MD/QUA/EN52.ANI (EN)

STATE of the ARTNumerous studies show that the analysis of Respiratory Sinus Arrhythmia allows us to open a window into the autonomic nervous system (ANS), which is influenced by nociception. Mdoloris Medical Systems (MDMS) develops, manufactures and markets technologies which reflect variations in a patient’s nociception/antinociception balance and which have been validated to date by an increasing number of scientific publications.

Physiological mechanisms related to nociception and to its removal are located at various subcortical levels of the brain. MDMS aims to provide doctors with a non-invasive and user-friendly monitoring system which offers a continuous and reliable index of nociception and antinociception treatments. MDMS monitors only require an electrocardiogram (ECG) as an entry point.

Analgesia Nociception Index (ANI®) technology is unique in using the sympathovagal balance in order to measure nociception and antinociception. In addition to being a nociception monitoring system, ANI technology also monitors the parasympathetic tone, which provides information about the patient’s comfort, i.e. the appearance of pain or stress.

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The monitor can be used with unconscious as well as conscious patients. With unconscious patients under general anaesthesia, the ANI range [50-70] relates to adequate analgesia, which means that opioid antinociception is adequate and that the parasympathetic activity is mildly predominant over sympathetic activity.

When the ANI value falls below 50, if nociception persists, the occurrence of a hemodynamic response within the following 10 minutes is very likely (80% probability when the curve is under 40 and 100% probability when the curve is under 30). Anaesthetists can use this information in order to avoid a hemodynamic response and increase opioid analgesia. 1

In cases where the ANI value rises above 70, opioid overdose is likely. Practitioners can therefore avoid using additional opioid analgesia and avoid the side effects of an opioid overdose such as:

- longer time of recovery - nausea, vomitting in PACU- bradycardia- respiratory failures- post operative hyperalgesia 2

- dizziness- constipation- delirium 3

- hypotension - hallucinations 4

- stimulates cancer progression 5

1 Boselli E, Bouvet L, Bégou G, Torkmani S, Allaouchiche B. Prediction of hemodynamic reactivity during total intravenous anaesthesia for suspension laryngoscopy using Analgesia/Nociception Index (ANI) : a prospective observational study. Minerva Anestesiol 2015 March; 81(3):288-97 2 Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014 Jun;112(6):991-1004 3 L. Krenk, L. S. Rasmussen, T. B. Hansen, S. Bogø, K. Søballe and H. Kehlet . Delirium in the fast-track surgery setting. Best Pract Res Clin Anaesthesiol. 2012 Sep;26(3):345-53 4 The Joint Commission, Issue 49, August 8,2012 5 J Nguyen, K Luk, D Vang, W Soto L, Vincent, S Robiner, R Saavedra, Y Li, P. Gupta and K. Gupta. Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer.

OUR BEST,FOR THE BETTER. Some clinical studies demonstrated that both a low ANIi (instantaneous)

value and a fast decrease of ANIi were predictive of a hemodynamic response to painful stimuli. Following these observations, we developed a new visualization mode (“classic”) which allows a simplified interpretation. This mode continuously displays the ANIm (average) trend which is related to the imbalance between analgesia and nociception (picture a). In case of a response to a painful stimulus characterized by a low ANIi or a significant ANIi drop, the ANIi is displayed in numerical value as well as on trends (picture b).

A new composite algorythm

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After 23 years of research and development and thanks to independant international publications, we are able to provide to anesthesiologists a device and an index which will individualize and refine their daily practise of anesthesiology. There are many benefits about the ANI technology:

Helpful to diagnose the etiology of an haemodynamic event

Predict postoperative pain

Predictivity of haemodynamic reactivity

Refine opioids titration avoiding infra and overdosing

Better than heart rate and blood pressure variations to detect nociception

WH

Y ?

Funcke S et al. Anesthesiology, 2017.

Boselli E et al. British Journal of Anaesthesiology, 2013.

Daccache G et al. Anaesthesia Critical Care & Pain Medicine , 2016.

Jeanne M et al. Clin J Pain, 2014.

Logier R et al. IEEE, 2011.

LIMITS of useDrugs or any situation which interferes with the parasympathetic reflex loop:

- Apnea (interrupts the loop between bronchial stretch receptors and vagus nerve nucleus)

- Atropine (anticholinergic whose blocking action on the sinus node makes it improper to measure the vagus nerve influence). The ANI is not interpretable during around 20 minutes after injection depending on the pharmacocinetic effect. However, as long as the energy value is within normal range [0,05-2,5], ANI is interpretable.

- Ephedrine (indirect sympathetic stimulation); the ANI is not interpretable during around 10 minutes after injection, except if the energy value is within normal range.

