Effect of Different Concentrations of Propofol

Used as a Sole Anesthetic on Pupillary Diameter:

A Randomized Trial
Nada Sabourdin, MD, Fleur Meniolle, MD, Sarah Chemam, MD, Agnes Rigouzzo, MD,
Jamil Hamza, PhD, Nicolas Louvet, MD, and Isabelle Constant, PhD

BACKGROUND: Pupillometry monitoring under general anesthesia is based on the assumption

that pupillary diameter variations reflect the adequacy of the provided analgesia to the intensity
of the nociceptive surgical stimulus. The accurate interpretation of pupillometric data requires
establishing clearly what the expected baseline unstimulated pupillary diameter at each spe-
cific level of hypnosis is. Opioids decrease pupillary diameter in a dose-dependent fashion. In
contrast, the effects of hypnotic drugs on pupillary diameter are not well known. Our aim was to
describe the potential relationship between propofol predicted effect-site concentrations (Cets)
ranging from 1 to 3 µg/mL and pupillary diameter.
METHODS: Patients were randomized to receive propofol by target-controlled infusion at a pre-
dicted Cet of 1, 2, or 3 µg/mL (groups P1, P2, and P3, respectively). Pupillary diameter mea-
surements were performed after 10 minutes of steady-state propofol infusion at the randomized
Cet. No stimulation was performed during the study. Heart rate and bispectral index (BIS) were
continuously recorded.
RESULTS: Forty patients were included: (13, 14, and 13 in groups P1, P2, and P3, respectively).
Mean pupillary diameter was 5.7 mm (1 mm) in group P1, 4.8 mm (1.3 mm) in group P2, and
3.3 mm (0.8 mm) in group P3. Propofol had a dose-dependent effect on pupillary diameter (lin-
ear regression R2 = 0.45, P < .001). Pupillary diameter was positively correlated with the BIS
(Spearman r = 0.75 [95% confidence interval (CI), 0.54 to −0.87] P < .001).
CONCLUSIONS: From 1 to 3 µg/mL of predicted Cet, propofol has a dose-dependent effect on
pupillary diameter. Within this concentrations range, there is a positive correlation between BIS
and pupillary diameter. The subcortical effect of propofol on pupillary diameter is correlated to
its effect on the cortex. Studies assessing pupillary diameter as a marker of the nociception–
antinociception balance should be performed in patients with a standardized depth of hypnosis. 
(Anesth Analg XXX;XXX:00–00)

KEY POINTS
• Question: Does propofol given as a sole anesthetic influence resting pupillary diameter?
• Findings: Propofol decreases baseline pupillary diameter in a dose-dependent fashion.
• Meaning: Depth of hypnosis should be taken into account when interpreting pupillometric
data or designing pupillometric studies.

GLOSSARY
ANOVA = analysis of variance; ASA = American Society of Anesthesiologists; BIS = bispectral index;
bpm = beats per minute; CI = confidence interval; Cets = effect-site concentrations; CONSORT =
Consolidated Standards of Reporting Trials; CPP = Comité de Protection des Personnes; EEG =
electroencephalogram; GABA = γ-aminobutyric acid; IRB = institutional review board; IV = intrave-
nous; NMDA = N-methyl-d-aspartate; OAAS = Observer Assessment of Alertness/Sedation Scale;
SD = standard deviation; Spo2 = peripheral oxygen saturation; TCI = target-controlled infusion

