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Nociception Monitors in 2024: Validity and Usefulness for Clinical Practice in Anesthesia

Aug 8, 2024, 06:15 AM by Walid Oulehri, MD, MSc, DESAR, Olivier Verdonck, MD, MSc, DESAR, and Philippe Richebe, MD, PhD, DESAR

Cite as: Oulehri W, Verdonck O, Richebe P. Nociception monitors in 2024: validity and usefulness for clinical practice in anesthesia. ASRA Pain Medicine News 2024;49. https://doi.org/10.52211/asra080124.010.

This narrative review focuses on the four most commonly used nociception monitors in 2024: the Analgesia Nociception Index (ANI, Mdoloris Medical System, Loos, France), the Surgical Pleth Index (SPI, GE Healthcare, Helsinki, Finland), pupillometry (AlgiScan/Neurolight, IDMed, Marseille, France), and the Nociception Level (NOL) index (Medasense, Ramat Gan, Israel). These monitors were designed to measure intraoperative nociception and help anesthesiologists better guide the administration of analgesics, including opioids. These monitors aim to improve intraoperative nociception management and positively impact postoperative pain-related outcomes, mainly by improving patient postoperative recovery. Studies assessing nociception monitoring in the intensive care unit, the recovery room, or awakened patients (such as chronic pain patients) were not considered in the present review. More literature is needed to draw interesting and robust conclusions and recommendations.

Description of the Four Selected Nociception Monitors

Among the four devices, pupillometry was the first technology described to monitor nociception. Pupillometry measures the pupillary diameter and its variations in response to nociceptive stimuli, thus studying the sympathetic activity of the autonomic nervous system (ANS). Numerous devices have been developed to measure pupillary diameter and its variations. Recently, the French company IDMed developed the AlgiScan to measure these parameters in response to calibrated nociceptive stimuli. However, the accuracy of pupillometry can be limited by ocular lesions, head access during surgery, and artifacts due to high luminous intensity in the operating room. Moreover, a continuous measure of the pupillary diameter is not entirely safe because it would expose the patient to the risk of corneal lesions, such as dryness and its possible consequences.

The Surgical Pleth Index (SPI), formerly called the Stress Surgical Index, reflects the sympathetic activity of the ANS. A finger photoplethysmograph provides information, namely the microvascular wave impulse, which calculates the two parameters constituting the SPI, the heart rate variability and the pulse of the photoplethysmography amplitude (PPGA). Thus, no consumable is needed with SPI. The SPI is a dimensionless continuous numerical index from 0 to 100, where 0 represents no stress and 100 high-intensity stress. It was previously developed to give a numeric measure of the surgical stress in patients under general anesthesia. The manufacturer recommends a SPI < 50 during surgery. The accuracy of the SPI can be limited by cardiac arrhythmia (atrial fibrillation, flutter, atrial or ventricular extrasystoles if very frequent), cardiac pacing, and peripheral vasoconstriction.

The Analgesia Nociception Index (ANI) is based on heart rate variability. This technology continuously analyses the impact of the respiratory sinus arrhythmia on the heart rate, leading to a measure of the parasympathetic tone. Each R wave in the EKG signal is used to measure the time variation of the RR interval. This signal is normalized and filtered between 0.15 and 0.4 Hz. The ANI is a dimensionless index from 0 to 100, where 0 is the sign of a high ANS response to stress, and 100 is a low ANS response to stress and possibly less nociception. The accuracy of the ANI can be limited by cardiac arrhythmia, cardiac pacing, and the administration of drugs interfering with the RR variability, such as ephedrine, phenylephrine, atropine, and glycopyrrolate etc.

The Nociception Level (NOL) index is a multiparametric index. The NOL index noninvasively collects and measures physiological parameters, such as heart rate, PPGA, cutaneous conductance and temperature, and associated time derivatives. These are collected by a finger probe (PMD-200TM, Medasense Biometrics Ltd, Ramat Yishai, Israel) and are analyzed using nonlinear regression of Forest, providing a dimensionless number from 0 to 100, where 0 is no nociception, and 100 is a very high nociception. The accuracy of the NOL index can be limited by cardiac arrhythmia, cardiac pacing, peripheric vasoconstriction, and the administration of drugs, such as ephedrine, phenylephrine, atropine, and glycopyrrolate etc.

What Pathophysiological Reasons Might Justify the Use of Intraoperative Nociception Monitoring?

