Wintermeeting 2024: Luc Barvais

Multimodal monitoring to guide TIVA:more windows more light?

Luc Barvais MD, PhD1 and Sean Coeckelenbergh, MD2

Saturday 20 January 8:30-9:00

  1. Erasme University Hospital, Brussels
  2. Paul Brousse Hospital, Paris

Improving TIVA by personalizing monitoring

TCI titration is very important in the daily clinical anaesthesia practice to decrease the risk of agitation and sometimes delirium in the postoperative period which could be associated with postoperative cognitive dysfunction.  The aim of new TCI techniques is to get perfect recovery with patients walking rapidly after moderate to major surgery without any mental alteration.

In an international survey published in 2022, the rate of responses was essentially in Europe with 255 respondents in Western Europe, 96 respondents in Southern Europe and 76 respondents in Eastern Europe (1).  The majority of respondents considered anaesthetic depth monitoring EEG either always or on most occasions important while a majority never or occasionally found antinociception monitoring important with a statistically significant difference.  The respondents use EEG monitoring more often during IV than inhaled anaesthesia.  Users of hypnotic monitoring perceived that EEG can help to prevent delirium, POCD, episodes of awareness whereas antinociception monitoring could help to reduce myocardial infarction.  So, there was a high variability in perceiving the importance of monitoring anesthesia depth and antinociception in the survey, despite it was being considered useful to improve outcome.

Why does this high variability and differences in experience and practice still happen? The role of this presentation is to give a rapid overview of the basis of monitoring of unconsciousness and antinociception and to evaluate if guiding TCI with modern anesthetic monitoring could play a role to reduce postoperative morbidity?


Unconsciousness is the state of being without normal sensory awareness.  The consequences of poorly equilibrated unconsciousness are the risk of awareness and if anesthetic overdose, the risk of neurological and cardiovascular toxicity.

Anesthetics have different mechanisms to affect the EEG in various ways.  EEG anesthesia monitors analyze the real-time signal EEG processing of an epoch (period of raw EEG), by converting the raw EEG signal using a Fourier transformation into component sine waves of identifiable frequency.  The voltage over time is converted to frequency and amplitude over time.  The shorter is the epoch, the more « real time » the data are evaluated.  If the epoch is long, the precision of the EEG measurement increases but could become not representative of the real time of the depth of anesthesia.  Most EEG anesthesia monitors display calculated number (BIS, SE, …) which usually decrease with increased depth.  EEG anesthesia monitors also often combine a bispectrum analysis which measures as a function of time the degree of nonlinear coupling between pairs of frequencies in the spectrogram.  They displayed either compressed spectral array which is a graph representation of the EEG frequency over amplitude with a new tracing superimposed every epoch to represent time or a density spectral array which is a graph of the EEG frequency over time, where the amplitude is expressed by colors.

Processed EEG monitors have several limitations. Most EEG signal artefacts are processed with the EEG desired signal and the believable display number could be wrong.  Processed EEG use less electrodes and have uncomplete cerebral coverage, especially when the probe is unilateral.  Finally, the proposed calculated numbers are derived from algorithms coming from specific populations and drugs and are not adapted in case of pediatric population or vulnerable brain. Ketamine bolus doses of more than 1 mg/kg yield to high frequency oscillations and high indexes values. Dexmedetomidine for deep sedation is associated with predominant slow oscillations, thus lower EEG indexes, but patients are easily awakened. During deep general anesthesia, the combination of benzodiazepines, opioid and either volatile or propofol TCI is associated with high drug synergy and a high risk of Burst Suppression

The BIS (Medtronic) was the first EEG index introduced in the mid-nineties.  It is often considered as the EEG « golden standard » index because most of the articles in the international literature studying EEG during general anaesthesia have used the BIS index.  The BIS index has either an unilateral or a bilateral montage with a 20 to 30 seconds delay.  It is an index from 0 to 100 with a recommended target from 40 to 60 during general anesthesia.  The proprietary algorithm is not known to public! BIS monitoring measures also the Burst Suppression Ratio and the electromyographic activity and displays a density spectrogram.

