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Anesthetic Clinical Pharmacology: Original Clinical Research Report

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

Sabourdin, Nada MD*; Diarra, Coumba MD*; Wolk, Risa MD; Piat, Véronique MD*; Louvet, Nicolas MD*; Constant, Isabelle PhD*

Author Information
doi: 10.1213/ANE.0000000000003681
  • Free



  • Question: Does pupillary reactivity, measured by the novel pupillary pain index, change after a bolus of 10 µg·kg−1 of alfentanil in patients under sevoflurane anesthesia?
  • Finding: Pupillary pain index was lower after the bolus of alfentanil.
  • Meaning: Pupillary pain index might be a relevant tool to monitor the level of analgesia in anesthetized patients.

The intraoperative monitoring of response to noxious stimuli is an important issue for anesthesiologists. The objective is to optimize the dose of analgesics for each patient during the different stages of a surgical procedure, avoiding both under- and overdosage. Several monitors have been developed to assess intraoperative nociceptive transmission.1 Even if their physiological substrates and methods of analysis differ, they are all based on an evaluation of the balance between sympathetic and parasympathetic neural activity. These monitors share another characteristic: they all provide a retrospective diagnosis that analgesia is either insufficient or excessive and thus only allow a posteriori correction of inadequate analgesia. No current index can predict if an individual patient will have a clinical reaction (eg, heart rate increase) after a painful stimulus, such as skin incision.

The pupillary pain index (PPI) is a novel pupillometric measurement system that has been designed to provide an evaluation of the level of analgesia in anesthetized subjects. It can be used in the same population as general pupillometry: adults and children from 2 years of age. The PPI uses tetanic stimuli of increasing intensity to assess pupillary reactivity. It is based on the hypothesis that if the pupil reacts to low-intensity stimuli, then the level of analgesia is low. Conversely, if the pupil does not react to sustained high-intensity stimuli, then the level of analgesia is high. The index ranges from 1 (low level of pupillary reactivity, high level of analgesia) to 10 (high level of pupillary reactivity, low level of analgesia).

The physiological principle on which the PPI is based and the device used to measure it have been described, validated, and investigated in several former studies.2–6 The PPI is based on the pupillary reflex dilation (PRD) to noxious electrical stimuli. PRD persists under general anesthesia in children and in adults; its amplitude is proportional to the intensity of the stimulus and inversely correlated to the amount of administered opioids.7 Compared to the hemodynamic or motor response to noxious electrical stimuli, PRD has been demonstrated to be more sensitive: pupillary response occurs earlier, for smaller stimulations, and its amplitude is wider.8–10 PRD has been successfully used in patients receiving sevoflurane,9 isoflurane,11 desflurane,12 propofol,2 and ketamine10 as hypnotics. It has been used in patients receiving no hypnotics in various settings, such as in the postanesthesia care unit13 and in healthy volunteers.14,15

The noninvasive device used to measure the PPI is the videopupillometer Algiscan (IDMED, Marseille, France). Like other similar devices, it can continuously measure pupillary diameter (PD) via an infrared camera, and it can also be connected to cutaneous electrodes to deliver a calibrated tetanic stimulation. This specific device has been safely used in several published studies.2–4,6

The novelty of the PPI is not the device or the underlying physiological mechanism. It is the algorithm of automated increase in stimulus intensity, with the end of the stimulation being determined by a threshold of pupillary dilation.

As a first approach to this new tool, the objective of this pilot study was to assess whether the PPI score after a standardized bolus of alfentanil was different from the PPI score before this bolus in patients under steady-state sevoflurane anesthesia. Our hypothesis was that a standardized bolus of alfentanil would increase the level of analgesia and that the PPI after alfentanil administration would be lower.


This open pilot study was registered before patients’ inclusion ( NCT 02646592, April 1, 2016, principal investigator: Isabelle Constant) and approved by our Institutional Review Board (Comité de Protection des Personnes Ile-de-France 5, approval number 15011). All patients were included in Armand Trousseau Hospital, Paris, France. Written informed consent was obtained from the parents and, if possible, from the child.

