Ability of the Analgesia Nociception Index Monitor to Distinguish Between Excessive Analgesia and Inadvertent Parasympathetic Nerve Stimulation During Surgery of Large Cerebellopontine Angle Tumours
Conditions: Bradycardia
Sponsor: Association de Developpement de la Neuroanesthesie Reanimation

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Study ID : DC 215/143
 
 
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Cover Page 
OFFICIAL TITLE OF THE STUDY: 
Ability of the Analgesia Nociception Index monitor to distinguish between 
excessive analgesia and inadvertent parasympathetic nerve stimulation during 
surgery of large cerebellopontine angle tumors 
 
BRIEF TITLE:  
ANI Parasympathetic monitoring in neurosurgery 
 
STUDY ID: DC 2015/143 
 
DATE OF THE DOCUMENT: 
5th June 2019 
 

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AIM OF THE STUDY  
To determine the Ability of the Analgesia Nociception Index monitor in 
distinguishing between excessive analgesia and inadvertent parasympathetic 
nerve stimulation during surgery of large cerebellopontine angle tumors 
PROTOCOL  
Background 
The cerebellopontine angle (CPA) is an inverted triangular cisternal space within the posterior 
fossa bounded by the petrous temporal bone laterally, the cerebellum and pons medially and 
the lower cranial nerves (CN IX: glossopharyngeal, X: parasympathetic (pƩ) and XI: 
accessory) inferiorly (fig.1).1 Surgery of large CPA tumors (>2 x 2 cm diameter), with 
compression of the pons exposes the patient to inadvertent pƩ nerve stimulation (IPNS) 
leading to bradycardia and asystole.2 The analgesia nociception index monitor (ANI™, 
Metrodoloris, France) detects the pƩ tone based on the interaction between the respiratory 
cycle and heart rate variability (HRV).3  The device uses a wavelet-based  algorithm to 
provide an index ranging from 0 (minimal pƩ tone, maximal stress level and nociception) to 
100 (maximal pƩ tone, low stress level and analgesia) with a value of 50 being considered by 
the manufacturer as the cut-off. High ANI values (>70) are generally attributed to opioid 
overdose. 4 In a pilot study, the investigators previously demonstrated a shift to high ANI 
values (> 90) induced by IPNS.5 Despite the abundant clinical reports about this index, to the 
knowledge of the investigators, only a few studies have been published in the neurosurgical 
setting.6, 7  

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The aim of this study was to assess the ANI monitor’s ability to distinguish between excessive 
analgesia and IPNS during surgery of large CPA tumors.  
 
 
 
 
 

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Study design 
This prospective observational study was approved by the Institutional Review Board (Comité 
de Protection des Personnes Sud-Ouest et Outre Mer III, study identifier:  DC 2015/143) and 
performed between November 2015 and November 2017. After written informed consent was 
obtained, 75, ASA physical status II-III, participants undergoing surgery of large CPA tumors 
were included. Exclusion criteria were age below 18yr, pregnant women, arrhythmia, 
preoperative use of vagolytics, β-blockers and clonidine.  
Anesthetic technique 
The participants fasted for 6 h and were premedicated with oral hydroxyzine 1 mg kg-1 1 h 
before induction of anesthesia. After arrival in the operating room, standard monitoring 
included a five-lead ECG, pulse oximetry (spo2), non-invasive arterial pressure (General 
Electrics, Helsinki, Finland) and an intravenous line was placed at the forearm or hand of the 
patient. An EEG sensor was then placed at the partipant’s forehead to calculate the bispectral 
index (BIS) for the continuous assessment of the depth of anesthesia (Aspect A-2000 XP™ 
version 3.31, Aspect Medical systems, Newton, MA, USA). The ANI monitor (PhysioDoloris 
monitor; Metrodoloris™, Lille, France) was connected to the ECG analogue output of the 
anesthesia  monitor (GE-Healthcare™, Helsinki, Finland)  for online extraction of the ECG 
signal and calculation of two ANI values: instantaneous (ANIi) and mean (ANIm) based on a 
4 min moving average period.   
Anesthesia was performed by anesthesiologists and nurse anesthesists not involved in data 
analysis. Target-controlled total intravenous anesthesia (Orchestra® Base Primea, Fresenius 
Kabi™, France) was done with propofol (Schnider model site-effect concentration: 4-
6µg/mL) guided by a BIS of 30-40 and Remifentanil (Minto model site-effect concentration: 