From the Département d’anesthesiologie, Hôpital Armand Trousseau, Paris,
France.
Accepted for publication June 24, 2019.
Funding: None.
The authors declare no conflicts of interest.
Registration was completed at clinicaltrials.gov (NCT02998424) before
enrollment of the first patient.
Reprints will not be available from the authors.
Address correspondence to Nada Sabourdin, MD, Département
d’anesthesiologie, Hôpital Armand Trousseau, 26 Avenue du Dr Arnold Net-
ter, 75012 Paris, France. Address e-mail to nada.sabourdin@aphp.fr.
Copyright © 2019 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000004362
T
he intraoperative monitoring of nociception has
recently attracted the interest of the anesthetic com-
munity. Several monitoring devices are now available
for this purpose. Studies are being performed to more pre-
cisely assess how they should be used to improve the clini-
cal benefit they can bring to the patients.1–4 Among these
devices, pupillometry has been shown to decrease intraop-
erative and postoperative opioids requirements.1
Pupillometry monitoring is based on the assumption
that pupillary diameter variations reflect the adequacy of
the provided analgesia to the intensity of the nociceptive
surgical stimulus. In addition to these nociception-induced

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 Pupillary Diameter in Patients Receiving Propofol
variations, pupillary diameter is also influenced by anes-
thetic agents. Pupillometry measures global pupillary
variations. To accurately assess the nociception-induced
variations, it is important to know how much of the global
pupillary variation can be attributed to effect of anesthet-
ics. Hence, the accurate interpretation of pupillometric data
requires investigating the specific effects of each anesthetic
agent on pupillary diameter, in the absence of nociceptive
stimulation. This will allow establishing clearly what the
normal baseline pupillary diameter is, at each specific level
of hypnosis.
The effects of opioids on pupillary diameter have been
described extensively. In awake and anesthetized patients,
opioids decrease pupillary diameter in a dose-dependent
fashion, until a plateau phase.5–7
In contrast, data regarding the effect of hypnotics on
pupillary diameter are scarce. In a former study, with a
crossover design, we have shown that at a constant and
low predicted effect-site concentration (Cet) of remifen-
tanil, when only propofol Cet varied, pupillary dilation
was significantly greater at bispectral index (BIS) 55 than
at BIS 25, in response to a standardized nociceptive stimu-
lus.8 In other words, despite unchanged opioids administra-
tion, and similar nociceptive intensity, pupillary response
was modified when the amount of propofol was different.
These results raised the question of the effect of propofol on
pupillary diameter. However, this former study used pro-
pofol in combination with opioids. Thus, it was difficult to
conclude whether the lesser pupillary dilation was caused
by specific effects of propofol on pupillary diameter or by
a synergic effect with remifentanil. In another recent study,
Behrends et al9 suggested that during propofol sedation,
pupillary diameter and BIS decreased along with the level
of wakefulness.
The present study was performed to investigate the
effects of propofol on pupillary diameter. By studying
pupillary diameter in patients receiving different concen-
trations of propofol, without opioids or any other analge-
sic drugs, and no stimulation, the aim of this study was
to describe the potential relationship between propofol
concentrations ranging from 1 to 3 µg/mL and pupillary
diameter. We hypothesized that pupillary diameter would
decrease for increasing propofol predicted effect-site target
concentrations.
METHODS
This was a prospective, randomized, double-blind, descrip-
tive study, conducted in Armand Trousseau teaching hos-
pital (Paris, France). This study was approved by our