Inclusion criteria were: children >2 years, elective surgery under general anesthesia requiring orotracheal intubation, and intraoperative intravenous opioids. Recruitment took place on the day of surgery, according to the availability of the investigators (N.S., C.D.). All patients were included in 1 center (Armand Trousseau Hospital, Paris, France). Standard monitoring included a cardioscope (Datex Ohmeda, Helsinki, Finland) recording the electrocardiogram, noninvasive blood pressure, bispectral index (BIS; Covidien, Dublin, Ireland), arterial oxygen saturation, and gas analyzer. Anesthesia was induced with sevoflurane 6% in 100% oxygen. After placement of an intravenous line, a bolus of 1 mg·kg−1 of propofol was injected, and 1 minute later, the patient was intubated. Then a steady-state period was maintained for 10 minutes, with an expired fraction of sevoflurane at 2%, and ventilation parameters were adapted to keep the expired fraction of carbon dioxide between 30 and 40 mm Hg.

At the end of that steady-state period, a baseline PD was measured (PD-1) without any nociceptive stimulation. Prestimulation heart rate, blood pressure, and BIS were also recorded at that time. Then the first measurement of PPI (PPI-1) was performed. Please see below for a description of how PD and PPI were measured. Maximal values of heart rate and BIS in the minute after PPI-1 were recorded. Blood pressure was recorded 1 minute after PPI-1.

After this first set of data recording, a standardized bolus of 10 µg·kg−1 of alfentanil was administered intravenously. Two minutes later, without any stimulation, PD was measured (PD 2), along with heart rate, BIS, and blood pressure. Then the second measure of PPI (PPI-2) was performed. Maximal values of heart rate and BIS in the minute after PPI-2 were recorded. Blood pressure was recorded 1 minute after PPI-2.

Figure 1.
Figure 1.:
Study design. Etco 2 indicates end tidal carbon dioxide; PD, pupillary diameter; PPI, pupillary pain index.

The design of the study is summarized in Figure 1.

Pupillometric Measurements

Pupillometric measurements were performed with the pupillometer Algiscan (IDMED, Marseille, France). This device measures PD using an infrared camera that identifies, tracks, and measures the pupil. The pupillometer includes a light-occlusive rubber cup that surrounds the eye. No part of this noninvasive device comes in contact with the patient’s eye. In addition, this pupillometer can deliver calibrated tetanic stimulations (5–60 milliamps, 100 Hz) via 2 cutaneous electrodes placed along the ulnar nerve. The tetanus consists of a continuous electrical current, with 200-microsecond impulses. All measures were performed on the patient’s left eye. The right eye remained closed during the study period.

PD Measurements: PD-1 and PD-2

Simple PD measurements (PD-1 and PD-2) were obtained by instantaneous snapshots. These require maintaining the eyelid open for <10 seconds (1–2 seconds to open the eyelid, 3–5 seconds to place the pupillometer, 1 second to take the snapshot), and then the eyelid can be closed again until the next measurement.

PPI Measurements: PPI-1 and PPI-2

For PPI measurements, tetanic stimulations are delivered by the pupillometer via the cutaneous electrodes placed along the patient’s left ulnar nerve. The first electrode is placed just above the wrist, the second approximately 4 cm above. The tetanus consists of a continuous electrical current (200-microsecond impulses, 100 Hz). The current’s initial intensity is 10 milliamps (mA). Then the intensity increases by 10 mA steps every second to a maximum of 60 mA (10–20–30–40–50–60 mA). The 60-mA stimulation is maintained for 3 seconds. Thus, the total duration of the stimulation in a complete PPI protocol is 8 seconds. PD is continuously recorded during the tetanic stimulation and during the following 15 seconds. Baseline PD is defined as PD at the beginning of the scan, before the onset of the electrical stimulation. The tetanus is interrupted if, at any time, PD increases by >13% compared to baseline PD. The maximal intensity reached by the current before interruption is the main determinant of the PPI: if the pupil dilates >13% for weak stimulations (10, 20 mA), then the level of analgesia is considered poor. By contrast, if the PD increases by <13% for sustained high-intensity stimulations (60 mA), then the level of analgesia is considered high. The maximal pupillary dilation recorded during the 15 seconds after tetanus discontinuation is also a determinant of the PPI score calculation (Figure 2).