- A sinusal rhythm is needed (e.g. cardiac arrhythmia by atrial fibrillation of more than 9 minutes is a limit)

- The ANI is only interpretable when the Energy parameter is within the range of [0,05-2,5]

For WHO?

Awake adults patients

Adult patients during surgery under general anesthesia

Adult patients in intensive care unit

Awake children

Children during surgery under general anesthesia

Design of the study n Results Conclusion References

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During laborANI and NRS during and between uterine contractions

45 Negative linear relationship between ANI and NRS (p=-0.18) Good correlation between ANI and NRS during labor

Le Guen M et al., Int J Obstet Anesth, 2012.

ANI and NRS in PACU after general anesthesia,ANI performance for the pain detection (NRS > 3) in PACU

200 Negative linear relationship between ANI and NRS (r²=0.41)Good pain detection performance in PACU (AUC ROC=0.86) ANI ≤57 Se =78% and Sp=80%

Good correlation between ANI and NRS during immediate postopera-tive pain

Boselli E et al., Br J Anaesth, 2013.

ANI variations and VAS scores during physical therapy procedure, 24 and 48 hours

12 Decrease of ANI when VAS > 30. Good pain detection (AUC ROC=0.76, ANI Se=76%, SP=78%)

ANI can be used for pain manage-ment during physical therapy

De jonckheere J et al., Conf Proc IEEE Eng Med Biol Soc, 2014.

ANI variations during the projection of a violent film, comparisons between controls and anorexia nervosa patients

24 Decrease of ANI during the projection, with a delay anorexia nervosa patients

ANI is decreased after an unplea-sant emotion

Rommel et al. Psy-chiatry Res, 2015.

Clinical studies with ANI in conscious and anesthetized patients

Design of the study n Results Conclusion References

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Pediatric (8 ± 5 years old)ANI variations after tetanic stimulation (50 mA, 50 ms, 5s) with desflurane and different concentrations of remifentanil (0.04 to 0.2 µg/kg/min)

12 Decrease of ANI after tetanic stimulation, more im-portant with the lowest remifentanil concentration

ANI is decreased after tetanic stimulation during pediatric surgery and seems more sensitive than the skin conductance

Sabourdin N et al., Paediatr Anaesth, 2013.

Pediatric (2 – 16 years old)Locoregional anesthesia before surgery and sevoflurane only,ANI performance for the detection of a locoregional anesthesia failure (increase HR ≥ 10 % 2 min after incision)

58 ANI performance for the detection of locoregional anesthesia failure: AUC ROC=0.75 (0.61 - 0.88) ANI ≤ 51, Se=79% and Sp=62%

ANI is able to detect locoregional anesthesia failure

Migeon A et al., Paediatr Anaesth, 2013.

Intravenous anesthesia with propofol and remifentanilANI variations after tetanic stimulation (50 mA, 60 Hz, 30 s) at different targets of remifentanil (0., 2 and 4 ng/mL)

25 Decrease of ANI after tetanic stimulation ANI is efficient for the detection of pain response during surgery under general anesthesia

Gruenewald M et al., Br J Anaes-th,2013

One hundred and eighty adults presenting for elective surgery were included. All received total intravenous anaesthesia with propofol adjusted to entropy and remifentanil adjusted to the ANI.

180 Anaesthesia was achieved without any episode of reactivity in 160 (89%) patients. The median remifen-tanil dose was 0.042 [0.040-0.044]µg.kg - 1.min -1. At 24hours, the maximal NRS pain score was 2 [2,3]. One hundred and fifty-five patients (86%) did not receive any postoperative opioids.

ANI can be used to adequately guide intraoperative remifentanil administration during vascular surgery. Such guidance resulted in low remifentanil consumption, low postoperative pain rates and low opioid rescue analgesia.

G Daccache et al. Anaesth Crit Care Pain Med. 2016

Design of the study n Results Conclusion References

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General anesthesia under sevoflurane and remifentanilANI variations after tetanic stimulation (50 mA, 60 Hz, 30 s) at different targets of remifentanil (0, 2 and 4 ng/mL),

24 delta ANI significantly indicated patient’s movement after tetanic stimulation (Se=77% and Sp=84%)

ANI is efficient for the detection of pain response during surgery under general anesthesia

Gruenewald M et al., Minerva Anestesiol, 2014.

Intravenous anesthesia with propofol and remifentanilAbdominal laparoscopic surgeryANI variations at different times and after tetanic stimulation (80 mA, 100 Hz, 5 s)

15 Decrease of ANI during different no-ciceptive stimuli.

ANI is able to detect painful stimu-lations under general anesthesia

Jeanne M et al., J Comput, 2012.

