Association of Analgesia Nociceptive Index With Preoperative Anxiety: A Prospective Observational Study
Phase: NA
Conditions: Anxiety, Opioid Consumption, Cesarean Section
Sponsor: University of British Columbia

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ANI Study 
 
Research Protocol ANI Project 
 
Protocol Title: Association of Analgesia Noceceptive Index with Pre-Operative Anxiety 
and Post-Cesarean Opioid Consumption: A Prospective Observational Study    
 
Abbreviated Title: ANI Project 
 
Principal Investigator:  
Anton Chau, MD FRCPC MMSc  
 
Co-Investigators:  
Cyrus Bhiladvala, BSc 
Charles Prior, BSc, MBChB, FRCA 
William Shippam, MBChB, FRCA 
Arianne Albert, PhD 
 
Site: British Columbia Women’s Hospital (BCWH), Vancouver, Canada 
 
Background: 
 
Cesarean section is the one of the most common operative procedures in 
modern surgical practice, and is the mode of delivery for approximately 30% of all 
births1. Pain following cesarean section can decrease patient satisfaction and confer a 
number of negative outcomes. High post-operative pain scores have been shown to 
correlate positively with the rate of post-partum depression, longer hospital stays, sleep 
disturbances, and a reduction in the ability to breastfeed2,3.  Current interventions 
aimed to prevent post-cesarean pain use a ‘one-size-fits-all’ approach, in part, due to 
the difficulty in predicting interindividual variability in degree of pain and response to 
analgesic treatment. Accurate prediction and targeted treatment of patients who have a 
high predicted likelihood of experiencing severe pain can provide a more tailored 
approach to post-cesarean pain management. 
 
Prior research on personalized post-cesarean analgesia found that pre-operative 
anxiety is a predictor of severe post-cesarean pain.4 A recent, validated preoperative 
questionnaire for women undergoing elective cesarean delivery found that subjective 
patient-reported, preoperative anxiety scores directly correlated with post-cesarean 
pain scores reported at 24 hrs4. There currently exists no objective means of quantifying 
preoperative or intraoperative stress.  
 
A potential method for objective measurement of pre-operative anxiety may be 
through the analysis of high frequency heart rate variability (HRV). Heart rate variability 
is defined as being the variability in peak-to-peak distance on an electrocardiogram 
(ECG), and it is regulated by the sino-atrial (SA) node. The SA node is a part of the 
autonomic nervous system (ANS), and is influenced by the vagus nerve6.  

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Action potentials in the vagus nerve in response to 
heighted parasympathetic tone stimulate the release of 
acetylcholine, which has an inhibitory effect on the SA node, 
increasing HRV. This effect has been researched in depth in 
several studies, most notably by Thayer and Lane7. One of 
their key findings was a decrease in HRV in awake patients 
that corresponded with the application of a stressful 
stimulus.  
 
The Mdoloris Analgesia Nociception Index (ANI) 
Monitor is a non-invasive HRV monitoring tool that was 
approved by Health Canada in 2017.  The ANI score is 
determined by high frequency HRV analysis. The monitor first 
finds an R-R spectrum, which is a plot of the peak-to-peak distance between adjacent 
beats on the ECG. This spectrum is then normalized, and passed through a wavelet filter 
to extract the high frequency spectrum (see figure 1). The area under the high 
frequency curve correlates directly with the stimulation of the parasympathetic nervous 
system: the greater the area, the more heightened the parasympathetic response, and 
the higher the ANI score will be. 
 
 
 
 
The parasympathetic nervous system is defined as being the body’s “rest and 
digest” response, which is in a heightened state when a patient is relaxed, and happy. 
Depending on an individual’s tolerance for stress, their parasympathetic tone, or 

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relaxation score, will dip accordingly. Under general anesthesia, the ANI monitor has 
shown some very promising results as a detection of nociception, the somatic response 
associated with pain.  
 
In patients who are given regional anesthesia, and are thus awake during 
surgery, it has been shown that the ANI monitor is not useful for the detection of 
incisions, or tissue disruption. This is due to the fact that a nerve block physically stops 
the sensory fibers from transmitting a nociceptive stimulus to the brain. In addition, 
when a patient is conscious, other stimuli, such as arousal, anxiety, agitation, body 
position, and noise, have all been shown to affect the parasympathetic tone of the 
patient5. We plan to explore this idea with the monitor, and investigate how much ANI 
would correlate to emotional stimuli.  
 
