A Prospective, Randomized, PACU Blinded Study to Compare ANI-guided Analgesic Administration Versus Standard Care in Surgical Patients Receiving Balanced Sevoflurane-Fentanyl Anesthesia
Phase: NA
Conditions: Acute Pain
Sponsor: University of Texas Southwestern Medical Center

Form A 
IRB # 
STU-2018-0096 
 
STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
1 
vMar2018 
Title: A Prospective, Randomized, PACU Blinded Study to Compare ANI-guided Analgesic 
Administration versus Standard Care in Surgical Patients Receiving Balanced Sevoflurane-
Fentanyl Anesthesia 
NCT03684590 
Document Date: 8/22/2019 
 

Form A 
IRB # 
STU-2018-0096 
 
STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
2 
vMar2018 
PROTOCOL FORM / RESEARCH DESCRIPTION 
 
If an item does not apply to your research project, indicate that the question is "not applicable” – do not leave sections blank 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter or word, if hyperlinked, 
for detailed instructions for that question.  If your response requires inserting a table, picture, etc, you may need to first delete the 
box that surrounds the answer and then insert your table or other special document. 
 
 
1.  Purpose and objectives.           List the purpose and objectives: 
 
Specific Aim 1: To determine if intraoperative opioid administration guided by the ANI will decrease patient pain scores 
in the PACU compared to standard practice. 
 
Primary Hypothesis: Patients who have intraoperative opioid administration guided by the ANI will have a 40% 
decreased incidence of severe pain (VAS ≥7) in the PACU compared to patients in the standard practice group. 
 
 
 
 
2.  Background. 
• 
Describe past experimental and/or clinical findings leading to the formulation of your study.   
• 
For research involving investigational drugs, describe the previously conducted animal and human studies.   
• 
For research that involves FDA approved drugs or devices, describe the FDA approved uses of this drug/device in 
relation to your protocol.   
• 
Attach a copy of the approved labeling as a product package insert or from the Physician’s Desk Reference.   
You may reference sponsor’s full protocol or grant application (section number and/or title) or if none, ensure background 
includes references. 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
a. 
Background 
Pain after surgery is one of the biggest concerns for surgical patients. A large percentage of patients experience 
severe pain in the recovery period, which increases the risk of developing chronic pain and contributes to an overall 
poor experience for the patient [1-3]. The Analgesia Nociception Index (ANI; MetroDoloris Medical Systems, Lille, 
France) is a non-invasive monitor that uses heart rate variability to determine the analgesic state of a patient. It 
calculates HR variation with respiration, which is mediated by the parasympathetic nervous system’s effect on the 
sinoatrial node of the heart. Heart rate variability depends on the effects of the sympathetic and parasympathetic 
nervous systems. Studies suggest that pain leads to a decrease in heart rate variability in adults [4]. A painful 
stimulus increases sympathetic tone relative to parasympathetic tone, which causes the ANI number to go down. 
Alternatively, if the patient is at an adequate or abundant level of analgesia, the parasympathetic tone would be high 
and thus the ANI number would be high. The highest ANI is 100, which indicates maximum parasympathetic tone 
(no pain) whereas the lowest number is 0, which indicates minimum parasympathetic tone (significant pain). 
The ANI may offer a method to administer intraoperative analgesics in a more objective manner compared to 
current standard clinical practice. It is important to provide sufficient analgesia during surgery, but it is also important 
to use the minimum dosage necessary in order to avoid unwanted side effects. Determining the optimal dosage of 
opioids during general anesthesia is difficult and traditionally has been guided by vital signs and the anesthesia 
provider’s clinical judgement. However, inadequately treated pain can increase the stress response, increase 
sympathetic activity, predispose to postoperative myocardial ischemia, and lead to a suboptimal experience for the 
patient [7, 8]. The ANI may be able to more objectively guide opioid administration intraoperatively, which may result 
in decreased pain and improved patient satisfaction postoperatively. 

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The ANI Monitor has received 510k clearance in the US, but is not currently cleared for sale.  It is being used for 
research purposes only at the time of this writing. 
 
 
b. 
Current practice 
The current practice is to administer intraoperative analgesics according to the anesthesiologist’s best clinical 
judgment, based on surgical factors, patient factors, and changes in vital signs.  
 