institutional review board (IRB: Comité de Protection des
Personnes CPP Ile-de-France 3, approval number S.C.3386),
and written informed consent was obtained from each par-
ticipant (or their legal representative if they were <18 years
of age) before enrolment. The trial was registered before
patient enrolment at clinicaltrials.gov (NCT02998424,
principal investigator: I.C., on December 13, 2016). This
article adheres to the applicable Consolidated Standards of
Reporting Trials (CONSORT) guidelines.
We included American Society of Anesthesiologists
(ASA) I-II postpubertal subjects <60 years of age, scheduled
for an elective surgery under general anesthesia. Patients
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were not included if their body mass index was >30, if they
had a neurologic, ophthalmologic, or metabolic disease,
if they were experiencing pain before surgery, and if they
were receiving any beta-blocker or analgesic treatment
before the procedure.
After inclusion, patients were randomized to receive pro-
pofol by target-controlled infusion (TCI) at a predicted Cet
of 1, 2, or 3 µg/mL (groups P1, P2, and P3, respectively). The
randomization list was generated by a computer (http:/bio-
stat.med.univ-tours.fr), in blocks of 6 consecutive patients.
Our main objective was to determine if propofol Cet
influenced pupillary diameter, which was our main out-
come measure. Our secondary aims were to determine if
propofol Cet influenced heart rate, BIS, and a clinical seda-
tion score (Observer Assessment of Alertness/Sedation
Scale [OAAS]). In addition, we studied the relationship
between BIS and pupillary diameter, as well as the relation-
ship between heart rate and pupillary diameter.
Anesthetic Management During the Study Period
According to the standard practice of our institution,
patients received an oral premedication with hydroxyzine
1–2 mg·kg−1 1 hour before surgery. After entering the opera-
tion room, patients were monitored by an electrocardiogram
(Datex-Ohmeda, Helsinki, Finland), peripheral oxygen sat-
uration (Spo2), noninvasive blood pressure, and a gas ana-
lyzer. The bispectral index electrode (BIS V4.1; Covidien,
Dublin, Ireland) was placed according to manufacturer
instructions. Patients were in the supine position, and a
20- to 22-gauge IV line was inserted and secured before the
beginning of the study period. A facemask was held by an
assistant (anesthetic nurse), and patients were spontane-
ously breathing 100% oxygen throughout the study.
Propofol was administered by a TCI pump (Base Primea;
Fresenius Kabi, Bad Homburg, Germany), using the
Schnider model. The infusion was started at the predicted
effect-site target concentration determined by the random-
ization. When this target concentration was reached, a
steady-state period of 10 minutes was maintained. At the
end of this steady-state period, pupillary diameter was
measured by an independent investigator (see paragraph
below for details). Neither the patient nor the investigator
performing pupillary measurements was aware of the pro-
pofol Cet. Throughout the study period, no stimulation was
applied to the patient and no additional drugs were admin-
istered. After pupillary diameter measurement, the anesthe-
siologist was free to complete general anesthesia according
to his standard practice.
Data Recording
Heart rate, Spo2, and BIS were continuously monitored.
The following data were recorded before the beginning
of propofol infusion (T0: baseline) and at the end of the
10-minute steady-state period (T1): pupillary diameter,
heart rate, BIS. In addition, the level of sedation was
assessed at T0 and T1 using the OAAS, ranging from 0
(patient fully awake and alert) to 5 (deep sedation, patient
unresponsive to any stimulation). Each patient was ran-
domized to receive only 1 concentration of propofol: only
1 measurement at T0 and 1 measurement at T1 were per-
formed for each patient.
ANESTHESIA & ANALGESIA

