ESCTAIC Amsterdam 06–09 oct 2010

Analgesia / Nociception Index

Calculation

Dr Mathieu JEANNE – pôle d’anesthésie réanimation R. Salengro – C.H.U. de Lille

contact : mathieu.jeanne@chru-lille.fr
 disclaim – conflict of interest
MetroDoloris – startup : bio incubateur Eurasanté

• commercial development of institutionnal research by the

university hospital of Lille

• scientific adviser

www.metrodoloris.com
 Heart Rate Variability
Respiratory sinus arrhythmia
• Each respiratory cycle is associated with a fall in paraS tone
• this leads to a brief increase of heart rate (shortening of RR intervals)
• that can be best seen on a bi-dimensionnal RR series as successive
local minima (I)
Spectral Analysis
 Spectral Analysis
Fast Fourier Transform
HR
[bpm2]

0,4 Hz
0,004 Hz 0,04 Hz 0,15 Hz

VLF LF HF f [Hz]
Very Low frequencies (0.004-0.04 Hz) express thermoregulatory and endocrine
activities
Low frequencies (0.04-0.15 Hz) are related to sympathetic and parasympathetic
tone modulations, and baroreflex activity

High frequencies (0.15-0.40 Hz) express parasympathetic tone variations only,

mainly in relation with respiratory sinus arrhythmia
 Spectral Analysis
Effect of induction of anesthesia

• Propofol (0.3 mg/kg/min) dampen HF content

• but not sevoflurane (5%) in O2 100%

Kanaya et al. Anesthesiology 2003 ; 98 : 34-40

 Respiratory sinus arrhythmia
Spectral Analysis

Respiratory sinus arrhythmia plays a prominent role among the various influences
exerted on the sinus node

Example of spectral analysis in a patient during general anesthesia :

the high frequency content is mainly explained by the influence
of ventilation on the RR series
Respiratory arrhythmia and respiratory pattern

Respiratory arrhythmia can be visualized directly on the RR series

In the absence of nociception : respiration is the main influence of variability

motif respiratoire

In case of nociception or anxiety : respiratory influence is lost, replaced by LF

components (sympathetic activation) not visible in the high frequency field
 Para-sympathetic reflex loop
Brain stem

vagus node (X)

sinus node
bronchial
strech
receptors
 Clinical trial
Total intra venous
general anesthesia
 General anesthesia
two components
• Loss of consciousness
– Hypnotic agents (propofol, halogens, …)
– Effect on superficial cortex and thalamo
cortical loops
– measurable on the surface EEG (e.g. BISTM)

• Reactivity
– sub cortex reactions
– Opioids
– measurable on the pupillary response /
diameter
 Group 1 Group 2 Group 3
N=19 N=18 N=12
Sufentanil 0.5 µg/kg Alfentanil 30 µg/kg Remifentanil 2 µg/kg
puis 0.24 µg/kg/min

No No No
additionnal additionnal additionnal
opioid opioid opioid
n=16 n=7 n=7

earlylight-lightAnalg
earlylight-lightAnalg earlylight-lightAnalg n=5;
n=3; bolus 0.1 µg/kg n=11; bolus 10 µg/kg increase of 0.04 µg/kg/min

19 « first » nostim -earlyLight - lightAnalg sequences

1 à 4 sequences per patient
Total of 51 sequences
 Preliminary results
• TIVA; constant Bispectral index (Aspect A2000)
• objective : anticipate hemodynamic reactivity (20% increase of HR
or SBP)
• total of 51 sequences « noStim – earlyLight – lightAnalg »

Jeanne M et al. Auton Neurosci. 2009;147(1-2):91-6

 Prediction of reactivity
during general anesthesia ?

? • How can we make it simple ?

 Respiratory influence on the RR series

adequate analgesia

inadequate analgesia
• Série RR
– resampled, mean-centered, normalised
– band pass filtered [0.15-0.5 Hz] (wavelets transform)
– each respiratory cycle leads to a shortening in the RR series
– surfaces T1, T2, T3, T4 : measure of respiratory influence on the RR
series
– AUCminnu = min(T1, T2, T3, T4) and AUCtotnu = (T1, T2, T3, T4)
 Results
• n=90 RR series
• Two distinct situations
– A : inadequate analgesia, during 5 min before hemodynamic
reactivity (n=54 series)
– B : adequate analgesia, long before reactivity (n=36 series)

Hemodynamic and HRV results; Mann Whitney U test, non paired test
 Results (2)

2.2 Correlation between

2
1.8
• AUCminnu and HFnu (r2=0,81)
1.6 • AUCtotnu and HFnu (r2=0,88)
1.4
AUCmin(nu)