In December 2019, the ANI monitor was being trialed in the operating room for 
potential clinical adoption. One obstetric patient undergoing an elective c-section was 
consented to having the ANI monitor placed and used during the operation. Following 
two failed neuraxial blocks, the patient required general anesthesia. She had a 
significant emotional response to these events, and we observed that there was an 
unexpected rapid drop in ANI score by 30 points. This observation gave rise to the 
question of whether the ANI monitor could, in addition to being used to detect 
nociception in an asleep patient, be used to detect increased anxiety in an awake 
patient. We therefore hypothesize that the frequency and magnitude of ANI change > 
30 would positively correlate with pre-operative anxiety level, and that secondarily, an 
ANI change >30 would be positively correlated with postoperative pain score (at 24h) 
and mean total opioid consumption at 24h. 
 
 
Study Design: 
 
This will be a prospective observational study aiming to determine the associations 
between the Metrodoloris ANI score and patient’s self-reported anxiety during elective 
cesarean delivery. 
 
Hypothesis: 
The frequency and magnitude of ANI change > 30 will be positive correlated with 
patient’s reported preoperative anxiety score. 
 
Primary Outcome: 
 Correlation between frequency and magnitude of drops in the ANI>30 during 
the perioperative time period with patient’s reported perioperative anxiety 
scores.  
 
 
 

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Secondary Outcomes: 
 Correlation between frequency and magnitude of drops in the ANI>30 with 
patient’s reported evoked and resting pain scores at 24h and 48h 
 Correlation between frequency and magnitude of drops in the ANI>30 with 
patient’s total opioid consumption in oral morphine equivalents at 24h and 48h 
 frequency and magnitude of instances of ANI<50  
 Standard deviation in ANI as a measure of top-down regulation 
 
 
Inclusion Criteria:  
 Patient over the age of 19, receiving an uncomplicated, scheduled caesarean 
section 
 
Exclusion Criteria:  
 History of cardiac arrhythmia 
 Contraindications to neuraxial analgesia (ex. patient refusal, infection at the site 
of injection, uncorrected hypovolemia, allergy, increased intracranial pressure, 
coagulopathy, sepsis, fixed cardiac output states, or indeterminate neurological 
status), or risk factors likely to affect placement or function of the spinal needle 
(ex. previous back surgery, significant uncorrected scoliosis, or morbid obesity 
(BMI >40)) 
 History of hypersensitivity or idiosyncratic reaction to local anesthetics or opioids 
 Current or historical evidence of any significant medical conditions, including 
diseases of pregnancy 
 Clinical settings in which general anesthesia may be preferable (ex. patient with 
failed regional anesthetic, patient with history of bleeding, fetal shoulder 
dystocia etc.) 
 Anticipated fetal abnormalities 
  
Withdrawal Criteria: 
 Every effort will be made to obtain all outcome measures from the study; 
however, patients may be withdrawn from the study at any time based on the 
following criteria: 
o Voluntary withdrawal of consent at any time 
o Change in fetal or maternal condition mandating the removal of 
electrodes 
o Clinical judgment of the investigator, anesthesiologist, or any other 
providers in care of the patient. 
 
Recruitment: 
Only a member of the study team who is fully aware of the study protocol, 
hypothesis, outcomes, and operation of the ANI monitor will be permitted to consent 
the patients. All study team members have taken the TCPS II Core course, and have 

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recently reviewed the material, to ensure ethical protocols will be followed throughout 
the consenting process.  
 
The study will be advertised with an information poster displayed in the pre-
surgical room. This will ensure the patient will be able to ask questions about the study 
before being approached for consent; while waiting for their procedure. After calling the 
charge nurse to ensure eligibility, one of the study team members will approach them 
directly to be recruited for the study. If the patient provides consent, the study will 
begin. Consent can be revoked by the patient at any time.  
 