Most often, general anesthesia combines unconsciousness, antinociception, and immobility. Assessing hypnosis and muscle relaxation has been extensively studied, and some consensus exists for these two components of anesthesia. However, intraoperative nociceptive monitoring has yet to be studied extensively, even though evidence suggests that a high level of pain response intraoperatively could impact clinical outcomes. Indeed, animal experimental studies have precisely described the molecular mechanisms underlying peripheral and central sensitization of pain pathways during and after surgery.1-3 The link between this central sensitization and the development of persistent postoperative pain (PPSP) has also been extensively studied and reported in animals and humans.4-6 This even led to a new classification by the International Association for the Study of Pain on the definition of chronic postsurgical pain,7 and many authors proposed preventive strategies to avoid PPSP.4, 8,9 Thus, a lack of proper analgesia during surgery might expose the patient to a high level of nociceptive inputs from the surgical noxious stimuli directed to the central nervous system, inducing a high level of pain sensitization. The stress response (via an over-activation of the sympathetic system) leads to a higher risk of poor hemodynamic conditions during and after surgery, as well as metabolic and coagulation dysregulations and immune system alterations.10,11

Historically, opioids were the mainstay for perioperative pain management. However, their prominence in perioperative pain management protocols is now being questioned. The main reasons for avoiding intraoperative opioids were the higher risk of postoperative opioid-related side effects as well as the possibility of inducing postoperative opioid-induced hyperalgesia (OIH). Recent reviews on OIH revealed that all opioids given at high doses and for an extended period (long-lasting anesthesia for major surgeries) may also be responsible for OIH.12-14

More precise and patient-tailored intraoperative pain monitoring may be warranted to guide intraoperative analgesics administration.

Opioids are also well-known to promote or enhance opioid-related adverse effects and events, such as postoperative nausea and vomiting, shivering, ileus, and urinary retention.15 Poor pain management can also harm the immune system. Therefore, more precise and patient-tailored intraoperative pain monitoring may be warranted to guide intraoperative analgesics administration.

In daily clinical practice, clinical parameters, such as variations in heart rate, blood pressure, sweating, tears, or even simple movements, were the only physiological parameters the anesthesiologist could trust to guide the administration of intraoperative analgesics. Nevertheless, these classically used clinical parameters need to be revised to comprehensively assess nociception levels intraoperatively, as they have been shown to lack sensitivity and specificity. More specific and sensitive indexes16-20 have been developed, validated, and proposed to anesthesiologists for personalized anesthesia and to administer perioperative medicine more precisely. These monitors and their related indexes will also allow anesthesiologists to more precisely study the real impact of anesthetics21 or analgesics20 to effectively block noxious stimuli and allow for an optimal balance between nociception and antinociception.

Did These Monitoring Devices Demonstrate a Relevant Clinical Impact on Outcomes During and After Surgery?

Are the devices efficient in detecting nociception, and are they more efficient than variations in heart rate or mean arterial pressure to measure nociception?

ANI, SPI, pupillometry, and the NOL index were compared to the classical clinical parameters for intraoperatively detecting nociception, such as heart rate (HR) and mean arterial blood pressure (MAP). ROC curve analysis of the sensitivity and specificity of each parameter to detect intraoperative nociception under general anesthesia conditions was made, and the area under the curve (AUC) was determined. More than 80 studies evaluated the ability of these four indexes to detect nociception. They demonstrated they could detect and measure intraoperative nociception more efficiently than HR and MAP with much higher AUCs for the index and higher sensitivity and specificity.16,17,19,20,22-27 This literature supports that these indexes are more precise in detecting intraoperative nociception under general anesthesia and controlled ventilation conditions.

However, questions remain about their impact on the intraoperative management of antinociceptive agents administered during general anesthesia. One recent study demonstrated that the NOL index was also able to identify the analgesic effect of intraoperatively administered opioids more precisely than HR and MAP, which resulted in better intraoperative administration of opioids.28

Finally, the concomitant intraoperative use of nociception monitors (NOL index) with EEG monitors (Bispectral index) improves the time for emergence from anesthesia and post-anesthesia care unit (PACU) recovery.29 In clinical practice, the correlation between the autonomic nervous system and the pain response may not be direct and exact. This can result in the nociception monitor’s lack of specificity.

Does the use of the devices improve intraoperative management of analgesics?

As previous studies validated the nociception indexes discussed, it was important to determine whether their use would decrease the need for intraoperative opioids or other analgesic agents. They found the device helped to identify if regional techniques used intraoperatively offered proper antinociception during major surgery.30 Also, many clinical studies reported a strong reduction of intraoperative opioids in the groups for whom opioids were given based on this index versus based on HR and blood pressure. For example, pupil diameter monitoring reduced intraoperative remifentanil consumption in gynecological surgery.27 The same intraoperative opioid reduction was also reported in gynecological laparoscopic surgery when fentanyl was administered under the guidance of the NOL index, allowing for a 22% reduction of the total amount of fentanyl in the NOL-guided group.31 The NOL index also reduced intraoperative remifentanil administration by 30% in patients scheduled for major abdominal procedures.32 In another study, the same group of researchers also demonstrated that stress hormones (adrenocorticotropic hormone and cortisol) were drastically reduced in the NOL-guided group during surgery.33 The ANI index enabled a decrease in intraoperative fentanyl by about 50% in patients undergoing lumbar discectomy and laminectomy.34 The SPI also demonstrated a similar ability to reduce intraoperative opioid requirements.35,36

Nevertheless, one systematic review of randomized trials published did not provide a strong conclusion on reducing opioids when intraoperative nociception monitors are used.37 However, this review did not include more recent publications on the topic (from 2020 to 2023) and used only 12 studies with small sample sizes, where most were only completed in a single center. The high level of heterogeneity in the surgery type was also one factor that could explain why we did not reach a stronger conclusion. As for managing acute pain after surgery, which is most often recommended to be procedure-specific, perhaps the management of intraoperative nociception should also be based on a procedure-specific approach. Indeed, laparoscopic versus major open surgeries might have different outcomes in opioid consumption and nociception monitoring. This will have to be examined more precisely in future studies.

