Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:

1. Explain how use of an antinociceptive device can assist in assessment of pain treatment.

2. Describe how antinociception index values correlate with pain scores.

3. Assess how an antinociception index monitor can provide an objective way to measure autonomic nervous system regulation under anesthesia and anticipate nociception balance.

Pain is a highly plastic neurophysiological process that appears to be necessary to human existence.1 When we speak of pain, we understand it as a deeply human experience, because it involves not only nociception and the immediate physiological reactions to it, but also emotional, cognitive, and social consequences.2

The International Association for the Study of Pain defines pain as an "unpleasant sensory and emotional experience associated with current or potential tissue damage," or it is described in terms of such damage. The term "emotional" in the definition makes pain a subjective experience.3

The main characteristic of these feelings is the affective aspect that characterizes a homeostatic role.4 Acute pain serves an immediate protective purpose and may produce subsequent learned behaviors to avoid trauma and injury, whereas pathologic pain is a major cause of human suffering, especially when, as frequently happens, the relationship between ongoing nociception and the subjective perception of pain is obscure.1 Throughout history, the relationship of pain to other sensory experiences from the body has presented a major conceptual hurdle in defining its underlying mechanisms.5

Nociception, the neural process of encoding a noxious stimulus,6 is not synonymous with pain, which is experienced as a conscious percept. Nociception can trigger brain responses without necessarily causing the feeling of pain, and pain can occur in the absence of nociceptive input.4

Under most circumstances, pain is associated with a subjective component-suffering. The language of pain has been confounded by the use of the same words to describe both the perceptual recognition of the experience and the unpleasantness or emotion associated with it.5 Thus, patient self-rating scales such as the Numeric Rating Scale (NRS), the Visual Analog Scale (VAS), and Wong-Baker FACES Scale are used for perioperative pain assessment (Figure 1). These scales can be problematic for rating pain in pediatric, geriatric, or critically ill patients, and in patients with communication difficulties or who are under sedation.3

Figure 1. Scales used in preoperative pain assessment.

The difference between pain and nociception is well defined. Pioneering English anesthetist, Cecil Gray,7 while explaining the autonomic nervous system (ANS) as the center of the main activity, redefined his triad as narcosis, relaxation, and reflex control. Various studies have explained the role of the sympathetic and parasympathetic (pS) activities as main drivers of the immune response and inflammation8 and future drivers of postoperative acute9 and chronic pain.10 Nociception and the activity of the ANS are directly linked,4 and what should be controlled are the effects of nociception-and surgical stress-rather than nociception itself.11 Nociception causes a response of the ANS that can be called surgical stress, and its consequences may go from short term to long term.

It is well-known that undertreatment of pain and the severe intensity of postsurgical pain are key factors in developing persistent postsurgical pain (PPP)12 and other negative sequelae13 that directly affect the quality of life. Current understanding of the molecular basis of how acute pain is produced after surgery has led to the creation of tools to understand the interaction between sympathetic and parasympathetic reactions to stressful stimuli and to the surgery itself.

These inventions have the potential not only to monitor the vagal neural reflex that has been demonstrated to be a key component of the inflammatory process but also to predict and precede changes in the release of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-[alpha], and C-reactive protein. Several studies have demonstrated that the release of inflammatory cytokines like IL-6 can modulate peripheral nociceptors leading to a peripheral sensitization, and possibly, to a subsequent central sensitization, a central process of PPP. Therefore, in this review, we analyze current clinical trials that leave us important insights into the Analgesia Nociception Index (ANI) monitor and how we can eventually personalize management of stress-induced inflammation by modulating heart rate variability (HRV) during surgery.

ANI Concept

In recent years, various monitoring modalities estimating the effect of analgesia during unconsciousness have become available14 (Figure 2). Most are based on HRV and the predominance of the parasympathetic versus sympathetic response to noxious stimulation. It is better to have a real and direct measure of the activity of the ANS than composed indices that lose the essence of the object of measure.15 The indices are really measuring what is important-the ANS balance-and go to the essence of the idea that what needs to be controlled is the allostasis and the inflammatory response with cytokines release, which causes poor postoperative outcomes.16

Figure 2. Sensitivity and specificity in detecting standard painful stimulus without opioid administration. (Data from Funcke S, Sauerlaender S, Pinnschmidt HO, et al.