Our main outcome measure was pupillary diameter.
Our secondary outcome measures were heart rate, BIS, and
OAAS.
Pupillometric Measurements
Measurements were made using the portable video pupil-
lometer Algiscan (IDMed, Marseille, France), which has
already been used in several published studies.1,8,10,11 This
noninvasive monitor is equipped with an infrared camera
that automatically recognizes, tracks, and measures the
pupil. Attached to this camera, there is a smooth occlusive
oval rubber cup (60 × 70 mm) which is placed on the skin,
around the studied eye. This rubber cup is the only compo-
nent of the device that touches the patient; no part of the
pupillometer is ever in direct contact with the eye.
In this study, pupillary measurements were performed
on the right eye of each patient. During the measurement
procedure, the investigator held the patient’s right eye
open by gently touching the upper eyelid, while the left eye
was manually masked by an assistant (the assistant gently
placed his hand on the patient’s face to mask the left eye,
without applying any pressure). The investigator placed
the pupillometer according to manufacturer instructions.
The device was maintained in place for 15 seconds before
the measurement, to allow the pupillary diameter to stabi-
lize after accommodation. Then, by pressing a button on the
pupillometer, the investigator obtained an instantaneous
snapshot of the patient’s pupil, with its corresponding diam-
eter. After this, the device was removed, the right eyelid was
released, and the assistant removed his hand from the left
eye. Thus, the total duration of time used for measurement
was approximately 20 seconds. We only measured “resting”
pupillary diameter, as opposed to “pupillary response” to
stimulation: no stimulus (tetanus, loud noise, etc) was per-
formed during the study period.
As a note, because our first measurement was made
at baseline, before initiating the propofol infusion, and
because we were studying low concentrations of propofol,
we expected most patients would be aware of the pupillary
measurements during the study. In consequence, before
patients signed the informed consent, the investigator
showed them the pupillometer and performed one or sev-
eral pupillary diameter measurements until the patient was
fully familiar with the device and felt no more apprehen-
sion regarding the procedure.
Statistical Analysis
Demographic data and baseline measurements (before
the beginning of propofol infusion) were calculated for
the whole population (40 subjects). Normal distribution
of continuous data was evaluated using the Shapiro–Wilk
test. Normally distributed variables were reported as mean
(standard deviation [SD]), and non-normally distributed
values as median (25th to 75th percentiles).
The mean pupillary diameters were compared among
the 3 groups using a 1-way analysis of variance (ANOVA).
Linear regression with propofol Cet treated as a continuous
variable was used to test for a linear trend of the effects of
increasing propofol effect size concentrations on pupillary
diameter and on BIS. Heart rate values were compared at
T1 between each group of propofol concentration, using
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a 1-way ANOVA. The correlation between propofol Cet
and OAAS scores, the correlation between BIS and pupil-
lary diameter, and the correlation between heart rate and
pupillary diameter were studied with Spearman correla-
tion coefficients. A P value <.05 was considered statistically
significant.
Based on previous studies describing pupillary diam-
eter under propofol anesthesia,5,8 we made the assumption
of a baseline pupillary diameter of 5 mm. The sample size
was calculated for a 1-way ANOVA with 3 groups, to detect
a 20% minimum difference between any treatment group
(ie, a difference of 1 mm), with an estimated SD within the
underlying population of 15% (ie, a SD of 0.75 mm), a power
of 0.8 and a type 1 error probability of 0.05. This sample
size calculation leads to 12 patients by group. To account
for incomplete data recording, we decided to include 40
patients.
Statistical analysis was performed using XLSTAT
2009.3.02 (Addinsoft, Bordeaux, France) and STATISTICA
8.0 (Statsoft, Tulsa, OK).
RESULTS
Forty patients (26 years [11 years], 58 kg [10 kg]) were
included in the study: 13 in group P1, 14 in group P2, and
13 in group P3. There were no differences in demographic
characteristics and baseline pupillary diameter between the
groups (Table 1). All patients remained in spontaneous ven-
tilation throughout the study; no intervention was required
in any patient to maintain airway patency. Pupillary mea-
surements at T0 and T1 were successfully performed in
all patients. No adverse effect related to pupillometry was
recorded.
The mean baseline pupillary diameter, before propofol
infusion, was 6.7 mm (0.8 mm). Mean pupillary diameter at
T1 was 5.7 mm (1.0 mm) in group P1, 4.8 mm (1.3 mm) in
group P2, and 3.3 mm (0.8 mm) in group P3 (Figure 1). The
mean pupillary diameter was statistically different within the
3 groups of propofol Cet (F(2,37) = 15.9, P < .001). In the stud-
ied range of propofol Cet, propofol had a dose-dependent
effect on pupillary diameter. A linear regression was calcu-
lated to analyze this effect. A significant regression equation
was found (F(1,38) = 31, P < .001), with an R2 of 0.45:
PD=7.0 − 1.2 × Cet
with PD representing pupillary diameter (mm). Pupillary
diameter decreased by 1.2 mm (95% confidence interval
[CI], −1.6 to −0.8) with each increase of 1 µg/mL of propofol
Cet.
The mean baseline heart rate was 82 beats per minute
(bpm; 17 bpm). At T1, no statistical difference in heart rate
was identified at the 3 studied propofol concentrations
(ANOVA P = .48; Table 2).
Mean baseline BIS was 97 (1). BIS values significantly
decreased when propofol Cet increased. At T1 and in the stud-
ied range of propofol concentration (1–3 µg/mL), a significant
linear relationship was identified between BIS and propofol
Cet (F(1,38) = 52, P < .001), with an R2 of 0.58. BIS was 100 − 15
× Cet (µg/mL). BIS decreased by 15 units (95% CI, −19.2 to
−10.8) for each increase of 1 µg/mL of propofol Cet.
Median baseline OAAS score was 5 (5–5). The OAAS
sedation score was significantly and negatively correlated
 Pupillary Diameter in Patients Receiving Propofol