The study team is sent the elective c-section slate for the following day at 
approximately 2pm. The study team then selects viable candidates from the slate based 
on the inclusion and exclusion criteria (See 5.2 and 5.3). The team then notifies the 
charge nurse, who is familiar with the protocol. The charge nurse will confirm their 
eligibility, and will inform the study team when they should approach the patient. With 
this organizational help, we can ensure that the patient is approached with adequate 
time to consider the study, and that their normal flow of pre-surgical care is not 
interrupted. Consent can be revoked by the patient at any time during the procedure.  
 
             Recruitment will be done in the pre-surgical waiting room, the data collection 
will begin after consent is provided. After 10 minutes, the device will be disconnected 
and moved to the OR, and placed safely and unobtrusively on the anesthesia cart. The 
device is disconnected during skin-to-skin with the baby, and moved to the post-
anesthesia care unit (PACU) where it will be reconnected for post-surgical data 
collection. Consent can be revoked by the patient at any time. 
 
All patients will be asked to rate, using a 0–100 mm visual analog scale (VAS) the 
following validated questions4: 
 
1) Their surgical anxiety level (“On a scale of 0–100, with 0 being not anxious at all 
through 100 being extremely anxious, how anxious are you about your upcoming 
surgery?”) 
2) Their anticipated pain (“On a scale of 0–100, with 0 being no pain at all and 100 
being pain as bad as you can imagine, how much pain do you anticipate experiencing 
after your upcoming surgery?”), and  
3) Using a categorical scale, their anticipated pain medication need (“On a scale of 0–5, 
with 0 being none at all, 1 being much less than average, 2 being less than average, 3 
being average, 4 being more than average, and 5 being much more than average, 
how much pain medication do you anticipate needing after your upcoming 
surgery?”).  
 
All patients will also complete the validated 15-question B-MEPS perioperative anxiety 
questionnaire, appended below. 

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Electrode Placement 
If the patient provides consent, the study team member will immediately 
position the ANI data collection electrodes on the patient as instructed by the 
manufacturer, in order to create a cardiac vector. The placement is shown in the 
following image. 
 
Pre-Surgical Care Room 
The patient’s baseline data will be collected in the pre-surgical care room, so 
that the study team is able to assess the variability of ANI without direct operative 
stress. Here, the patient will complete the anxiety questionnaires seen above.  The 
patient is monitored on the ANI machine for at least 10 minutes before the case. The 
patient is disconnected from the monitor before they have to walk to the OR. If the 
patient revokes consent at this time, the patient will be ineligible to remain in the study.  
 
Operating Room 
The patient’s ANI score will be collected for the duration of their operation, and 
a study team member will be in the OR with them for the duration of the case. The team 
member’s duties are to record the times of specific stimuli that all patient’s experience 
during a routine procedure. The times recorded are: block check, skin cleaning and 
catheterization, bed tilt, curtain drawing, incision, surgeons pushing, and baby out. If 
any events occur that are not mentioned above (ie. patient is emotional, pain 
medication administered etc.) the study team member will record the time at which 
that happens. Once the baby has been delivered, the study team disconnects the ANI 
machine to optimize skin to skin between mother and newborn. If the patient decides to 
revoke consent at this time, the data can still be analyzed for the primary outcome. 
 
Post Anesthesia Care Area (PACU) 
Once the patient has left the OR, they are taken directly to PACU where the 
electrodes are once again applied, and data collection commences. The patient stays in 
PACU for between 45 minutes and 2 hours. The data collected in the time following the 
surgery will give the team valuable information about the secondary outcome of 
tracking the regression of the spinal block. Once the patient is assigned to the wards, 
they may be attached for further data collection with their continued consent. If 

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consent is not given to leave the monitor on in the ward, the patient’s data can still be 
analyzed for primary and secondary outcomes.  
 
Sample Size: We expect to collect data from 70 patients 
 
Data Management: 
Study participants will be assigned non-identifying study numbers that will be 
used on the data collection sheets. The Research Assistant will keep a study list of the 
participants with their non-identifying numbers in a separate folder in a locked cabinet. 
De-identified participant data will only by collected by members of the research team 
using paper data collection forms. Once collated, the data will be entered into a 
password protected Microsoft Excel spreadsheet on a password-protected computer in 
the locked Research Assistant’s office at the BCWH. The paper data collection forms will 
be stored for 5 years following publication of the study and then destroyed using the 
hospital’s privacy and confidentiality shredding service. Participant identifiable data will 
not be recorded. 
 