Figure 2.
Figure 2.:
Pupillary pain index (PPI) calculation algorithm.

A PPI measurement requires maintaining the eyelid open for a maximum of 30 seconds (1–2 seconds to open the eyelid, 3–5 seconds to place the pupillometer, 8 seconds of stimulation, 15 seconds of observation); then the eyelid can be closed again until the next measurement.

Our main outcome measure was the PPI measurement before and after alfentanil. Secondary outcome measures included baseline PD before each PPI measurement, as well as heart rate and systolic blood pressure before and after each PPI measurement.

Statistical Analysis

PPI-1 and PPI-2 are expressed as median (interquartile range). Heart rate, blood pressure, PD, and BIS are expressed as mean ± standard deviation (SD).

PPI-1 and PPI-2 were compared using a Wilcoxon signed rank test. The estimate of location shift was measured by the median difference (Hodges-Lehmann estimate) with its 95% confidence interval (CI). PD-1 and PD-2 (PDs before PPI measurements) were compared using paired t test.

Heart rate, systolic blood pressure, and BIS were compared from before to after the 2 PPI measurements at each time period, and we assessed whether that change differed after the administration of alfentanil. To achieve this, we assessed the effect of PPI (ie, difference between pre- and post-PPI, measured at each time point), the effect of alfentanil (ie, the difference between pre- and post-alfentanil, averaging the 2 measurements at each time point), and the interaction between these 2 factors (ie, whether the administration of alfentanil modified the effect of a PPI measurement). For this analysis, an analysis of variance with mixed-effect modeling was used (Statistica8, Statsoft, Tulsa, OK). A mixed linear model was used with 2 main factors: the effect of a PPI measurement and the effect of an alfentanil administration. Variance component was estimated using the restricted maximum likelihood. A significant PPI effect would mean that the parameter values were modified after a PPI measurement. A significant alfentanil effect would mean that the parameter values were modified after the administration of alfentanil. A significant interaction would mean that the PPI measurement effect was different between before and after an alfentanil administration. A nonsignificant interaction would mean that the effect of PPI measurement is not modified after an alfentanil administration. Post hoc analysis, using least square mean tests, was conducted (if a factor or an interaction was significant) to compare parameters values before and after PPI at each time point.

The correlation between PPI and heart rate change ([poststimulation HR – prestimulation HR]/prestimulation HR) was investigated using Spearman correlation test. Our aim was to assess the relationship between the level of PPI and heart rate changes, whatever the anesthetic conditions. Consequently, all PPI measurements were analyzed together regardless of alfentanil administration.

Statistical significance was defined as P < .05. Descriptive data are presented as mean ± SD. Mean difference estimate are presented as mean (95% CI).

This is the first pilot study involving the PPI index, and no published data were available to calculate a sample size. After doing some preliminary measurements (personal data), we estimated that a PPI value of 7 would be a usual value under sevoflurane without alfentanil. Considering that a 20% decrease between PPI-1 and PPI-2 would be significant, a mean difference of 1.4 between PPI-1 and PPI-2 was used for the sample size calculation. Using a paired t test and an SD of 2, a study with 19 participants provided 80% power with a type I error of 0.05. We decided to include 20 patients to account for incomplete data recording.


Twenty patients (9 ± 5 years, 36 ± 22 kg) were included in the study. There were 11 boys and 9 girls. There were no anesthetic complications, protocol modifications, or patients excluded from the study.