Can processed EEG prevent awareness? The B-Aware double blinded randomized controlled trial compared BIS guided versus no BIS monitoring in 2463 frailty patients at risk of peroperative awareness using either intravenous or inhaled anesthesia. There were two reports of awareness in the BIS-guided group and 11 reports in the routine care group (2).  So, processed EEG helps to decrease episodes of awareness in a population at risk during general anesthesia.
Can processed EEG improve outcome?  In a sub-analysis of 2662 adults enrolled in the BAG-Recall and B-Unaware studies (3), a cohort was defined with more than five cumulative minutes of EEG suppression, and was compared with a 1:2 propensity-matched to a non-suppressed cohort (less than 5 min EEG suppression).  The association between EEG suppression and mortality was evaluated using multivariable logistic regression. Although EEG suppression was associated with increasing anaesthetic administration and comorbidities, the hypothesis that intraoperative EEG suppression is a predictor of postoperative mortality was only supported if it was coincident with low mean arterial pressure.
Can processed EEG help to decrease delirium?  In the ENGAGES randomized clinical trial, even relatively small amounts of two minutes of burst suppression ratio was linked with delirium (4).  From 2 to 5 minutes, the risk was even stronger.  
This was also found in a randomized study comparing BIS-guided anesthesia or usual care in 921 elderly patients undergoing major non-cardiac surgery (5).  The neuropsychology battery of tests, called CAM (Confusion Assessment Method) was performed before and at 1 week and 3 months after surgery.  In both groups, the mean arterial pressure was maintained within 15% of baseline and HR maintained between 40 and 90.  BIS-guided anesthesia reduced anesthetic exposure and decreased the risk of POCD at 3 months after surgery. For every 1000 elderly patients undergoing major surgery, anesthetic delivery titrated to a range of BIS between 40 and 60 would prevent 23 patients from POCD and 83 patients from delirium (5).  A meta-analysis of five randomized controlled trials demonstrated also that use of intraoperative processed electroencephalogram monitoring is associated with a decreased risk of postoperative delirium but the mechanism explaining this association is yet to be determined (6).

So, in 2024, it is well demonstrated that processed EEG monitoring tools contribute to guide anesthetic depth.  Burst suppression is associated with delirium, which is associated with increased mortality if associated with low mean arterial pressure.  Low alpha power predicts burst suppression.

It looks evident that processed EEG monitoring must be placed for each patient undergoing major surgery and for each frailty or older than 60-year patient undergoing moderate surgery longer than one hour.


Nociception refers to the detection, transduction, and transmission of a noxious stimulus that elicits an autonomic response even in an unconscious subject.  The response is sympathetic stimulation which can cause cardiac ischemia or heart failure in patients with underlying cardiac pathologies! Too-low antinociception may also lead to episodes of connected consciousness following noxious stimulation. Too-much antinociception may compromise the hemodynamic status and organ perfusion. It can also be associated with delayed recovery and postoperative hyperalgesia.

During routine anesthesia clinical practice, the anesthesiologist has to limit the autonomic response by an appropriate and anticipative anti-nociception titration, according to the intensity of surgical stimulation. Recently, new techniques to measure the ANS response to noxious stimulation during general anesthesia have been developed. They involve the measurement of the amplitude of the plethysmogram pulse wave, the variability of the heart beat interval, the pupil dilation or skin conductance.  In young healthy patients, the use of these new ways of assessing the balance between nociception and antinociception may probably be efficient at reducing the intraoperative opioid consumption, and to limit opioid overdose or insufficiency. These new indexes of the NAN balance are non-invasive, but they are less validated and less routinely used than the processed EEG indexes of the hypnotic component of anesthesia.

The Surgical Plethysmographic Index (SPI, General Electric, USA) is derived from a formula which involves two normalized parameters, the pulse wave amplitude and the heart beat interval { SPI = 100 - (0.7 x normalized pulse wave amplitude + 0.3 x normalized heart beat interval)}. SPI is not invasive, does not require a consumable probe. It seems to reduce the remifentanil consumption. However, it is not reliable in awake patients or in the recovery room to assess pain. Its interpretation must be adapted to the risk of artefacts, such as vasoconstriction, hypovolemia, hypothermia, β-blocking agents, vasoactive amines and heart pacing.