Table 1.  Demographic Data and Baseline Pupillary Diameter

Group P1 Group P2 Group P3
No. of patients 13 14 13
Baseline pupillary diameter (mm) 6.8 ± 0.7 6.5 ± 0.8 6.8 ± 0.8
Age (y) 26 ± 12 (14–45) 25 ± 10 (14–43) 25 ± 11 (14–45)
Weight (kg) 60 ± 13 56 ± 7 59 ± 12
Demographic data and baseline pupillary diameter (before propofol infusion) in each group. Group P1: propofol Cet 1 µg/mL; group P2: propofol Cet 2 µg/mL;
group P3: propofol Cet 3 µg/mL. Data are given as mean ± SD (range).
Abbreviations: Cet, effect-site concentration; SD, standard deviation.

Figure 1. Pupillary diameter

(mm) according to randomized
propofol Cet. Black circles:
propofol Cet 1 µg/mL (group
P1); grey circles: propofol Cet
2 µg/mL (group P2); and white
circles: propofol Cet 3 µg/mL
(group P3). For each group, the
horizontal line represents mean
value. Dotted line represents
linear regression, R2 = 0.45 P
< .001. Cet indicates effect-site
concentration.

Table 2.  Data Recording at T1

Baseline P1 (n = 13) P2 (n = 14) P3 (n = 13)
Propofol Cet (µg/mL) 0 1 2 3
Heart rate (bpm) 82 ± 17 73 ± 16 71 ± 16 74 ± 9
BIS 97 ± 1 85 ± 8 71 ± 9 55 ± 14
OAAS 5 (5–5) 5 (4–5) 4 (3–5) 2 (1–3)
Heart rate, BIS, and OAAS at T1 (after 10 minutes of steady state at the randomized propofol Cet). Results are expressed in mean ± SD or median (quartiles).
Abbreviations: BIS, bispectral index; bpm, beats per minute; Cet, effect-site concentration; OAAS, Observer Assessment of Alertness/Sedation Scale; SD,
standard deviation.

with propofol Cet (Spearman r = −0.69 [95% CI, −0.84 to

−0.45] P < .001).
Pupillary diameter was significantly and positively cor-
related with the BIS (Spearman r = 0.75 [95% CI, 0.54 to
−0.87] P < .001; Figure 2). There was no significant correla-
tion between heart rate and pupillary diameter (Spearman
r = 0.07 [95% CI, −0.25 to 0.37] P = .65; Figure 3).
DISCUSSION
In this study, performed on patients anesthetized with
propofol alone, we demonstrated that propofol Cet influ-
enced resting pupillary diameter. From 1 to 3 µg/mL of Cet,
pupillary diameter significantly decreased as propofol Cet
increased. These findings confirm that in the studied range
of Cet, the effects of propofol on pupillary diameter are a
dose dependent.
These results offer interesting insights into the target-spe-
cific pharmacology and mechanisms of action of propofol.
To explain our findings, the first step is to understand the
determinants of pupillary dynamics. Pupillary diameter is
under both sympathetic and parasympathetic control. The
autonomic centers of the midbrain send efferent nervous
fibers toward the iris. The sympathetic pathway connects
to the radial muscle of the iris and is responsible for active
pupillary dilation. The parasympathetic pathway connects
via the Edinger–Westphal nucleus to the circular sphinc-
ter of the iris, responsible for active pupillary constriction.
In addition, light-sensitive fibers originating in the retina
send an excitatory input to the Edinger–Westphal nucleus,
which also results in pupillary constriction. Thus, in awake
unstimulated patients, pupillary diameter depends on both
the autonomic balance and on the intensity of ambient light.
In our study, there were no modifications in the intensity
of ambient light during the experiment. In addition, pupil-
lary measurements were performed with 1 eye surrounded
by the occlusive rubber cup of the pupillometer, and the
other eye masked by the assistant’s hand, after 15 seconds
to allow stabilization of pupil diameter to the dark environ-
ment. So we may consider that in our patients, pupillary