PD and PPI Changes Before and After Alfentanil Administration

Values of Heart Rate, Blood Pressure, Bispectral Index, and Pupillary Diameter Before and After PPI at Each Time Point (Before and After Alfentanil)
Figure 3.
Figure 3.:
Pupillary pain index (PPI) before and after alfentanil: individual traces.

No difference in resting PD was evidenced after alfentanil administration: PD-1 (baseline, before PPI-1) was 2.2 ± 0.2 mm, and PD-2 (after alfentanil, before PPI-2) was 2.2 ± 0.3 mm (P = .86; Table). PPI scores were decreased after the administration of alfentanil (median difference [95% CI], −3 [−4 to−2]: the median PPI-1 [baseline, before alfentanil] was 6 [4–7], and the median PPI-2 [after alfentanil] was 2 [2–3]; Wilcoxon P < .001; Figure 3).

Heart Rate, Systolic Blood Pressure, and Bispectral Index Changes After PPI and Alfentanil Administration

Heart rate, blood pressure, and BIS before and after PPI-1 and PPI-2 are given in the Table. Heart rate was significantly decreased after alfentanil administration (P < .001). There was a significant interaction between the administration of alfentanil and PPI measurement (P < .001): before alfentanil administration, the heart rate increased after PPI-1 measurement (mean difference estimate [95% CI], 4.9 [1.9–7.9]; P = .003); but after alfentanil administration, heart rate decreased after PPI-2 measurement (mean difference estimate [95% CI], −3.5 [−6.5 to −0.4]; P = .03). There was a moderate but significant correlation between PPI and heart rate changes (r = 0.35, P = .03; Figure 4).

Figure 4.
Figure 4.:
Changes in heart rate (bpm) for each pupillary pain index (PPI) measurement. Gray circle, measurement after alfentanil. Black circle, measurement before alfentanil. All PPI measurements were analyzed together regardless of alfentanil administration. Spearman r = 0.35, P = .03.

No systolic blood pressure changes occurred after alfentanil or PPI measurement (Table).

BIS was significantly increased after both alfentanil administration and PPI measurement, without interaction evidenced (Table): alfentanil: mean difference estimate (95% CI), −3.9 (−6.0 to −1.9); P < .001; PPI: mean difference estimate (95% CI), −1.9 (−3.3 to −0.4); P = .01.

No movement was observed apart from the tetanus-related muscular contractions of the left forearm.


In this pilot study, we observed a significant change in PPI after a 10 µg·kg−1 bolus of alfentanil in children anesthetized with 2% sevoflurane. This result is encouraging and raises several hypotheses. The main hypothesis is that there is a causal link between alfentanil administration and PPI decrease. If this finding is confirmed in a larger controlled study, then we may be able to state that PPI indeed reflects the level of analgesia.

Prestimulation PDs were not diminished after the bolus of alfentanil. This result might seem surprising because opioids have a direct action on PD. By decreasing the inhibitory control over the Edinger-Westphal nucleus, opioids increase the activity of the efferent parasympathetic pathway between the Edinger-Westphal nucleus and the pupil, leading to a contraction of the circular sphincter of the iris.16 However, because they are powerful sympathetic inhibitors, GABAergic hypnotics by themselves also decrease PD. Sevoflurane, more specifically, is a potent autonomic nervous system depressant, and this global sympathetic and parasympathetic inhibition results in miosis.17 PD under most volatile anesthetics used at surgical concentrations, in patients receiving no opioids, is described by several authors around 2 mm,9,11,12,18 close to the prealfentanil PDs reported in our study. It is possible that the PD might already have reached its minimum value before we administered alfentanil. Besides, we used a relatively low dose of alfentanil, which might not have been sufficient to induce further miosis at this deep level of anesthesia (mean BIS values <45).