The Analgesia Nociception Index (ANI, Metrodoloris, France, is derived from the area under the curve of the heart beat interval variation as compared to the mean interval.  This index is independent on heart and respiratory rates, and essentially reflects the parasympathetic tone. When there is no stimulus, only the respiratory sinusal arythmia influences the RR interval and ANI is over 50.  In case of pain, stress, anxiety, noxious stimulation or insufficient antinociception, the amplitude of HRV decreases, the area under the RR interval variability decreases and leads to a concomitant ANI decrease, less than 50.  Several factors may interfere with its adequate interpretation, such as electrocautery, atropine, cardiac arrhythmia, a slow or irregular respiratory frequency and of course apnea.

The Pupil Dilation Reflex (PDR, Algiscan, IDMED, France, in response to pain or surgical nociception exists in awake and anesthetized subjects. PDR has a very short onset of less than one second, and the peak effect is reached after 1.25 seconds. PDR stops very rapidly once noxious stimulation is over, and does not fade with time and repetition of the stimulus. PDR is mediated through thick myelinated A fibers. PDR-guided intraoperative analgesia has been demonstrated to allow a significant reduction in the intraoperative remifentanil and postoperative morphine consumption, as compared with standard practice (7). PDR is useful during the immediate postoperative period to assess pain in young children or disabled patients. Consequently, PDR seems to be complementary to the EEG indices at guiding anesthetic agent administration. However, PDR is altered in elderly and diabetic patients, and in case of ocular diseases, Unfortunately, it does not allow continuous monitoring.

Up to now, all these monitors of the balance between nociception and antinociception have only demonstrated a decrease of the peroperative opioid consumption.  None of them have shown any effect on perioperative morbidity.  Moreover, there are still no data in elderly or frailty patients,

The NoL index (Medasense Biometrics, Israel) is based on a multi-parametric approach to quantify nociception. A non-invasive finger probe, equipped with consumable expensive electrodes, records multiple pain-related physiological parameters through 4 sensors: the pulse rate, the pulse rate variability, the amplitude of the photoplethysmographic signal and a measure of skin conductance.  The Nol uses an algorithm incorporating artificial intelligence but the proprietary algorithm is not publicly available.  The NoL is individually calibrated and provides continuous and real time monitoring.  The NoL ranges between 0 (no pain) and 100 (extreme pain).  In ASA 1 and 2 patients receiving Nol-guided antinociception, combined frontal processed BIS and Nol monitoring can measure peroperative dexmedetomidine's hypnotic and opioid-sparing effects during remifentanil-propofol TCI anesthesia (8). So, Nol monitoring could help to detect the antinociceptive effect of alpha agonists.  However, intravenous ephedrine, phenylephrine and atropine could induce an increase in NoL within 1-2 minutes, and the changes might last up to 5 minutes. Nol could be also influenced by a low intravascular volume status.

In a ROC analysis study on 58 ASA I to 3 patients undergoing elective surgery under general anesthesia, Nol outperforms several other parameters to discriminate between noxious and non-noxious stimuli (9).

In a randomized controlled study performed in 80 adult patients scheduled for major abdominal surgery under remifentanil and propofol TCI, Meijer et al observed a 30% less remifentanil consumption in the Nol-guided group of patients (P < 0.001) (10).  Moreover, among nociception level-guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (P = 0.006). In the nociception level-guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (P = 0.044) (10).  By the decrease of the remifentanil TCI consumption using the personalized Nol antinociception, the authors assume that the decrement of the sympatholysis allows to individualize the autonomic tonus and consequently to reduce the risk of hypotensive episodes and the dose of vasopressors.

However, in a single-blinded randomized study in patients having moderate-to-high risk cardiovascular surgery with goal-directed hemodynamic management, there was no clear benefit of Nol-guided antinociception in 48 patients anesthetized with propofol-remifentanil TCI (11). Patients were randomized to NOL-guidance with remifentanil titrated to maintain the Nol index between 10 and 25 or to routine management (with the Nol blinded) with remifentanil adjusted per clinical hemodynamic responses.  Slightly less remifentanil was given to patients randomized to Nol guidance: (0.11 ± 0.03 vs. 0.13 ± 0.03 µg kg-1 min1, p=0.0034). The amounts of other drugs, including that of norepinephrine and infused fluids, did not differ significantly. There was no significant difference in intraoperative hemodynamics between groups.