1.2
• AUCtotnu and AUCminnu (r2=0,92)
1
.8
.6
.4
.2 Linear regression
0
0 .2 .4 .6 .8 1 AUCtotnu = 5,1 * AUCminnu + 1,2
HF/(HF+LF)
 Results (3)
Analgesia Nociception Index
• The maximum possible surface of respiratory influence is 0.2*64=12.8
• The occupied part of that surface is AUCtotnu / 12.8

ANI = 100 * AUCtotnu / 12.8

or ANI = 100 * [(5.1*AUCminnu + 1.2) / 12.8]

 Results (4)
100
90

80
**
ANI
70
60
• p<0,0001 (Mann Whitney)
ANI

50
40
30

20
10
adequAnalg insuffAnalg

sensibilité

ANI at 48
• sens=76% et spec=72%
surface=0.80
ANI at 30
• spec=100% > insuffAnalg
ANI at 82
• sens=100% > adequAnalg

1-spécificité
 Simulated RR series
variable respiratory rate
 Spectral analysis: Fourier transform
Effect a resp. rate change

• A change in respiratory rate leads to a shift of HF

spectral peak
• Two peaks are present during the transition period
 Simulated RR series
• Aim : to measure the
performance of HRV analysis
tools (spectral and graphical)
• Typical respiratory pattern
from a recording during
anesthesia (adequate
analgesia)

• Creation of RR series with different resp. rates

• 8, 10, 12 et 15 c/min
Simulated RR series

• HF spectral
measurements are under
estimated when resp.
rate < 12 c/min
 Variable respiratory rate
Graphical measurements are constant

• Graphical measurements (AUCminnu, AUCtotnu) are

constant despite various resp. rates

Jeanne M et al. IEEE EMBS 2009; 1:1840-3

 Clinical trial
Laparoscopic cholecystectomy
 Protocol
• Adult patients
• Emergency laparoscopic cholecystectomy
• ASA status I or II ; no known alteration of autonomous
nervous system

• TIVA propofol, remifentanil, myorelaxation

• controlled ventilation Vt=8ml/kg – RR 12 c/min

• Bispectral index maintained in [40-60] range

• remifentanil target lowered at 2 ng/ml after tracheal
intubation ; increase in case of hemodynamic reactivity
(20% incrase in HR or SBP)
• ANI measurements
 Preliminary results
• n=9 patients included
• Hemodynamic reactivity
is always preceded by an
ANI decrease
 Case report
Mesenteric artery occlusion
and general anesthesia
 Mesenteric ischemia
• Man, 43 year, no known disease
• Comes to the casualty ward for acute abdominal pain

• abdominal CT scan : upper mesenteric artery occlusion

• first attempt at surgery

– dissection of upper mesenteric artery
– no bypass possible
– conservative treatment (heparin)

• second look after 48h

– small bowel necrosis over 10cm and sub ischemia over 1m
– bowel resection
– ilio-mesenteric bypass
 Blind anesthesia
• TIVA
– propofol (Schnider)
– ultiva (Minto)

• Tachycardia from the

beginning (110 / min)
– leading to fluid expansion 2000ml
– increasing remi targets

• After 2h surgery
– persistent tachycardia : 110 / min
– BP 98/60 mmHg
– total blood loss : 150 ml
– ultiva : target = 6 ng/ml
– propofol : target = 3.5 µg/ml

Question : are analgesia and hypnosis adequate ?

 EEG monitor + ANI monitor
• ANI
– elevated index : 100
– high para tone
– > remi target is halved
from 6 to 3 ng/ml
– no effect on HR or BP
during the next hour

• Bispectral index (Aspect

A2000)
– measure is whithin the [40-
60] range
– >> propofol target is
maintained constant at 3.5
µg/ml
Future validation...
 A.N.I.
• Test whether cardiovascular drugs modify ANI
predictibility of hemodynamic reactivity
– beta bloquing drugs
– catecholamines

• Test whether ANI guided opioid delivery during

general anesthesia could prevent hemodynamic
reactivity and opioid overdose ?
– primary endpoint : number of avoided hemodynamic events

• Limitations
– no recording during apnoea
– sinus rythm only
 before
induction
Irregular tidal volume during induction
spontaneous
followed by apnoea
Ventilation
with constant ANI non usable
tidal vol : ok controlled
ventilation : ok

100
90
80
70
60
50
40
30
20
10
0
0 100 200 300 400 500 600 700 800

apnoea controlled ventilation

Induction
Base Primea intubation
 Conclusion
• Last years have witnessed the surge of ANS
monitoring, esp. analgesia / nociception
balance.

• Several complementary monitoring techniques

do assess the status of ANS: pupillometry (p),
skin conductance and Cardean (, ANI (p

• These new monitoring devices underline the role

of anesthesia as an ANS oriented disciplin