 
3.  Study Design.  
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme to visually present the 
study design. 
 
This study aims to be a randomized, controlled study of ANI-guided opioid administration versus standard clinical 
practice in female patients undergoing abdominal hysterectomy.  Patients will be randomly assigned to 2 groups- ANI 
vs. standard care.  A member of the study team that is not involved in patient care (i.e., statistician) will make the 
randomization table based on a random number generator.  The assignments will be written and sealed in opaque 
envelopes and not opened until each subject has signed all the necessary paperwork.  The intraoperative and 
postoperative management of all patients will be standardized by protocol.   
 
The PACU nurses and postop assessor will be blinded as to which group the patient is in.  Patients will be followed in 
the PACU to assess pain scores and any adverse events. 
 
The criteria for inclusion: 
• 
18-75 years’ old 
• 
American Society of Anesthesiology (ASA) physical status 1-2 
• 
Patients undergoing surgery with general anesthesia with sevoflurane-fentanyl 
• 
Planned abdominal or spinal surgery lasting 1-3 hours 
• 
Willing and able to consent in English or Spanish 
• 
No current history of advanced pulmonary or cardiovascular disease  
 
The criteria for exclusion: 
• 
Age less than 18 or older than 75 
• 
Patient does not speak English or Spanish 
• 
Patient refusal 
• 
Monitored anesthesia care (MAC) or regional anesthesia planned 
• 
Pregnant or nursing women 
• 
“Stat” (emergent) cases 
• 
ECG rhythm other than regular sinus rhythm  
• 
Implanted pacemakers 
• 
On antimuscarinic agents, alpha 2 agonists, antiarrhythmic, or beta blockers 
• 
Presence of pacemaker 
• 
Autonomic nervous system disorder 
• 
Use of chronic opioids  
 
 
All female subjects have a urine pregnancy test on the morning of surgery. The pregnancy test result will be reviewed 
as a part of the screening procedure. 
 
 
 
 

Form A 
IRB # 
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STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
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4.  Research Plan / Description of the Research Methods:   
4.a.  Provide a comprehensive narrative describing the research methods.   
1) Provide the order in which tests/procedures will be performed,  
2) Provide the setting for these events and a description of the methods used to protect privacy during the study.   
3) Provide the plan for data analysis (include as applicable the sample size calculation) 
 
Please respond to all components of this item, or clearly indicate which components are not applicable. 
 
1) Order in which tests/procedures will be performed  
Screening and Informed Consent 
A member of the research team will use a screening form to look for surgical patients that meet all the inclusion and 
exclusion criteria. He/she will approach potential subjects in the preoperative area and the study will be explained in 
detail in a private room.  Patients will be informed that they will receive no compensation for participating in the study 
and there will be no adverse consequences if they choose not to participate. If the subjects agree to participate, 
informed written consent will be obtained prior to any study procedures and this document will be sent to 
pmhresearchparticipants@phhs.org, for inclusion in the patient’s medical record, per Parkland regulations. The study 
duration is one day. 
 
Anesthetic Protocol 
The anesthesia team that will be caring for the subject during surgery will be given the protocol for the study, which 
standardizes the general anesthetic technique.  All patients will be monitored with standard ASA monitors and a BIS 
(bispectral index) for depth of anesthesia monitoring.   
 
2) Setting and methods used to protect privacy  
Setting 
The study will take place in the pre-operative rooms, the operating rooms, and the PACU at Parkland Hospital.  
 
Randomization 
The research coordinator will make randomization envelopes by using a random number generator. A patients will be 
randomized to 2 groups: 
1. Group 1- standard practice 
2. Group 2- ANI-guided opioid administration 
 
The ANI leads (2 non-invasive stickers that are placed on the anterior chest wall) will be attached to the patient’s chest 
per manufacturer guidelines.   
 
3) Plan for data analysis  
The following parameters will be recorded intraoperatively: ECG, NIBP, ET sevoflurane concentration, ETO2, ETCO2, 
temperature, BIS readings. 
 
