Analgesia / Nociception Index

Mathieu JEANNE, MD, PhD

Anesthesia & Intensive Care

Cic-It 807 Inserm

University Hospital

Lille, France

Conflict of interest

• Mathieu JEANNE is consultant for MetroDoloris®

State of the art

Current understanding of general anesthesia

• Cortical reactions– consciousness– hypnosis > EEG assessment of depth of

hypnosis (bispectral index, entropy, etc)

• Sub cortical reactions : autonomous nervous system

• eye• heart rate• blood pressure• sweat (> pain monitor)

• analgesia / nociception balance evaluation through ANS reactions assessment

State of art

State of artAutonomous nervous system

parasympathetic system

sympathetic system

• pupil contraction

• slowing of heart rate

• bronchial constriction

• digestive system

• pupil dilation

• lacrimation

• increased heart rate and blood pressure

• bronchial dilation

• sweating

Why use the ECG signal ?

• electrical signal easy to measure on the skin surface

• used for standard clinical monitoring• standard during anesthesia practice / ICU / neo

natalogy• non invasive• provides continuous monitoring and assessment

of ANS reactions to stress / nociception• still usable in case of :

– hypovolemia– shock (hypovolemic, septic, cardiogenic...)– hypothermia

State of art

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)

State of art

Spectral Analysis using Fourier transform

• Fourier transform has been widely used for heart rate variability analysis

– spectral powers measured on the RR series result from various actions of the ANS

– ANS sympathetic and paraS tones can be measured in the low (LF) and high frequency (HF) fields

– Very Low Frequencies (VLF) are influenced by thermo regulation and the endocrine system

Bpm

Time

70

90

50

instantaneous heart rate

Fourier transform

Power spectrum

Quantification

LF HF

Frequency

VLF

State of art

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 paraS tone modulations, and baroreflex activity

High frequencies (0.15-0.40 Hz) express parasympathetic tone variations only, mainly in relation with respiratory sinus arrhythmia

Fourier Transform Power SpectrumState of art

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 rate

Respiratory spectral peak

State of art

Why is Fourier transform not used routinely ?

• The increase of respiratory rate from 8 to 12 cpm leads to two respiratory spectral peaks during the 5 min transition in the analyzing window

• ANS assessment is not possible during that period

State of art

Main disavantages of the fourrier transform analysis

-Just applicable for stable signals-Needs 5 minutes of recording to be accurate

Pichot et al. J Appl Physiol 1999 ; 86:1081-91

Fast wavelet transform

Mallat S. Une exploration des signaux en ondelettes. Ed Ecole Polytechnique

R&D

Main advantages:

- applicable with unstable signals

- Provide a reliable countinuous assessment

Focused on the high frequencies range analysis of the HRV, the ANI technology objectively assess the parasympathetic

reflex loop

ANS

Sinus node

Stretch receptor

s

Limitation:

Apnea

Limitation: Sinusal rythm

only

Technology

Respiratory arrhythmia and respiratory pattern

ventilatory pattern

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

State of art

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 dampen reactivity– measurable on ANS reactions

• HF measurements of HRV provide direct paraS evaluation

hypothesis / clinical research

From ECG to ANI

1

2

3

hypothesis / clinical research

1

hypothesis / clinical research

1

2

hypothesis / clinical research

1

2

3

hypothesis / clinical research

Instead of the former methodology, here are our main advantages:

• 1: Exclusion of all artefacts from the ECG signal

• 2: Normalization

• 3: Fast wavelet transform analysis

• 4: Graphical measurement

• 5: Simple index

Change in respiratory rate : graphic measure not altered

The change in respiratory rate does not lead to a change in graphical measurements.

Simulated RR series during an increase of respiratory rate

hypothesis / clinical research

• Adult patients scheduled for surgery

• Total intra venous anesthesia : propofol + opioid;

• propofol adapted in order to keep Bispectral index in the predefined range [40-60]

• ECG recordings and post hoc processing of RR series in order to obtain «noStim – earlyLight – lightAnalg» sequences

• primary objective : anticipate hemodynamic reactivity (defined as a 20% increase of HR or SBP)

Clinical settinghypothesis / clinical

research

Patients and anesthetic protocol

• 49 patients included– sufentanil : 19 patients (0.3 µg.kg-1 at induction and 0.1

µg.kg-1 in case of reactivity)