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Figure 2. Scatter plot showing

the relationship between BIS
and pupillary diameter (mm).
The correlation was calculated
for all measurements together,
regardless of the group (n =
40). Spearman coefficient r =
0.75, P < .001. Black circles:
propofol Cet 1 µg/mL (group
P1); grey circles: propofol Cet
2 µg/mL (group P2); and white
circles: propofol Cet 3 µg/
mL (group P3). BIS indicates
bispectral index; Cet, effect-site
concentration.

Figure 3. Scatter plot show-

ing the relationship between
heart rate (bpm) and pupillary
diameter (mm). Black circles:
propofol Cet 1 µg/mL (group
P1); grey circles: propofol Cet
2 µg/mL (group P2); and white
circles: propofol Cet 3 µg/mL
(group P3). bpm indicates beats
per minute; Cet, effect-site
concentration.

diameter reflected the autonomic balance, modulated by the
autonomic midbrain centers.
The second step is to understand the physiological and
pharmacological mechanisms by which propofol can modify
the autonomic balance and thus influence pupillary diame-
ter. Propofol is one of the most commonly used intravenous
(IV) hypnotic drugs. It is an agonist of γ-aminobutyric acid
(GABA) and glycine receptors, an antagonist of nicotinic
(cholinergic), glutamatergic, and muscarinic receptors, as
well as an agonist of G-protein linked voltage-dependent
sodium channels.
Propofol acts on the midbrain autonomic centers by
inhibiting the sympathetic nervous activity.12 This was first
evidenced by Ebert et al,13 in patients receiving a 2.5 mg·kg−1
bolus of propofol followed by a continuous infusion. The
subjects had a marked decrease in sympathetic activity:
their peripheral muscular sympathetic nervous activity
decreased by 76% and their baroreflex by 70%.13 It was also
demonstrated that the decrease in blood pressure associ-
ated with propofol infusion was mediated by a decrease in
vascular sympathetic nervous activity.14,15 Finally, in a study
performed in spontaneously breathing healthy volunteers,
using propofol at doses inducing moderate to deep seda-
tion (BIS = 70 and 54, very close to our groups P2 and P3),
Ebert16 evidenced a significant reduction in muscular sym-
pathetic nervous activity, considered as the gold standard
of sympathetic nervous activity assessment. These results
were, respectively, associated with a 9% and 18% decrease
in blood pressure, again very similar to our findings. Thus,
propofol is a potent sympathetic inhibitor, and this inhibi-
tion is already significant at doses inducing moderate to
deep sedation. Considering the underlying physiology of
pupillary diameter variation, it is possible that the pupillary
constriction reported in our results directly reflects this inhi-
bition of the sympathetic drive occurring during moderate