Data Sources 
Protected health information including name, medical record number, and date of birth will be recorded and stored 
securely in an IRB approved, secured REDCap database.  
 
Parameters: 
1. Protected health information (PHI):  name, medical record number, date of birth 
2. Demographic information (age, weight, height, BMI), medical and surgical history, ASA status  
3. Intraoperative parameters  
• 
Baseline vital signs upon arrival to operating room 
• 
Intraoperative vitals (systolic, diastolic, and mean blood pressures, temperature, heart rate) 
• 
ECG rhythm 

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IRB # 
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• 
ANI numbers  
4.  Adverse event monitoring 
• 
ANI malfunction 
• 
Patient movement 
• 
Delayed emergence 
• 
PONV 
• 
Respiratory depression 
• 
Prolonged hypoxia (SpO2 less than 92% for > 1 min) 
• 
Critical respiratory adverse event including bronchospasm, atelectasis, pulmonary edema 
• 
Cardiovascular adverse events such as tachycardia, bradycardia, cardiac arrhythmias, hypotension, and 
hypertension 
 
4) Statistics: 
The study is powered to detect a 40% reduction in the incidence of severe pain (VAS > 6) with 80% power and a two-
sided type I error rate of 0.05.  Assuming an incidence rate of 75% in the standard of care group, the study would 
require a total of 80 patients randomized in a 1:1 ratio between the standard of care and ANI groups.  Continuous 
outcomes will be summarized as mean and standard deviations or median and interquartile range.  Categorical data 
will be summarized as frequency and percentages.  Normality of the continuous outcomes will be assessed using 
normal probability plots and groups will be compared using Student’s t-test or Mann-Whitney U test if gross violation 
of the normality assumption were found.  Chi-square or Fisher’s exact test will be used to compare groups in terms of 
categorical variables. 
The primary efficacy analysis will be performed on the evaluable population of subjects who complete the schedule 
of assessments.  Secondary analyses will be on all randomized subjects (the intent-to-treat population) with various 
methods of imputation of missing data.  All statistical tests will be two-sided with a significant level of 0.05 unless 
otherwise specified.  All confidence intervals will be two-sided with a confidence level of 95%, unless otherwise 
specified. 
 
 
Sample size for this prospective validation was estimated using the following assumptions: 
 
– 
Mean NRS for controls at each time point = 5.0 
– 
Standard Deviation at each time point = 3.0 
– 
Presumed difference in mean NRS between active treatment group and control at each time point = -2.0   
– 
Primary Statistical test method: mixed effects, repeated measures  
– 
Within-patient correlation is 0.55 or less 
– 
Minimum Statistical Power = 80% 
A minimum of 48 evaluable patients (24 per group) will be required for this two-treatment parallel-design study under 
the above assumptions. 
An enrollment target of 80 (40 per treatment group) is proposed to account for potential drop-outs and uncertainty 
regarding the variability and intrapatient correlation of NPS pain scores, as well as to allow focused robustness 
testing.  
 
 

Form A 
IRB # 
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STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
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4.b.  List of the study intervention(s) being tested or evaluated under this protocol 
 
N/A -  this study does not test or evaluate an intervention.    Skip to item 4.d. 
# 
Study intervention(s) being tested or evaluated under the protocol 
 
 
 
Pain scores after surgery 
Nausea/vomiting after surgery 
Vital signs after surgery 
 
Affiliate 
 
Place a check 
next to 
institution(s) 
where the  
intervention will be 
performed 
Local Standard 
Practice?  
Indicate whether 
the intervention is 
considered 
acceptable 
practice locally for 
applicable 
institutions 
1 
Analgesia Nociception Index (ANI; MetroDoloris Medical Systems, 
Lille, France) 
☐ UTSW 
☐ Yes 
☐x PHHS 
☐ Yes 
☐CMC 
☐ Yes 
☐THR 
☐ Yes 
☐TSRH 
☐ Yes 
☐ Other: _____ 
☐ Yes 
 
 
4.c.  Risk:Benefit Analysis of study interventions being tested or evaluated under this protocol 
For each study intervention identified in section 6b above, complete a risk:benefit analysis table. 
 