Nociception monitors allow for better hemodynamic intraoperative profiles, less hypotensive events, and less need for vasopressor administration,32,35 which suggests a higher level of patient safety during general anesthesia. Nevertheless, this latter point needs to be better explored in future studies, using this as the primary outcome. There is still a gap between theoretical physiological changes that the nociceptive monitors focus on and clinical observation and how patients behave under general anesthetic or having a localized regional technique.

Are the devices efficient in decreasing postoperative pain levels and analgesic consumption?

Most studies using intraoperative nociception monitoring reported lower postoperative pain scores and opioid consumption for several hours after surgery. This was true when using pupil diameter monitoring in gynecological surgery.27,38 This was also reported when ANI was used during general anesthesia for spinal surgery34 or when the NOL index was used in major abdominal surgery33 or gynecological surgery.31

Unfortunately, many of these studies did not use postoperative outcomes as their primary outcome, making their study underpowered and unable to precisely determine the impact of nociception monitoring on postoperative pain levels, opioid consumption, and related side effects. Future studies powered on a primary objective are needed, such as a composite score combining pain scores and opioid consumption and their postoperative trajectories.

High-quality studies are lacking to evaluate the impact of nociception monitoring during general anesthesia on long-term postoperative outcomes, such as PPSP or Opioid Use Disorder (OUD).27 Those postoperative acute or chronic outcomes can be regarded as patient-centered outcomes (pain levels, quality of recovery, and quality of life), which are of major importance in research and clinical relevance of trials.

Can these devices help predict which patient will present with acute pain and high opioid requirement postoperatively in the post-anesthesia care unit, the wards, or the long term?

Based on the currently available literature, there is still time to answer this question comprehensively. Nevertheless, there are trends in recently published materials based on ancillary analyses of previous RCTs that can help inform what might come in future study results. Indeed, some authors reported that the ANI values at the end of the surgery (just before extubating) when anesthesia was based on a combination of sevoflurane and remifentanil were predictive of the immediate level of postoperative pain in the PACU.39 Similar results were reported for SPI.40,41 More recently, the NOL index values recorded during surgery and, more precisely, NOL values after skin incision correlated with the pain level in the PACU.42 One more recent ancillary analysis of the NOLGYN study31 evaluated the ability of new machine-learning algorithms to predict moderate to severe acute postoperative pain based on intraoperative NOL values. This study revealed that NOL post-intubation (P = 0.05), median NOL during surgery (P = 0.027), percentage of surgical time spent with NOL > 25 (P = 0.036), NOL Time-Weighted Average < 10 (P = 0.044), and percentage of surgical time spent with NOL < 10 (P = 0.022) were associated with moderate to severe PACU pain. The authors concluded that a multivariate machine-learning algorithm better predicted acute postoperative pain than individual intraoperative nociception variables.43

Conclusion

It is certainly too early to draw strong conclusions and recommendations based on the limited literature on this subject. However, these monitoring devices help evaluate intraoperative nociception more precisely and better guide administering analgesics during surgery. Whether their use will drastically change postoperative pain-related outcomes remains yet to be seen and understood. More robust multicentred trials are required to understand the relationship between intraoperative nociception monitors, acute postoperative pain, and other pain-related outcomes.

Walid Oulehri, MD, PhD, MSc, DESAR, is an anesthesia fellow in the department of anesthesiology and pain medicine at the Maisonneuve-Rosemont Hospital in Montréal, Québec, Canada. He is also a staff anesthesiologist in the department of anesthesia and intensive care at the University Hospitals of Strasbourg in France.
Olivier Verdonck, MD, MSc, DESAR, is an associate professor in the department of anesthesiology and pain medicine at the Maisonneuve-Rosemont Hospital in Montréal, Québec, Canada. He is also an associate professor in the department of anesthesiology and pain medicine at the University of Montréal.
Philippe Richebe, MD, PhD, DESAR, is a full professor with tenure in the department of anesthesiology and pain medicine at the Maisonneuve-Rosemont Hospital in Montréal, Québec, Canada. He is also a full professor with tenure in the department of anesthesiology and pain medicine at the University of Montréal. He is also Anesthesiologist at the Polyclinique Bordeaux Nord Aquitaine, PBNA, Bordeaux, France.

Acknowledgements: Thanks to Mr. Kyle Vaughn Roerick, MA, for his English language editorial work.

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