Under general anesthesia, PD increases in response to nociceptive stimuli: this phenomenon is also observed in awake subjects and is called PRD. The amplitude of PRD depends on the balance between analgesia and nociception: PRD increases with the intensity of the stimulation and decreases when more opioids are administered.14,19

The PPI protocol is based on the assumption that the level of analgesia determines the nociceptive intensity in response to which the pupil size will begin to increase. When analgesia is greater, the patient might be able to “tolerate” more intense noxious electrical stimuli before triggering PRD. The aim of the PPI is to provide a reliable assessment of the level of analgesia in anesthetized patients before an intended nociceptive stimulation actually occurs (eg, skin incision).

Sympathetic and parasympathetic effectors have often been used as physiological substrates to monitor the analgesia-nociception balance. Several monitors focusing on this balance have been developed and commercialized in the past 15 years.1 Photoplethysmographic monitors assess sympathetically mediated distal vasoconstriction20; electrocardiographic monitors assess parasympathetically mediated heart rate variability21; skin conductance monitors assess sympathetically mediated palmo-plantar sweat release22; and pupillometric monitors assess PD, which can be influenced by both the sympathetic and parasympathetic drives of the autonomous nervous system.19 Intraoperative opioids influence the balance between analgesia and nociception: they increase the level of analgesia and decrease neurotransmission in the nociceptive neural pathways. As a result, they shift the sympatho-vagal balance toward its parasympathetic component. So far, all these devices were designed to assess the “nociception” side of the balance and provide an a posteriori evaluation of the intensity of the reaction to a nociceptive stimulation. Indeed, they have all shown that increasing the dosage of opioids induced a decrease in the intensity of the reaction to nociceptive stimuli.7,23,24

The originality of the PPI is that it focuses on the “analgesia” component of the balance. Its purpose is to assess the intensity of analgesia before intense nociceptive stimulations occur. It might seem confusing that to achieve this goal, PPI includes tetanic stimulations, which might reach an elevated intensity (60 milliamps). However, using simultaneous PD feedback, the PPI protocol intends to limit the intensity of the stimuli, so that they remain below the threshold inducing a clinically significant hemodynamic reaction. These stimulations might be considered as minimally nociceptive. The train of stimulation is interrupted when simultaneous pupillary dilation reaches 13% of baseline value. This threshold was chosen by the manufacturer for 2 reasons:

  • First, baseline PD under general anesthesia is described in most studies around 2.0 ± 0.2 mm.9,11,24 The device measures the pupil with a precision of 0.1 mm. Thus, this precision corresponds to approximately 5% ± 0.5% of baseline PD in anesthetized patients. For the PPI protocol, the minimal PD variation considered as a genuine dilation, and not as a potential imprecision bias was chosen to be at least twice the precision of the device: 10% ± 1%.
  • Second, it has been demonstrated that the magnitude of PRD depends on the intensity of the stimulation and the intensity of perceived pain in awake patients.14 A report in the early postoperative period indicated that a pupillary dilation of 23% predicted a verbal pain score of >1 on a 4-point scale with 91% sensitivity and 94% specificity.13 To apply only minimally nociceptive stimuli, the selected 13% dilation threshold thus corresponds to approximately half the dilation associated with mild pain perception in awake patients.

For these 2 reasons, it has been hypothesized that the 13% threshold of pupillary dilation allowed by the PPI protocol is both sufficient to avoid precision-related measurements artifacts and low enough to maintain the intensity of the stimulations in the minimally nociceptive range. Our results are in favor of this hypothesis: no withdrawal movement, increase in systolic blood pressure, or significant increase in heart rate was observed after PPI measurements. In addition, many studies have reported pupillary dilation to be more sensitive than heart rate or blood pressure to characterize the physiologic response to stimulation.8,9 The fact that during our PPI measurements, the beginning of a pupillary dilation was observed while no hemodynamic reaction occurred is in accordance with this greater sensitivity.

After alfentanil, we observed a decrease in heart rate after PPI-2 compared to heart rate before PPI-2 (Table). This may seem surprising but might be the consequence of the ongoing decrease in heart rate induced by the bolus of alfentanil. This hypothesis should be confirmed in a controlled study, including a group of patients receiving alfentanil but not submitted to a second PPI measurement. In the context of our study, this result provides additional evidence that the stimulations delivered during the PPI measurement were, as expected, not intense enough to induce a significant hemodynamic response. In addition, even if heart rate changes after PPI were not significant, they were positively correlated to PPI score (Figure 4), suggesting that patients with a higher PPI might actually be less analgesic.