(Two tables are provided, copy & paste additional tables as needed or delete both tables if this study does not test an 
intervention) 
 
 

Form A 
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STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
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4.c. 
Study Intervention #1 
Analgesia Nociception Index (ANI; MetroDoloris 
Medical Systems, Lille, France) 
List each group exposed to this 
intervention on a separate line. 
 
For each group, list the benefits of this intervention.  (Benefits can be directly from 
the intervention or from a monitoring procedure likely to contribute to the subject’s 
well being).  If there are no benefits, state “none”. 
Experimental group 
None 
If you are requesting a Waiver of Informed Consent, complete the table below. 
 
If you have a consent form, list the reasonably foreseeable risks in the consent form (and do not complete this section).   
 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
Do not delete frequency.  Frequency must be estimated because it will assist you with determining which adverse events will require 
prompt reporting.   
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 out of 100 subjects. 
• 
 
• 
 
 
Not serious 
Serious 
Less likely  
These risks are expected to occur in 5-
20 subjects or less out of 100 subjects. 
• 
 
• 
 
 
 
Serious 
Rare  
These risks are expected to occur in 
less than 5 subjects out of 100  
 
• 
 
 
 

Form A 
IRB # 
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STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
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vMar2018 
 
 
4.d. List ALL other research procedures or components not listed in table 4.b. 
        The combination of Tables 4b and 4d should account for all of the research 
procedures that will take place during this study. 
 
Consider grouping similar procedures under a single component (e.g., blood work, CT = safety 
assessments) 
 
 
 
# 
Research component 
• 
Individual 
procedures 
 
Eligibility 
Assessments 
• 
History and 
physical 
• 
Questionnaire 
• 
Laboratory 
tests 
Add or delete rows as 
needed 
Column A 
Local Standard 
Practice Indicate 
the number of times 
each procedure will 
be performed as 
stipulated in the 
research plan that 
would be 
performed if the 
participant were 
not participating in 
the study. 
Column B 
Research Only  
Indicate the number of 
times each procedure will 
be performed solely for 
research purposes 
(meaning that the 
participant would not 
undergo the same 
number of procedures or 
would not undergo the 
procedure(s) at the same 
frequency if they were 
not participating in the 
study) 
Column D 
Risks 
If you are requesting a Waiver of Informed 
Consent, complete the table below. 
 
List the reasonably expected risks for each 
procedure or group of procedures under the 
following categories as appropriate: 
• Serious and likely; 
• Serious and less likely; 
• Serious and rare; 
• Not serious and likely; 
• Not serious and less likely 
1 
Insert component 1 
here 
 
Monitoring of 
intraoperative analgesic 
state with non-invasive 
ANI monitor 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
2 
Insert component 2 
here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
3 
Insert component 3 
here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
4 
Insert component 4 
here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
Insert procedure here 
 
 
 
 
 
 
5.  Safety Precautions.  (Describe safeguards to address the serious risks listed above.) 
a.  Describe the procedures for protecting against or minimizing any potential risks for each of the more than minimal risk 
research procedures listed above. 
There is minimal risk to subjects by participating in this study.  The anesthetic management of subjects will not differ from the 
standard of care, with the exception of the intraoperative management of analgesic administration (e.g., opioids). The ANI is a 
non-invasive monitoring device that has no known adverse effects.  There is minimal risk for psychological stress to the patient 
as a result of participation in this study.  Subjects may refuse to answer any of the questions or take a break or stop participation 
in the study at any time. 

Form A 
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STU2018-0096, Moon, Form A, Mod_5, 08-22-19 
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vMar2018 
 
b.  Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in the event of adverse 
events, or unanticipated problems involving subjects. 
Procedures to Maintain Confidentiality: 
A non-identifiable code will be assigned to the data collection sheet so that there is not a direct link to specific names.  Patient 
IDs will be standardized in chronological order as patient 1, patient 2, etc. A key to the coding system will be maintained in a 
locked storage cabinet with limited access until all the data is collected and analyzed. Access to study data will be restricted to 
authorized study personnel only. Following the completion of the analysis and the project, the key to the coding system or 
subject identifiers themselves will be destroyed by shredding the documents so that there is no direct or indirect link to subject 
identifiers and information. 
 