– alfentanil : 18 patients (30 µg.kg-1 at induction and 10 µg.kg-1 in case of reactivity)

– remifentanil : 12 patients (0.24 µg.kg-1.min-1 decreasing until reactivity)

• 30 patients do not present reactivity

• 19 patients present reactivity– total : 51 sequences of reactivity– 1 to 4 sequences per patient

hypothesis / clinical research

Results

• RR series in two distinct situations– adequate analgesia, long before reactivity– 5 min before hemodynamic reactivity

Hemodynamic and HRV results; Mann Whitney U test

adequate analgesia

reactivity p

HR 59 (60-68) 72 (69-81) < 0.001

SBP (mmHg) 98 (89-126) 130 (113-142) < 0.001

HFnu 0.64 (0.46-0.74) 0.42 (0.30-0.51) < 0.001

AUCmin (nu) 1.33 (0.97-1.66) 0.82 (0.65-0.96) < 0.001

AUCtot (nu) 8.48 (6.13-10.41) 5.69 (4.39-6.67) < 0.001

hypothesis / clinical research

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)

hypothesis / clinical research

ANI

• p<0,0001 (Mann Whitney)

10

20

30

40

50

60

70

80

90

100

AN

I

adequAnalg insuffAnalg

**

Results (3) Analgesia Nociception Index

• The maximum possible surface of respiratory influence is 0.2*64=12.8

• AUCtot = T1 + T2 + T3 + T4

• AUCmin = min (T1, T2, T3, T4)

• 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

hypothesis / clinical research

How to interpret ANI ?

• Recommended target range based on available clinical data :

• 50-70

Actual thresholds

- 48

se=76% sp=72%

- 30

se=100% > reactivity

- 82

se=100% > adequate Analg

0

50

100

70

1-spécificité

sensibilitéSensitivity

1-Specificity

surface = 0.80

hypothesis / clinical research

clinical setting

ANI : relative paraS measurement

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% increase in HR or SBP)

• ANI measurements

Preliminary results

• n=9 patients included• Hemodynamic reactivity

is always preceded by an ANI decrease

Data presented as media (interquartile). * p<0.01 vs AprInd (after induction). + p<0.01 vs AprChir (after surgery)

Clinical trial:Tetanic stimulation at 2 remifentanil targets

during TIVA

NeurosurgeryPreliminary results

• Adults• ASA I or II ; no know ANS alteration

• TIVA propofol + remifentanil + myorelaxation• controlled ventilation Vt=8ml/kg – RR 12 c/min

• Bispectral index maintained in [30-50]• Remifentanil target at 3 ng/ml after tracheal intubation

• 3 stimuli before incision– TET1 : remifentanil Ce = 3 ng/ml (tetanic stimulation)– TET2 : remifentanil Ce = 6 ng/ml– head holder insertion : remifentanil Ce = 6 ng/ml

• ANI• Papillary dilation reflex (Neurolight, IDMED)

Results

• N=14 patients included

• Propofol Ce = 2.6 (2.5-3.0) µg/ml

• Heart rate (FC), blood pressure (PA) and BIS did not change during tetanos and head holder insertion (TAP)

• ANI

• decreased significantly after all 3 stimuli vs nostim

• less ANI decrease after TET2 vs TET1

• Pupilary dilation reflex decreased also after TET2 vs TET1

Results

- propofol target : 2,6 µg.ml-1 (2,5-3,0)

0

5

10

15

20

25

30

35

40

NoStim TET 1 TET 2 TAP0

5

10

15

20

25

30

35

40

NoStim TET 1 TET 2 TAP

RDP (%)

0

20

40

60

80

100

00:00 00:02 00:05 00:08 00:11 00:14 00:17temps (minute)

NoStim TET 1 TET 2 TAP

Example of ANI variation and HR during nociceptive stimuli

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)– remifentanil (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– remifentanil : 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 within 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 predictability of hemodynamic reactivity– beta bloquing drugs– catecholamines

• Limitations – no recording during apnea– sinus rhythm only

controlled ventilationInduction

Base Primea

apnea

intubation

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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

Conclusion

• The surge of ANS monitoring devices is probably a promise of personalized anesthetic care in the coming years, esp. analgesia / nociception balance monitoring.

• These new monitoring devices underline the role of anesthesia as an ANS oriented discipline.