1. Analgesia / Nociception Index Calculation Dr Mathieu JEANNE – pôle d’anesthésie réanimation R. Salengro – C.H.U. de Lille contact : mathieu.jeanne@chru-lille.frmathieu.jeanne@chru-lille.fr ESCTAIC Amsterdam 06–09 oct 2010

2. 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

3. 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)

4. Spectral Analysis

5. 0,04 Hz0,15 Hz 0,4 Hz HR [bpm 2 ] f [Hz] VLF LF HF 0,004 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 Analysis Fast Fourier Transform

6. Spectral Analysis Effect of induction of anesthesia Propofol (0.3 mg/kg/min) dampen HF content but not sevoflurane (5%) in O 2 100% Kanaya et al. Anesthesiology 2003 ; 98 : 34-40

7. 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

8. 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

9. Para-sympathetic reflex loop Brain stem vagus node (X) sinus node bronchial strech receptors

10. Clinical trial Total intra venous general anesthesia

11. 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. BIS TM ) Reactivity –sub cortex reactions –Opioids –measurable on the pupillary response / diameter

12. 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

13. 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

14. Prediction of reactivity during general anesthesia ? How can we make it simple ? ?

15. 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 –AUCmin nu = min(T1, T2, T3, T4) and AUCtot nu =  (T1, T2, T3, T4) adequate analgesia inadequate analgesia

16. 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

17. Results (2) Correlation between AUCmin nu and HF nu (r 2 =0,81) AUCtot nu and HF nu (r 2 =0,88) AUCtot nu and AUCmin nu (r 2 =0,92) Linear regression AUCtot nu = 5,1 * AUCmin nu + 1,2

18. 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 AUCtot nu / 12.8 orANI = 100 * [(5.1*AUCmin nu + 1.2) / 12.8] ANI = 100 * AUCtot nu / 12.8

19. Results (4) ANI p<0,0001 (Mann Whitney) ** 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

20. Simulated RR series variable respiratory rate

21. 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

22. 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

23. HF spectral measurements are under estimated when resp. rate < 12 c/min Simulated RR series

24. Variable respiratory rate Graphical measurements are constant Graphical measurements (AUCmin nu, AUCtot nu ) are constant despite various resp. rates Jeanne M et al. IEEE EMBS 2009; 1:1840-3

25. Clinical trial Laparoscopic cholecystectomy

26. 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

27. Preliminary results n=9 patients included Hemodynamic reactivity is always preceded by an ANI decrease

28. Case report Mesenteric artery occlusion and general anesthesia

29. 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

30. 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 ?

31. 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

32. Future validation...

33. 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

34. controlled ventilation Induction Base Primea apnoea intubation Irregular tidal volume during induction followed by apnoea ANI non usable controlled ventilation : ok before induction spontaneous Ventilation with constant tidal vol : ok

35. 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