All data from the study will be kept on encrypted computers belonging to the University, which are stored in secured areas. All 
electronic study data will be password protected and passwords will be changed on a regular basis. 
 
All data will be de-identified when exported from the REDCap database.  Patient data will be analyzed without patient identifiers 
by assigning study ID subject numbers that are de-linked from patient identifiers.  Signed consent forms, HIPAA forms, and 
study questionnaires will remain in a locked cabinet in the PI’s office. 
 
c.  Will the safeguards be different between/among groups?   
 
 
x
 
No 
If yes, describe here 
 
  
References: 
 
 
1. 
Gerbershagen HJ, Aduckathil S, van Wijck AJ, Peelen LM, Kalkman CJ, Meissner W: Pain intensity 
on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. 
Anesthesiology 2013, 118(4):934-944. 
2. 
Perkins FM, Kehlet H: Chronic pain as an outcome of surgery. A review of predictive factors. 
Anesthesiology 2000, 93(4):1123-1133. 
3. 
Apfelbaum JL, Chen C, Mehta SS, Gan TJ: Postoperative pain experience: results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 
2003, 97(2):534-540, table of contents. 
4. 
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(3):453-459. 
5. 
Bluth T, Pelosi P, de Abreu MG: The obese patient undergoing nonbariatric surgery. Curr Opin 
Anaesthesiol 2016, 29(3):421-429. 
6. 
Budiansky AS, Margarson MP, Eipe N: Acute pain management in morbid obesity - an evidence 
based clinical update. Surg Obes Relat Dis 2017, 13(3):523-532. 
7. 
Lovich-Sapola J, Smith CE, Brandt CP: Postoperative pain control. Surg Clin North Am 2015, 
95(2):301-318. 
8. 
Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL: Incidence, patient satisfaction, and 
perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin 2014, 
30(1):149-160. 
9. 
Borsook D, Kussman BD, George E, Becerra LR, Burke DW: Surgically induced neuropathic 
pain: understanding the perioperative process. Ann Surg 2013, 257(3):403-412. 
10. 
Fletcher D, Martinez V: Opioid-induced hyperalgesia in patients after surgery: a systematic 
review and a meta-analysis. Br J Anaesth 2014, 112(6):991-1004. 

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11. 
Jeanne M, Clement C, De Jonckheere J, Logier R, Tavernier B: Variations of the analgesia 
nociception index during general anaesthesia for laparoscopic abdominal surgery. J Clin 
Monit Comput 2012, 26(4):289-294. 
12. 
Gruenewald M, Ilies C, Herz J, Schoenherr T, Fudickar A, Hocker J, Bein B: Influence of 
nociceptive stimulation on analgesia nociception index (ANI) during propofol-remifentanil 
anaesthesia. Br J Anaesth 2013, 110(6):1024-1030. 
13. 
Sabourdin N, Arnaout M, Louvet N, Guye ML, Piana F, Constant I: Pain monitoring in 
anesthetized children: first assessment of skin conductance and analgesia-nociception index 
at different infusion rates of remifentanil. Paediatr Anaesth 2013, 23(2):149-155. 
14. 
Upton HD, Ludbrook GL, Wing A, Sleigh JW: Intraoperative "Analgesia Nociception Index"-
Guided Fentanyl Administration During Sevoflurane Anesthesia in Lumbar Discectomy and 
Laminectomy: A Randomized Clinical Trial. Anesth Analg 2017, 125(1):81-90. 
15. 
Szental JA, Webb A, Weeraratne C, Campbell A, Sivakumar H, Leong S: Postoperative pain after 
laparoscopic cholecystectomy is not reduced by intraoperative analgesia guided by 
analgesia nociception index (ANI(R)) monitoring: a randomized clinical trial. Br J Anaesth 
2015, 114(4):640-645. 
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Dundar N, Kus A, Gurkan Y, Toker K, Solak M: Analgesia nociception index (ani) monitoring in 
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