The results of our study will be compiled and submitted for presentation at 
medical conferences and publication in a medical journal. The findings will be 
disseminated to other clinicians with the aim to improve patient care at other sites. 
 
Safety: 
There is no anticipated risk associated with participating in this study. The 
electrodes being used are standard, and will not directly influence patient care or 
anesthetic protocols. The attending nurse or physician’s orders for correct clinical 
procedure will come before the study protocol, and if concerns for patient safety arise, 
the patient will be withdrawn from the study.  
 
Feasibility: 
At BCWH, the annual rate of elective cesarean sections is between 850 and 900 
patients per year. We expect to be able to collect data from at least 4 patients per week, 
meaning that we expect to see the data collection completed in 10 weeks.  
 
Financial Costs: 
There is no funding for this project, as it relies on a donated monitor, and 
electrodes.  
 
Potential benefits: 
If this study provides convincing evidence for the MDoloris ANI monitor’s use in 
predicting pain, or assessing perioperative anxiety, the associated ramifications and 
benefits are sweeping. A significant portion of an obstetric anesthetists practice is to 
keep a patient calm and comfortable during surgery. Having a tool to objectively 
measure a patient’s level of stress would serve as an invaluable indicator of when to 
step in. In addition, if the monitor can be used to accurately predict post-operative pain, 

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an anesthetist can use this device to tend to the patient’s pain before they report 
distress the following day.  
 
 
Disclosures: 
There are no conflicts of interest to report. This study will be supported by the 
Department of Anesthesia at BCWH and registered online at 
http://www.clinicaltrials.gov/. 
 
Bibliography: 
1. Martin, Joyce A. , Hamilton, Brady E., Births: Final Data for 2018. National Vital 
Statistics Report. November 2019. Available from: , 
https://www.cdc.gov/nchs/data/nvsr/nvsr68/nvsr68_13-508.pdf 
2. Babazade, Rovnat, et al. “Acute Postcesarean Pain Is Associated with in-Hospital 
Exclusive Breastfeeding, Length of Stay and Post-Partum Depression.” Journal of 
Clinical Anesthesia, Elsevier, 31 Dec. 2019, 
www.sciencedirect.com/science/article/pii/S095281801931013X. 
3. Sun, K.W., and P.H. Pan. “Persistent Pain after Cesarean Delivery.” International 
Journal of Obstetric Anesthesia, Churchill Livingstone, 9 June 2019, 
www.sciencedirect.com/science/article/pii/S0959289X18300992. 
4. Pan, Peter H, et al. “Predicting Acute Pain after Cesarean Delivery Using Three 
Simple Questions.” Anesthesiology, U.S. National Library of Medicine, May 2013, 
www.ncbi.nlm.nih.gov/pmc/articles/PMC3951732/. 
5. Ledowski, et al. “Analgesia Nociception Index: Evaluation as a New Parameter 
for Acute Postoperative Pain.” OUP Academic, Oxford University Press, 23 Apr. 
2013, academic.oup.com/bja/article/111/4/627/239659#targetText=The heart 
rate variability based,different levels of acute pain.&targetText=ANI values 0–
100 points,of pain) were recorded simultaneously. 
6. Karemaker, John M. “How the vagus nerve produces beat-to-beat heart rate 
variability; experiments in rabbits to mimic in vivo vagal patterns.” Journal of 
clinical and translational research vol. 1,3 190-204. 20 Dec. 2015 
7. Thayer, J. F., and Lane, R. D. A model of neurovisceral integration in emotion 
regulation and dysregulation. J. Affect. Disord. 61, 201–216. 2000. doi: 
10.1016/S0165-0327(00)00338-4 
8.  Gamez, Brock H. BS; Habib, Ashraf S. FRCA Predicting Severity of Acute Pain 
After Cesarean Delivery: A Narrative Review, Anesthesia & Analgesia: May 2018 
- Volume 126 - Issue 5 - p 1606-1614