Analgesia / Nociception Index Calculation

Dr Mathieu JEANNE – pôle d’anesthésie réanimation R. Salengro – C.H.U. de Lillecontact : mathieu.jeanne@chru-lille.fr

ESCTAIC Amsterdam 06–09 oct 2010

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 VariabilityRespiratory 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

0,04 Hz 0,15 Hz0,4 Hz

HR[bpm2]

f [Hz]VLF LF HF0,004 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 AnalysisFast Fourier Transform

Spectral AnalysisEffect 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 arrhythmiaSpectral 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

motif respiratoire

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

In case of nociception or anxiety : respiratory influence is lost, replaced by LF components (sympathetic activation) not visible in the high frequency field

Respiratory arrhythmia can be visualized directly on the RR series

Para-sympathetic reflex loopBrain stem

vagus node (X)

sinus nodebronchial

strech receptors

Clinical trial

Total intra venous general anesthesia

General anesthesiatwo 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 3

N=12

Remifentanil 2 µg/kg puis 0.24 µg/kg/min

Group 2

N=18

Alfentanil 30 µg/kg

Group 1

N=19

Sufentanil 0.5 µg/kg

No additionnal opioid

n=7

No additionnal opioid

n=7

No additionnal opioid

n=16

earlylight-lightAnalg

n=3; bolus 0.1 µg/kg

earlylight-lightAnalg

n=11; bolus 10 µg/kg

earlylight-lightAnalg

n=5;

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

• 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)

adequate analgesia

inadequate analgesia

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)

Correlation between• AUCminnu and HFnu (r2=0,81)• AUCtotnu and HFnu (r2=0,88)• AUCtotnu and AUCminnu (r2=0,92)

Linear regressionAUCtotnu = 5,1 * AUCminnu + 1,2

0

.2

.4

.6

.8

1

1.2

1.4

1.6

1.8

2

2.2

AU

Cm

in(n

u)

0 .2 .4 .6 .8 1HF/(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

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

ANI = 100 * AUCtotnu / 12.8

Results (4)

ANI• p<0,0001 (Mann Whitney)

10

20

30

40

50

60

70

80

90

100

AN

I

adequAnalg insuffAnalg

**

ANI at 48• sens=76% et spec=72%

ANI at 30• spec=100% > insuffAnalg

ANI at 82• sens=100% > adequAnalg

1-spécificité

sensibilité

surface=0.80

Simulated RR seriesvariable respiratory rate

Spectral analysis: Fourier transformEffect 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

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

Simulated RR series

Variable respiratory rateGraphical 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 occlusionand 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

controlled ventilationInduction

Base Primea

apnoea

intubation

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600 700 800

Irregular tidal volume during induction

followed by apnoea

ANI non usablecontrolled

ventilation : ok

before induction

spontaneous Ventilation

with constant tidal vol : ok

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