients: we will now enroll up to 25 pilot patients (replacing 10 
patients) 
• Study protocol: Routine opioid management. We now specify the bolus of fentanyl: 
“Boluses of fentanyl 1 µg/kg actual body weight (ABW), up to a maximum dose of 
100 µg per bolus” …Towards the end of the surgery (approximately 30-45 minutes 
before end of surgery, based on clinical judgment), the boluses of fentanyl will be 
reduced to 0.5 µg/kg ABW, up to a maximum of 50 µg per boluses. Boluses will be 
given per clinical judgment. 
• Study protocol: NOL guided opioid administration. We now specify the bolus of 
fentanyl.”NOL values exceeding 25 for more than 30 seconds will typically be 
treated with boluses of fentanyl 1µg/kg ABW, up to a maximum of 100 µg per 
boluses, 5-minute intervals. Towards the end of the surgery (approximately 30-45 
minutes before end of surgery, based on clinical judgment), the boluses of fentanyl 
will be reduced to 0.5 µg/kg ABW, up to a maximum of 50 µg per boluses, 5 
minutes intervals. The target of a NOL score below 25 will be maintained until 
surgery ends.” 
• Study protocol: NOL-guided opioid administration. Time above a NOL threshold 
above 25 exceeding 30 seconds (replaced 60 seconds). 
• Study protocol: NOL-guided opioid administration. “Boluses of fentanyl 1 µg/kg 
actual body weight (ABW), up to a maximum dose of 100 µg per bolus” 
• Study protocol: we now standardize the preemptive bolus of opioid at the end of 
surgery: Approximately 20-30 minutes before end of the surgery, a preemptive 
bolus of hydromorphone will be given intravenously per clinical routine; 
- 
Patients younger than 70 years: 0.4 mg of hydromorphone for patients with an 
ABW <60 kg and 0.6 mg of hydromorphone for patients with an ABW > 60 kg 
- 
Patients aged between 70 and 75 years: 0.4 mg of hydromorphone, 
- 
Patients older than 75 years: 0.2 mg of hydromorphone. 
• The section on statistical analysis has been entirely revised.