The HRV uses the R-R wave interval to assess the activity of the nucleus accumbens, which is a main part of the reward center and associated with pain,17 and the nucleus ambiguus. Both the nucleus accumbens and the nucleus ambiguus manage the activity of the sinus node depending on breathing. Breathing modulates the ANS activity and is known to control the pain perception.18

ANI is a parameter obtained from the PhysioDoloris monitor and is a graphic measure of high frequencies of HRV on a scale from 0 (maximum of nociception) to 100 (complete analgesia)19 (Figures 3 and 4). It is the percentage of high frequencies related to the rest of the activity of ANS, and thus, has no dimensions.

Figure 3. ANI monitor.

Figure 4. Use of ANI in the operating room.

The method applied by the ANI monitor overcomes difficulties encountered by prior systems and produces a real-time reliable analysis of the pS activity of the ANS in a time window of 64 seconds. Thus, if the ANI demonstrates a value of 50, it means that the 50% of activity in the last 2 minutes is high frequency (ie, pS), and the other 50% is the remainder of the activity of the ANS, which is mainly sympathetic.

ANI computation relies on an algorithm that quantifies the relative amount of pS activity on a simple R-R series obtained noninvasively on a continuous electrocardiogram. Two electrodes placed on the chest of the patient enable staff to record a simplified electrocardiogram, detect R waves, and calculate the R-R interval. This series is then filtered using a fast wavelet transformer to keep only the high-frequency band (0.15-0.4 Hz), where respiratory sinus arrhythmia (RSA) is expressed.20 The calculated index varies between 0 and 100 in relation to the relative pS activity: the higher the pS activity, the higher the RSA.21

ANI was designed to be used basically in unconscious patients. Due to its graphical method analysis, it is not influenced by the change in the respiratory rate. To correctly measure the HRV, a constant breathing pattern is needed. If the patient speaks, it may cause a change in the measure due to the change in the respiratory volumes. To use ANI in awake patients, a very strict protocol is mandatory as to how to measure and when to measure the value.

The electrodes are composed of a 2-part device: a dual sensor and a single sensor connected together by an electrical thread. The sensor itself is divided into 2 areas. One part is an adhesive area and the other, the active area, is covered with conductive gel.

The principle of this 2-part device requires placing it on each side of the heart (thus on each side of the chest) to achieve a cardiac vector (the axis of the average cardiac vector according to the reference anatomical position is: forward, down, and left). In this case, the dual sensor is applied to the patient's chest-the larger patch on the upper chest and the smaller patch on the left side of the chest22 (Figure 5).

Figure 5. Position of the ANI sensors.

As the ANI measures the relative pS activity and thus the sympathetic-parasympathetic balance, which has been used as a surrogate for the antinociception/nociception balance,20 it has emerged as a new tool to also guide opioid administration.19 The pS activity is an anti-inflammatory response. The sympathetic activity is pro-inflammatory. So, a value over 50 means that more than 50% of the activity of the ANS is pS, the anti-inflammatory activity prevails, and the postoperative pain scores should be better.16 Use of standard clinical signs to guide opioid titration may result in overdosage with side effects that include nausea, vomiting, respiratory depression, and, more importantly, opioid-induced hyperalgesia.20

Current Evidence Concerning Applicability of the ANI

Recent trials have confirmed the ANI as a sensitive method to detect noxious stimuli,23 and, moreover, ANI values higher than 50 have been proposed as an ideal cutoff to determine adequate balance between antinociception and nociception.5 Some of these studies24-34 are reviewed in Table 1.

Table 1. ANI Studies Over the Past 7 Years

Many authors have hypothesized that ANI could reduce opioid consumption during surgery. However, Upton et al,16 in lumbar spine surgical procedures, and Szental et al,26 in laparoscopic cholecystectomy, failed to demonstrate the need for a reduced amount of intraoperative opioids. Although similar amounts of opioids were administered to the control group and the ANI-guided group, the pain scores of ANI-guided groups were lower in the recovery room in the Upton et al16 study. Therefore, the total amount of opioids used intraoperatively might not be the only factor that generates opioid-induced hyperalgesia; instead, a tailored and personalized opioid administration can possibly help to avoid N-methyl-D-aspartate (NMDA) receptor activation by overdose of opioids with the subsequent central sensitization of the central nervous system.13

In a study during bariatric surgery, Le Gall et al31 demonstrated a lower consumption of sufentanil using ANI monitoring. In patients undergoing scalp block versus incision-site infiltration for craniotomy, Theerth et al32 demonstrated a lower consumption of fentanyl in the scalp block group using the ANI. However, both studies had limitations. The Le Gall et al31 study was a retrospective cohort of control cases, and in Theerth et al,32 the study of noncontrol cases was included. Currently there is no strong evidence that indicates ANI to be useful in achieving opioid-free surgical procedures, or at least in reducing the use of opioids in practice.