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4-6ng/mL) guided by an ANIi between 50-70. A 0.5 to 1 point increment or decrement of the 
effect site concentration was allowed, at a time, with regard to the set anesthesia objectives. 
No neuromuscular blocking drug was used throughout the perioperative period. After tracheal 
intubation, ventilation was started at a rate of 12 cycles per min and tidal volume was adjusted 
in order to maintain the end-tidal CO2 between 30 and 45 mmHg 
 
 
Primary Outcome Measures: 
1. Differences in ANIi values during bradycardia versus when Remifentanil effect size 
concentration >6ng/mL. ANI, HR and Remifentanil effect site concentration were 
continuously recorded with event markers on the ANI monitor at the onset of 
bradycardia (HR<45 bpm) or Remifentanil effect site concentration>6ng/mL 
            Time Frame: ANIi values recorded at Day 1 only during surgery (duration: 4-6 hours) 
 
   2.    Differences in the area under the ROC curves between ANI values for IPNS and  
           excessive analgesia. ROC curves were built at different ANIi for IPNS or EA 
          Time Frame: ANIi values recorded at Day 1 only during surgery (duration: 4-6 hours) 
 
Secondary Outcome Measures: 
3. The percentages of IPNS and EA cases 
            The percentages of IPNS or EA cases on the overall study population were calculated. 
            Time Frame: Cases observed at Day 1 only during surgery (duration: 4-6 hours)] 
 
 
 

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Statistical Analysis Plan 
A sample size of 65 patients was calculated based on our pilot study which detected 18% of 
IPNS cases with an α-error of 0.05 and 90% Power.8 The changes in ANIi and HR triggered 
by intraoperative events were compared using paired t-tests and McNemar’s test. Receiver-
operating characteristic (ROC) curve was built at different ANIi points. The 95% confidence 
interval of the area under the curve (AUC) was calculated using the bootstrapping method 
(1000 iterations). The best cut-off ANI points (sensitivity close to specificity) for IPNS and 
EA were compared in order to test the ANI monitor’s ability to distinguish between these two 
events. The good diagnostic performance of the monitor was defined as an AUC ≥ 0.8. The 
closer both sensitivity and specificity are to 1 at the same time, the better the performance. 9 
For all analysis, a p value <0.05 was considered significant. Statistical analysis was performed 
using MedCalc Statistical Software version 18.11.6 (MedCalc Software bvba, Ostend, 
Belgium; https://www.medcalc.org; 2019) 
 
 
 

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Results 
Sixty nine participants (ASA 1-3, mean age: 53 ± 13 yr, body mass index: 23.9 ± 3.6 kg/m2, 
male/female ratio: 36/33) with large CPA tumors were included. Two were excluded because 
of incomplete data.  
 
The mean duration of surgery: 5.5 ± 1.2 h with mean consumption of propofol (3.3 ± 1.0 g) 
and remifentanil (3.6 ± 1.5 mg).  
 
Twelve cases of IPNS were observed with sudden bradycardia terminating in asystole in 4 of 
them. An abrupt increase in ANIi was observed before bradycardia in these participants.  
 
Excessive analgesia (Remifentanil site effect > 6 ng/mL) was observed in 7 cases with no 
significant change in heart rate (fig.2)  
 
The AUC of EA was significantly higher than the AUC of IPNS (fig.3). 
 
The best cut-off value of ANIi for excessive analgesia was ANIi >82 with a sensitivity of 
85% (95% CI: 42-99%) and specificity 82% (95%CI: 70-90). The best cut-off value of ANIi 
for IPNS was ANIi >88 with a sensitivity of 100% (95% CI: 74-100%) and specificity 96% 
(95%CI: 88-100). 
 

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