Traditionally, many aspects of perioperative anesthesia require a qualitative approach to managing patient care. Intraoperative intravenous fluid management is still typically based on estimated blood loss, calculated insensible losses, patient hourly fluid requirements, and urine output. General anesthetic level is based on blood pressure and heart rate relative to baseline values. Analgesic administration is based on heart rate and blood pressure changes and surgical stimulus. Although anesthesiologists understand that these are imperfect surrogate markers of the information sought, there have not been accurate quantitative methods to determine that information. Increasingly, technologies are becoming available that allow clinicians to quantitate fluid management (eg, noninvasive cardiac output monitors), anesthetic level (eg, electroencephalogram [EEG] analysis monitors), and analgesic administration (eg, monitors that evaluate changes in the sympathetic and/or parasympathetic nervous systems). Unfortunately, these monitors often have issues such as a high degree of error compared to the gold standard technique; although use of the gold standard may not be readily available or relevant for most cases (eg, noninvasive cardiac output monitoring devices for the perioperative care of patients).1 Or there is a lack of high-quality evidence for efficacy in improving postoperative outcomes (eg, postoperative delirium reduction after intraoperative guidance of anesthesia by processed EEG indices).2
Accurately quantitating the perioperative analgesic needs for patients is important because both too little and too much analgesic result in negative outcomes.3,4 Furthermore, interpatient variability exists in response to analgesics and analgesic requirements for nociceptive stimuli. Multiple monitors and techniques have been developed that use somewhat different patient sympathetic and parasympathetic nervous system measurements to evaluate the balance between nociception and analgesic level, including the nociception level (NoL) index, analgesia–nociception index (ANI), the surgical plethysmographic index (SPI), and pupillometry (although this is defined differently: variation coefficient of pupillary diameter, pupillary pain index [PPI], and others; Table). However, these monitors are not yet widely utilized clinically. One of the barriers to adoption is certainly the lack of data showing clinically significant changes in outcomes with their use in a wide variety of patient populations. For example, a recent study that targeted certain ANI and SPI scores for patients undergoing neurosurgical spinal procedures found that the indexes resulted in alterations in intraoperative opioid administration, but not postoperative pain and cortisol levels.5 The NoL index and ANI have been found to correlate with the intraoperative balance between nociception and analgesia,6,7 and in some studies, the titration of intraoperative opioids to a targeted range of ANI values resulted in less intraoperative opioid administration.8,9 However, only one study found that intraoperative opioid titration to a predefined range of ANI values resulted in decreased postoperative pain, and it was for just 90 minutes after surgery.9 Although results for some studies in which intraoperative opioids were titrated to predetermined SPI values have found similar results (a lack of altered postoperative outcomes),10 others have found differences in some outcomes such as time to extubation, pain scores, and opioid consumption.11 Generally, there are mixed results on the utility of both ANI and SPI monitors in correlating with pain in awake patients, but these devices may work best if preawareness values are used to predict postoperative pain.12,13 However, in these studies, pupillometry, defined as the variation coefficient of pupillary diameter, holds promise for the assessment of pain during acute pain states such as postoperatively14 and during labor.15 Another study that titrated intraoperative opioid administration to changes in pupillary diameter found decreased intraoperative and postoperative opioid use in the study arm.16 Other studies have shown some correlation of the PPI with analgesic administration and noxious stimuli.17,18
|Nociception Monitor||Measured Features||Output||References|
|Nociception level index||Photoplethysmogram amplitude, skin conductance and its fluctuation, heart rate and its variability, and their time derivatives||Index: 0–100
Lower number: less noxious stimuli; Higher number: more noxious stimuli
|Analgesia–nociception index (heart rate variability index)||High-frequency heart rate variability||Index: 0–100
Lower number: increased nociception relative to analgesia;
Higher number: decreased nociception relative to level of analgesia
|Surgical plethysmographic index||Photoplethysmographic amplitude and the photoplethysmographic pulse interval||Index: 0–100
Lower number: decreased stress;
Higher number: increased stress
|Pupillometry (used to define different measurements)||a) Variation coefficient of pupillary diameter||a) Ratio of the median deviation in pupillary diameter to the median pupillary diameter||14–16|
|b) Pupillary diameter fluctuations||b) Changes in pupillary diameter|
|Pupillary pain index||Pupillary light reflex and pupil reflex dilation amplitude in response to noxious stimuli||Index: 1–9
Lower number: greater stimulus required to increase pupil size;
Higher number: lower stimulus required to increase pupil size
In this issue of Anesthesia & Analgesia, Funcke et al19 describe results of titrating intraoperative opioid administration to the output from 1 of 3 different analgesia monitoring devices compared to a control group for which opioids were titrated to changes in vital signs alone in their article, “Guiding Opioid Administration by 3 Different Analgesia–Nociception Monitoring Indices During General Anesthesia Alters the Intraoperative Sufentanil Consumption and Stress Hormone Release: A Randomized Controlled Pilot Study.” The authors assigned patients who were undergoing radical retropubic prostatectomies to 1 of 4 study arms. In 3 of the study arms, patients received intraoperative sufentanil directed by 1 of 3 analgesia devices: SPI, NoL, or PPI. In the fourth study arm, sufentanil was administered based on clinical judgment of the anesthesiologist. Total intraoperative sufentanil administration, stress hormones (adrenocorticotropic hormone and cortisol at 4 time points), and recovery features were measured. The total amount of sufentanil administered and stress hormone levels, but not recovery end points, differed between the groups. Of particular interest is that PPI led to lower sufentanil administration but higher stress hormone levels. Although the SPI and control groups did not differ in opioid administration, the SPI group had lower stress hormone levels. Patients who received more opioids had lower stress hormone levels (Figure 4 from Funcke et al)19.
This article by Funcke et al19 describes a nicely designed and executed study with some subtle but interesting results. The subtle results are actually the questions raised by the outcomes of the study; this investigation is thought provoking not because total intraoperative opioid administration and stress hormone levels are different for each monitor. After all, given that each monitor is measuring somewhat different patient features, it is really not that surprising to learn that each directs clinicians somewhat differently. And it is interesting, but again not surprising, that greater analgesia leads to lower stress hormone levels. But there are a number of significant questions raised by these outcomes. What is it about the balance between nociception and analgesia that affects patient outcomes? Is there an optimal balance between these 2 states to positively affect patient outcomes? If so, what is that critical balance, and how do we get there and measure it? Where along the nociception–analgesia curve does the ratio begin to negatively affect patient outcomes? Do the timing, frequency, and amount of intraoperative analgesic administration matter? Because the answers may be different for diverse patient populations, based in part on sex, age, comorbidities, surgery type, and surgery location, it may be some time before we have definitive answers. Thus, for now, we are left without an optimal method for measuring the intraoperative balance between nociception and analgesia and certainly not one that definitively or meaningfully affects patient outcomes.
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14. Charier D, Vogler MC, Zantour D, et al. Assessing pain in the postoperative period: analgesia nociception indexTMversus pupillometry. Br J Anaesth. 2019;123:e322–e327.
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17. Sabourdin N, Diarra C, Wolk R, Piat V, Louvet N, Constant I. Pupillary pain index changes after a standardized bolus of alfentanil under sevoflurane anesthesia: first evaluation of a new pupillometric index to assess the level of analgesia during general anesthesia. Anesth Analg. 2019;128:467–474.
18. Vinclair M, Schilte C, Roudaud F, et al. Using pupillary pain index to assess nociception in sedated critically ill patients. Anesth Analg. 2019;129:1540–1546.