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 Pupillary Diameter in Patients Receiving Propofol
and deep sedation. At these hypnotic levels, the pupil might
be considered a peripheral sympathetic effector.
This hypothesis, however, has to be modulated by exam-
ining the effects of propofol on parasympathetic nervous
system activity. In a study based on heart rate variability
investigation, Win et al17 demonstrated that patients receiv-
ing IV propofol at sedative doses (BIS = 72 ± 6) had a sig-
nificantly decreased total spectral power, which shows that
propofol inhibited both sympathetic and parasympathetic
nervous activities. This global decrease was associated with
a shift of the autonomic balance toward its parasympathetic
component, demonstrating a relative preservation of the
parasympathetic component.17
Although propofol, as we have so far described, has
many subcortical effects, its main purpose remains to sup-
press consciousness, via an inhibitory modulation of corti-
cal neurotransmission. Our results suggest that the effects
of propofol on its cortical and subcortical targets are both
dose dependent. In a study describing simultaneous modi-
fications of the electroencephalogram (EEG) and of the
autonomic indices derived from heart rate variability anal-
ysis,18 it has been demonstrated that the cortex is the first
to respond to propofol, with the first EEG modifications
observed for blood concentrations of 0.8 µg/mL, while
autonomic heart control is not significantly modified. When
blood concentrations reach 1.6 µg/mL, (as in our groups
P1-P2), the cardiac baroreflex begins to decrease. Then, when
blood concentrations reach 3.2 µg/mL, (as in our group P3),
both EEG and autonomic nervous activity are significantly
modified. Another study, based on skin impedance, con-
firmed that sympathetic nervous activity correlated with
both the BIS and the OAAS.19 Finally, in a recent publica-
tion, Behrends et al9 reported that BIS values and pupillary
diameter decreased along with wakefulness in 8 patients
under spinal anesthesia, sedated with propofol. Our results
are in agreement with these aforementioned data: we found
a significant linear correlation between pupillary diameter
and BIS (P < .001). Taken together, these observations sug-
gest that for propofol concentrations between 0 and 3 µg/
mL, the cortical inhibition (BIS) is correlated with subcorti-
cal inhibition (autonomic centers inhibition).
This study has several clinical implications in the field of
intraoperative monitoring. Pupillometric monitoring of the
nociception–antinociception balance is based on the pupil-
lary reflex dilation to nociceptive stimulation. This reflex
compares a “stimulated” pupillary diameter to a baseline
diameter. In anesthetized patients, it was already known
that both the intensity of nociception and the amount of opi-
oid analgesia influenced pupillary diameter.5,6 This study,
along with our previous work,8 confirms that under propo-
fol, the dose-dependent level of hypnosis, assessed by the
BIS, is a third factor influencing pupillary diameter. Thus,
the pupillometric assessment of 1 of these 3 factors (analge-
sia, nociception, level of hypnosis) requires controlling or at
least integrating the 2 other factors. In practice, for example,
pupillometric studies assessing the amplitude of pupillary
dilation to a standardized stimulus at different doses of opi-
oids should probably be performed at a standardized level
of BIS, at least in patients receiving propofol. Considering
that the underlying mechanisms of pupillary dynam-
ics mainly involve the autonomic balance of the midbrain
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centers, these conclusions may also apply to all the other
available monitors of nociception, for they are all based on
the evaluation of the peripheral effectors of the autonomous
nervous system. This hypothesis, however, remains to be
tested in future studies.
Several factors limit the generalizability of our findings.
Our study only focused on propofol. The effect of hyp-
notic agents on the EEG is drug specific; their effect on the
pupil and other autonomic effectors might as well be drug
specific: whether our findings can be reproduced with a dif-
ferent hypnotic agent (sevoflurane, desflurane, thiopental,
etomidate, etc) remains to be demonstrated.
Besides, we studied the pupillary effects of propofol used
as a single anesthetic agent, but most anesthetic procedures
include >1 drug. The impact of pupillary diameter modula-
tion by propofol when other agents are used in combination
(opioids, N-methyl-d-aspartate [NMDA] antagonists, etc)
requires further evaluation.
In addition, we only studied propofol concentrations
within the sedation range. In that range, our lowest pupil-
lary diameters were around 2.5 mm. In a previous study
combining high-dose propofol (Cet = 6.0 ± 1.9 µg/mL, BIS
= 25) with low-dose remifentanil (Cet 1 ng·mL−1), unstim-
ulated pupillary diameters were 2.1 ± 0.2 mm.6 It is thus
likely that the decrease in pupillary diameter, associated
with propofol Cet increase, might reach a plateau for higher
propofol doses, within the surgical anesthetic range. We
did not study higher propofol doses, because we wanted to
preserve spontaneous ventilation, to avoid stimulation by
external maneuvers (jaw thrust, assisted ventilation).
Finally, there are 2 other limitations to this study.
Patients were premedicated with hydroxyzine, accord-
ing to the standard practice of our institution. There are
no data on the specific effects of hydroxyzine on pupillary
diameter in the perianesthetic period. However, hydroxy-
zine is an antihistamine that acts preferentially as an H1
receptor inverse agonist, but it also binds to the muscarinic
cholinergic receptors, although only with a very low affin-
ity. Thus, it might be responsible for a very mild anticholin-
ergic effect. It is not possible to eliminate a minor influence
of premedication on our results.
Our propofol concentrations were predicted by a TCI
device. We did not perform blood samplings to measure
individual plasma propofol concentrations. Despite the
good performances of the pharmacokinetic models,20 there
might remain some degree of interindividual variability.
In conclusion, we have demonstrated that propofol
Cet influences pupillary diameter: for propofol Cets rang-
ing between 1 and 3 µg/mL, pupillary diameter decreases
when propofol Cet increases. Moreover, we have evidenced
that within this range of concentrations, pupillary diameter
is directly related to the BIS. These findings have several
implications. From a pharmacodynamics point of view, our
results confirm that within this range of concentrations, the
autonomic inhibition induced by propofol seems to be pro-
portional to the cortical inhibition. In clinical practice, the
consequence of our results is that any study using pupil-
lary diameter as an outcome measure should probably be
performed in patients with a standardized depth of hypno-
sis, assessed by an EEG-based monitor. Propofol autonomic
modulation evidenced in this study should probably also
ANESTHESIA & ANALGESIA