Like the results of the international survey on the current trends in anesthetic depth and antinociception monitoring, processed EEG is required to reduce episodes of peroperative awareness and to reduce the risk of postoperative delirium and cognitive dysfunction in frailty and/or old patients.  Nociception monitors are complementary to processed EEG as they evaluate another essential component of the depth of anesthesia.  Pupil diameter variations looks very interesting because no probe and no cost but is intermittent. Nol index with his multivariable approach is promising but they are some limitations, such as sometimes the quality of signal and the cost.  The absolute value of the available nociceptive indexes obtained during periods of no stimulation has no predictive ability regarding future events. Secondly, although nociceptive indexes responses to noxious stimulation are more sensitive indicators than hemodynamic parameters, one must keep in mind that their value can be strongly influenced by several factors.  In 2024, even if many tools are available to optimize the titration of modern TCI anesthesia combining the population Eleveld pharmacokinetic set for propofol combined with an antinociceptive drug TCI technique, strategies of monitoring need to be validated in frailty, old and cardiac patients.  There is an urgent need of a randomized multicentre study of ASA 3 and 4 patients monitored by processed EEG alone compared with a similar group of patients monitored by a combination of processed EEG with a multiparametric nociceptive monitor.


  1. Current trends in anesthetic depth and antinociception monitoring: an international survey.  Coeckelenbergh S, Richebé P, Longrois D., Joosten A and De Hert S.  Journal of Clinical Monitoring and Computing, 2022; october; 36(5): 1407-1422.
  2. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial.  Myles P, Leslie K, MasNeil J, Forbes M and Chan M.  The Lancet, May, 2004; 363: 1757-63
  3. Association between intraoperative electroencephalographic suppression and postoperative mortality.  Willingham M, Ben Abdallah A, Gradwohl S, Helsten D, Lin N, Villafranca A, Jacobsohn E, Avidan M and Kaiser H. British Journal of Anaesthesia 2014; 113 (6): 1001–8.
  4. Effect of Electroencephalography-Guided Anesthetic administration on postoperative delirium among adults undergoing major surgery.  The ENGAGES randomized clinical trial.  Wildes T, Mickles A, Abdallah A and the ENGAGES group; JAMA 2019 February 5;321(5):473-483.
  5. BIS-guided anesthesia decreases postoperative ddelirium and cognitive decline.  Can M, Cheng B, Lee T, Gin T and the Coda Group.  J. Neurosurg Anesthesiol. 2013; 25: 33-42.
  6. Processed Electroencephalogram Monitoring and Postoperative Delirium: A Systematic Review and Meta-analysis. MacKenzie K, Britt-Spells A, Sands L and Leung J.  Anesthesiology September 2018, Vol. 129: 417–427.
  7. Pupillometry-guided Intraoperative Remifentanil Administration versus Standard Practice Influences Opioid Use: A Randomized Study. Sabourdin N, Barrois J, Louvet N, Rigouzzo A, Guye M-L, Dadure C, Constant I.  Anesthesiology 2017, 127: 284–92.
  8. Effect of dexmedetomidine on Nociception Level Index-guided remifentanil antinociception: a randomised controlled trial. Coeckelenbergh S, Doria S, Patricio D, Perrin L, Engelman E, Rodriguez A, Di Marco L, Van Obbergh L, Estebe JP, Barvais L and Kapessidou P.  European Journal of Anaesthesiology May 2021.38 (5): 524-533.    
  9. Preliminary Intraoperative Validation of the Nociception Level Index: A Noninvasive Nociception Monitor.  Edry R, Recea V, Dikust Y, Sessler D.  Anesthesiology 2016 Jul; 125(1): 193-203.

  1. Nociception-guided versus Standard Care during Remifentanil-Propofol Anesthesia:
    A Randomized Controlled Trial.  Meijer F, Martini C, Broens S, Boon M, Niesters M, Aarts L, Olofsen E, Dahan A.  Anesthesiology. 2019 May;130(5):745-755.
  2. Nociception level index-guided antinociception versus routine care during remifentanil-propofol anaesthesia for moderate-to-high risk cardiovascular surgery: A randomized trial.  Coeckelenbergh S, Sessler D, Doria S, Patricio D, Jaubert L, Huybrechts I,  Stefanidis C, Kapessidou P, Tuna T, Engelman E, Barvais L, Perrin L.  European Journal of Anaesthesiology  2023 Oct 1;40(10):790-793.