Eur J Anaesthesiol 2021; 38:975–984

ORIGINAL ARTICLE

Effects of pupillary reflex dilation-guided opioid

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administration on remifentanil and morphine

consumption during laparoscopic surgery
A randomised controlled trial
Philippe Guerci, Guillaume Jay, Chloe Arnout, Delphine Herbain, Noureddine Baka,
Olivier Poirel, Emmanuel Novy, Herve Bouaziz and Florence Vial

BACKGROUND Analysis of pupillary reflex dilation (PRD)
assesses the balance of nociception–antinociception. Lap-
aroscopic surgery induces haemodynamic variations that are
misleading. During laparoscopy, PRD guidance helps differ-
entiate haemodynamic changes because of excess nocicep-
tion from secondary changes related to the reflex release of
endocrine factors.
OBJECTIVE The present study evaluated the effect of PRD-
guided antinociception on the administration of intra-operative
remifentanil and immediate postoperative morphine consump-
tion in patients undergoing elective laparoscopic surgery.
DESIGN The study was a single-blind, randomised con-
trolled trial.
SETTING The study took place at two sites at the University
Hospital of Nancy from March 2014 to November 2017.
PATIENTS A total of 100 patients who underwent sched-
uled laparoscopic surgery were included.
INTERVENTIONS Patients were randomly given remifentanil
guided by PRD (PRD-guided) or standard anaesthesia care
(control).
MAIN OUTCOME MEASURES The primary outcome was
intra-operative remifentanil consumption. Secondary out-
comes included morphine consumption in the immediate
postoperative period and the number of intra-operative hae-
modynamic events.
RESULTS Data from 95 patients were analysed. Intraopera-
tive remifentanil consumption was lower in the PRD-guided
group than in the control group: median [IQR], 0.09 [0.07 to
0.11] vs. 0.14 [0.12 to 0.16] mg kg1 min1, with a mean
difference (95% confidence Interval, CI) of 0.048 (0.035 to
0.060) mg kg1 min1; P < 0.0001. Morphine consumption
was 0.13 [0.1 to 0.5] vs. 0.15 [0.11 to 0.4] mg kg1 (P ¼ 0.52)
in the PRD-guided and control groups, respectively. The
number of hypertensive and tachycardia events was greater
in the PRD-guided group than in the control group: Hyperten-
sive events 60.4% vs. 32.6%, relative risk 1.85 (95% CI, 1.24
to 2.84), P ¼ 0.004; tachycardia events 31.6% vs. 4.3%,
relative risk 2.09 (95% CI, 1.45 to 2.84), P < 0.001.
CONCLUSIONS When PRD is used to differentiate
between haemodynamic events arising from noxious stimuli
and those events because of other nonsurgical stimuli, then
intra-operative remifentanil administration is reduced intra-
operatively during laparoscopic surgery but there was no
change in postoperative morphine consumption.
TRIAL REGISTRATION Clinicaltrials.gov NCT02116868.
Published online 17 March 2021

Introduction
General anaesthesia results from the combined effects of
three main components: hypnosis, myorelaxation, and
antinociception.1,2 However, the assessment of intra-
operative nociception remains limited. Intraoperative
autonomic reactions are often considered to be signs of
nociception or inadequate antinociception. However,
these clinical signs have low specificity and sensitivity
to assess nociception balance during general anaesthesia.

From the Department of Anaesthesiology and Critical Care Medicine, University Hospital of Nancy-Brabois, Institut Lorrain du Coeur et des Vaisseaux (PG, GJ, EN),
Department of Obstetric Anaesthesia and Critical Care Unit, Maternity Hospital, University Hospital of Nancy (GJ, CA, DH, NB, OP, HG, FV, HB) and INSERM U1116,
Faculty of Medicine, University of Lorraine, Nancy, France (PG)
Correspondence to Philippe Guerci, MD, PhD, Department of Anaesthesiology and Critical Care Medicine, Institut Lorrain du Coeur et des Vaisseaux, University Hospital
of Nancy-Brabois, Vandoeuvre-Lès-Nancy, France
Tel: +33 3 83 15 79 95; e-mail: phil.guerci@gmail.com

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DOI:10.1097/EJA.0000000000001491
Copyright © European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.
 976 Guerci et al.

One current dogma is that a nociception–antinociception
imbalance must be managed by opioid administration. This
strategy may lead to opioid underdosing (with a risk of
movement, hypertension and tachycardia) or overdosing
(associated with lower blood pressure and postoperative
hyperalgesia). Pupillometry, which allows for the monitor-
ing of pupillary reflex dilation (PRD) in response to noxious
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neurological disorders affecting the central nervous sys-
tem, ophthalmological disease (including diabetic retinop-
athy), alcohol abuse and medications that could interfere
with the PRD (droperidol, metoclopramide).
Included patients were randomised into the pupillometry
or standard practice group. A biostatistician, with no other

involvement in the study, created a computer-generated

stimuli, has been proposed to assess the nociception–anti-
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randomisation sheet for assigning the patients (five-