However, the introduction of ANI to clinical practice is just beginning, and it might mean a critical step toward understanding several factors, such as when a noxious stimulus is intense enough to require treatment. The dosing of analgesics could be refined during procedures, as could the dynamics of opioid administration when NMDA receptors are activated. Another important consideration is that conflicted findings about ANI can be explained by the different physiological circumstances, intensity of noxious stimulus, and other surgery-related factors between studies in which ANI has been tested.

In addition to its application for opioid titration, other studies have focused on ANI to help predict postoperative pain. Boselli et al,34 in an observational study, found a negative linear relationship between ANI values and pain reported by the NRS on arrival in the postanesthesia care unit. However, ANI values did not help to differentiate between minor and severe pain.12 Nevertheless, ANI measuring the pS activity of the patient could be used as a means to detect the most noxious stimuli and enable the anesthesiologist to treat it quickly. Thus, the use of ANI in Enhanced Recovery After Surgery (ERAS) strategies could play an important role by individualizing treatments or tailoring analgesic protocols according to the type of patients and procedures. Moreover, the capability to predict and measure nociception balance in a more objective way could be a crucial step to address multimodal analgesia.

Clinical Caveats

The clinician should heed several caveats to effectively utilize ANI. Obtaining a reliable electrocardiogram (ECG) recording is necessary. Cautery will interfere transiently with the recording. Although it is not essential to place the pads before the start of the procedure, doing so would be useful in gauging the response to induction. The ANI improves as soon as surgical stimulation stops, and an elevated level before emergence from anesthesia predicts postoperative comfort. Some of our clinical cases are listed in Table 2.

Table 2. Summary of the Authors' Selected Clinical Cases

Animal Research

The PTA (earlier version) monitor was used to demonstrate analgesic titration in performance of a hemilaminectomy on a French bulldog, using isoflurane and fentanyl. The monitor provided a means of measuring the dog's response to analgesia. Other veterinary cases have been published. (Inputs from Mdoloris Medical Systems SAS HFVI Monitor User Manual Software Version 1.1.3.1.)

Conclusion

Use of the ANI monitor should be seen in light of some limitations. Most reports on ANI remain inconclusive, with no significant reduction in opioid consumption or opioid-related side effects.35 Several confounders can influence ANI values and, therefore, might be another reason for inconsistent reports.

ANI limitations include severe cardiac arrhythmias, atrial fibrillation, pacemakers, cardiopulmonary bypass, and antimuscarinic drugs.36 Other factors that decrease the quality of ANI signal are overweight patients and the position of sensors in relation to the anatomical location of the surgery.

Subsequent studies will require the need to minimize individual variability, increase sample size, standardize control groups, and consider the possible influence of certain anesthetics given during surgery.

Despite many limitations, ANI monitoring to assess nociception balance could change intraoperative anesthesiology practice and pain management, and, more importantly, decrease rates of chronic pain and improve recovery and quality of life. Thus, in real time, the ANI could help us see the balance between the activities of the surgeon with the response of the anesthesiologist in controlling surgical stress intraoperatively for postoperative benefit.

Practice Pearls

* Pain is the conscious perception of nociception.

* ANI is an index that measures HRV from 0 to 100 (maximum nociception to complete analgesia).

* ANI monitor provides an objective way to measure ANS regulation under anesthesia and anticipate nociception balance.

* ANI values greater than 50 have been demonstrated to correlate with lower stimulus and less pain score after surgery, therefore might be an alternate threshold to be considered.

* Clinical studies have demonstrated that opioid-guided analgesia during surgery using ANI monitoring might serve as a complementary tool to optimize pain control.

* More randomized prospective clinical trials are needed to demonstrate the real potential of ANI to tailor opioid consumption postoperatively, improve patient's recovery, and avoid common complications such as opioid-induced hyperalgesia.

References