This pilot study only provides a first approach to the novel PPI protocol. Several limitations and issues remain to be addressed. There was a wide interindividual variability in PPI scores before alfentanil administration; some patients had a low PPI, although they had not yet received any opioids. This finding probably reflects the interindividual variability in the sensitivity of subcortical autonomic structures to sevoflurane. Pupillary reactivity, like hemodynamic reactivity, can be blunted by sevoflurane. Bourgeois et al8 evidenced a minimal alveolar concentration of sevoflurane for which PRD to skin incision will be suppressed, even in the absence of opioids. This “MAC PUP” (pupillary) was close to the mean alveolar concentration blocking autonomic responses to skin incision in 50% of patients (MAC BAR)25 and indicated that high concentrations of sevoflurane are able to inhibit pupillary reactivity to nociceptive stimuli. However, this wide distribution of the PPI-1 can also be the consequence of an interindividual variability only related to the index itself, which requires further investigation.

PPI after alfentanil was lower than PPI before alfentanil in all our patients (Figure 3). However, the amplitude of the PPI decrease was not identical for all the subjects: a standardized bolus of alfentanil was not associated with a standard PPI decrease. This possibly reflects the interindividual sensitivity to opioids. However, this variability in PPI changes may also be due to the index itself, which might not be able to precisely quantify analgesia.

Finally, the duration of a PPI measurement (20–30 seconds) might be a concern for both the anesthesiologist and patient. If PPI is performed during the induction of anesthesia, then it might distract the attention of anesthesiologists from their numerous other responsibilities. No publication has reported any corneal damage associated with the use of infrared pupillometry19 for exposures ranging from 5 seconds2 to as long as 4 minutes.9 However, it might be cautious to instill sterile saline in the eye of the patient at the end of the procedure.

In conclusion, this pilot study evidenced a significant PPI decrease after alfentanil administration. It suggests that PPI could indeed assess the level of analgesia in patients under general anesthesia. Larger controlled studies are required to confirm this hypothesis. Further investigations are also required to assess the clinical benefits. The final purpose of the PPI should be to allow the individual prediction of the response to intraoperative painful stimuli. Potential PPI thresholds corresponding to “adequate” analgesia for different specific intraoperative stimuli such as laryngoscopy, skin incision, and laparoscopic insufflation should therefore be determined. Thus, opioid administration might be individually adapted to prevent motor/hemodynamic reactions but also unnecessary opioid overdosage.


Name: Nada Sabourdin, MD.

Contribution: This author helped in the following stages of the study: design of the study, inclusions, data acquisition, data analysis and interpretation, drafting of the manuscript, and approval of the submitted version of the manuscript.

Name: Coumba Diarra, MD.

Contribution: This author helped in the following stages of the study: inclusions, data acquisition, data analysis and interpretation, and approval of the submitted version of the manuscript.

Name: Risa Wolk, MD.

Contribution: This author helped in the following stages of the study: interpretation of the results, critical revision of the manuscript, language editing, and approval of the submitted version of the manuscript.

Name: Véronique Piat, MD.

Contribution: This author helped in the following stages of the study: design of the study, interpretation of results, critical revision of the manuscript, and approval of the submitted version of the manuscript.

Name: Nicolas Louvet, MD.

Contribution: This author helped in the following stages of the study: study design, data analysis and interpretation, statistical analysis, critical revision of the manuscript, and approval of the submitted version of the manuscript.

Name: Isabelle Constant, PhD.

Contribution: This author helped in the following stages of the study: coordination of the study, study design, data analysis and interpretation, statistical analysis, submission to IRB approval, study registration, critical revision of the manuscript, and approval of the submitted version of the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.


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