be taken into account when analyzing other indices derived
from autonomic effectors: standardizing depth of hypnosis
might also be relevant when other devices based on sympa-
thetic or parasympathetic activity are used to monitor noci-
ception. Further studies are required to describe whether
these correlations remain valid for deeper levels of hypnosis
and for different combinations of anesthetic drugs. E
ACKNOWLEDGMENTS
The authors would like to thank Dr Risa Wolk (Department
of Anesthesia, Columbia University Medical Center, New
York) for her help and advice in language editing and for
her critical review of the manuscript.
DISCLOSURES
Name: Nada Sabourdin, MD.
Contribution: This author helped with study design, patient
recruitment, data collection, data analysis, review of the literature,
writing of the first draft of the paper, and approval of the final draft
of the paper.
Name: Fleur Meniolle, MD.
Contribution: This author helped with patient recruitment, data
collection, data analysis, review of the literature, and approval of
the final draft of the paper.
Name: Sarah Chemam, MD.
Contribution: This author helped with study design, data analy-
sis, review of the literature, critical revision of the manuscript, and
approval of the final draft of the paper.
Name: Agnes Rigouzzo, MD.
Contribution: This author helped with study design, data analysis,
critical revision of the manuscript, and approval of the final draft
of the paper.
Name: Jamil Hamza, PhD.
Contribution: This author helped with data analysis, review of the
literature, critical revision of the manuscript, and approval of the
final draft of the paper.
Name: Nicolas Louvet, MD.
Contribution: This author helped with study design, statistical
analysis, data analysis and interpretation, critical revision of the
manuscript, and approval of the final draft of the paper.
Name: Isabelle Constant, PhD.
Contribution: This author helped with study design, statistical
analysis, data analysis and interpretation, advice in writing the
first draft of the manuscript, critical revision of the manuscript, and
approval of the final draft of the paper.
This manuscript was handled by: Ken B. Johnson, MD.
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