Intravenous anesthesia with propofol and sufentanil bolusKnee arthroplastyANI performance for the detection of peroperative hemodyma-nic reactivity (increase > 20% HR and/or BP in 5 min)

27 Good performance for the hemodyna-mic reactivity (AUC ROC=0.92)ANI ≤ 63 Se=80% and SP=88%

A drop of ANI values predicts a hemodynamic response lead by pain

Jeanne M et al., Clin J Pain, 2014.

TIVA propofol and remifentanilLaryngoscopy suspension proceduresANI performance for the prediction of hemodynamic reactivity and sedation.

50 Good performance for the hemodyna-mic reactivity (AUC ROC=0.88)ANI ≤ 55, Se=88% and Sp=83%

The prediction of hemodynamic reactivity is slightly reduced by the use of sevoflurane and/or fentanyl

Boselli et al. Minerva Anestesiol, 2015.

General anesthesia with sevoflurane and fentanylGeneral or orthopedic surgeryANI variations at different timesPK for the prediction of increase HR and Systolic BP >10%

30 Decrease of ANI after nociceptive stimulationIncrease of ANI after fentanyl adminis-trationModest prediction probability for increase HR (PK=0.61), increase BP (PK=0.59)

The prediction of hemodynamic reactivity is slightly reduced by the use of sevoflurane and/or fentanyl

Ledowski T et al., Acta Anaesthe-siol Scand, 2013.

General anesthesia with halogen and remifentanilORL surgery or inferior limb orthopedic surgeryANI performance before extubation for the prediction of imme-diate postoperative pain (NRS >3)

200 Negative linear relationship ANI before extubation and NRS in PACU (r²=0.33)Good ANI performance for the predic-tion of NRS > 3 (AUC ROC=0.89)ANI ≤ 50, Se=86%, Sp=86%

ANI values at the end of the sur-gery are able to predict postope-rative pain

Boselli E et al., Paris:SFAR, 2014.

General anesthesia with sevoflurane and fentanylAbdominal hysterectomy proceduresEffect of 0.5 mg/kg ketamine administration on ANI

20 No modifications of ANI 5 min after ketamine administration

Ketamine administration does not interfere with ANI response during surgery

Bollag L et al., J Clin Monit Com-put, 2014.

This study compares the analgesic indices Analgesia Nociception Index (heart rate variability), Surgical Pleth Index (photoplethys-mography), and pupillary dilatation, to heart rate, mean arterial pressure, and bispectral index, with regard to diagnostic accuracy and prediction probability for nociceptive response.

38 Under propofol sedation, sensitivity and specificity of the Analgesia Nociception Index (PK = 0.98) for detecting painful stimulations were high compared to heart rate (PK = 0.74), mean arterial pressure (PK = 0.75), and bispectral index (PK = 0.55)

The Analgesia Nociception Index, the Surgical Pleth Index, and pupillary dilatation are superior in detecting painful stimulations compared to heart rate and mean arterial pressure

Funcke S et al, Anesthesiology 2017

ANI M

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Spe

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Parameter Specification

Power Requirements 100-240 VAC through AC power adapterMains Frequency 50/60 HzBattery Type No batteryDC Input 12V 3,4A 40WPatient Leakage Current <5µA @ 220V and 50 Hz

Parameter Specification

Export Protocol UART interface

Data Export USB interface

Parameter Specification

DC Input (monitor) 3-pin power connector

ECG IN (monitor) 6-pin female connector for sensor cable connection

Export (monitor) Sub-D9 connector to export data in real time

Data Export (Monitor) USB connector to export data and snapshot to USB stick

Sensor cable 6-pin male connector

Sensor (Acquisition Device) 5-pin female connector for sensor

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Parameter Specification

Cooling Method Convection. Fan less

TemperatureOperatingStorage

5°C to 40°C-20°C to 60°C

DimensionsMonitor (width x height x depth) 256 x 214 x 81 mm

WeightMonitor 2,5 Kg

FinishMonitor Front : black and orange

Back : white

Parameter Specification

Type Color Liquid Crystal

Size 200 mm (8 inches)

Resolution 800 x 600 pixels

Active Viewing Area 173 x 130 mm

Pixel pitch 0.216 x 0.217 mm

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ANI Monitor V2 is a class IIa medical device, manufactured by Mdoloris Medical Systems, and CE marked. The ANI Monitor V2 name and logo are registered trademarks.

© 2018 Mdoloris Medical Systems. All rights reserved.MDQUAEN74.ANIV2 v.03 (EN)