nociception balance. The autonomic nervous system con-
patients block size). On the day of surgery, the investi-
stantly and quickly influences pupillary diameter.3 PRD is
gator opened the opaque sealed envelope containing the
proportional to the intensity of nociception and inversely
group allocation in the operating room.
proportional to the amount of opioid administered.4
CO2 insufflation, to create pneumoperitoneum during
Anaesthesia and monitoring in both treatment groups
laparoscopy, induces haemodynamic changes secondary
The anaesthesia protocol is described in detail in Sup-
to the increase in intra-abdominal pressure and the sub-
plemental digital content; http://links.lww.com/EJA/
sequent hormone release, even in the absence of hyper-
A534. Briefly, total intravenous anaesthesia was induced
carbia.5–8 These alterations in haemodynamic status may
and maintained with propofol and remifentanil using
be misinterpreted as ‘insufficient antinociception’. Con-
effect site target-controlled infusions and previously
sequently, opioids are sometimes administered unneces-
published models.14,15 For the induction of anaesthesia,
sarily with a risk of postoperative hyperalgesia.9 A reliable
the effect site concentrations (Ce) were set at 2 mg ml1
monitor of the nociception/antinociception balance
for propofol and 2 ng ml1 for remifentanil. After equilib-
would be interesting in this clinical context.
rium, the Ce propofol was then increased in steps of
Few clinical studies have compared intra-operative opi- 1 mg ml1 until BIS was in the range 40 to 60.
oid administration guided by a nociception monitor with
Pupil diameter and PRD were assessed in both groups
opioid administration in response to haemodynamic var-
using an Algiscan video pupillometer (ID Med, Mar-
iations.10–13 Laparoscopic surgery combines haemody-
seille, France) at different timepoints during anaesthesia
namic changes associated with both nociception and
and surgery. The anaesthetists were blinded to the
pneumoperitoneum. Therefore, we hypothesised that
pupillometer data in the standard anaesthesia care (con-
PRD would help differentiate the cause of the haemo-
trol) group. After loss of consciousness (no eyelash reflex)
dynamic variations and result in reduced opioid con-
the baseline PRD was recorded in response to a noxious
sumption. The primary outcome was intra-operative
stimulus. A tetanic stimulus (100 Hz at 60 mA) applied to
remifentanil consumption.
the skin of the inner forearm for 5 s served as a standar-
dised noxious stimulus. PRD was also assessed in
Methods
response to this standardised tetanic stimulation before
This prospective, single-blind, parallel-arm randomised
intubation and before skin incision. In addition, pupil
study was performed at two sites (Maternity and General
diameter was assessed during surgery without the tetanic
Adult) of the University Hospital of Nancy, France, from
stimulus. Each measurement required holding the eyelid
March 2014 to November 2017 after approval from the
open for approximately 5 s, and then the eye was gently
institutional review board (Comite de Protection des Per-
closed until the next assessment. The pupillary response
sonnes Est III, France, ANSM 2013-A01002-43 and CPP
to noxious stimulation was measured in real time with a
130903, chairman Dr P. Peton, University Hospital of
manufacturer-specified accuracy of 0.05 mm. The contra-
Nancy, France on 13 October 2013). This study is registered
lateral eye remained closed.
with clinicaltrials.gov (NCT02116868). Written informed
consent was obtained from all patients before participation, Before orotracheal intubation, the predicted remifentanil
and the trial was performed in accordance with the Decla- effect site concentration (Ce) was adjusted differently
ration of Helsinki. This report follows the CONSORT according to the patient’s group. Ce remifentanil in the
statement for the reporting of randomised controlled trials. control group was left to the discretion of the anaesthesi-
ologist in charge of the patient. Ce remifentanil in the
Patients pupillometry group was titrated in 0.5 ng ml1 increments
Patients over 18 years of age who were classified as ASA against the change in pupil diameter in response to the
physical status I to III and scheduled for elective laparo- noxious tetanic stimulus: remifentanil was increased until
scopic surgery under general anaesthesia were recruited to the PRD was less than 15% of the ‘resting’ pupil diameter
participate in the study. The exclusion criteria were body just before the application of the noxious stimulus (Sup-
mass index (BMI) >35 kg m2, intra-operative and/or post- plemental digital content; http://links.lww.com/EJA/
operative epidural analgesia, pre-operative neuropathic A534). The PRD assessments were repeated at roughly
pain or opioid medication, intolerance to trial medication, 2-min intervals to allow time for the new Ce remifentanil

Eur J Anaesthesiol 2021; 38:975–984

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target to be attained between each assessment. In both
groups, immediately after intubation, the pupil diameter
was assessed without the artificial noxious stimulus, and
this diameter was compared with the most recent ‘resting’
pupil diameter. Thereafter, the propofol and remifentanil
infusion rates were reduced to their initial baseline values.
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Standard anaesthesia care group (control)
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Intraoperative remifentanil administration was adjusted
at the discretion of the anaesthetist or nurse anaesthetist
in charge of the patient according to clinical signs and
haemodynamic changes. The pupillary diameter and
PRD were monitored independently every 10 min but
the anaesthetist was unaware of these measurements.
Pupillary reflex dilation-guided group
Before the first skin incision, Ce remifentanil in the PRD-
guided group was adjusted to the same level as used for
intubation and, after equilibrium, the pupil diameter was
recorded before any surgical stimulation (Supplemental
digital content; http://links.lww.com/EJA/A534). This
measurement served as the baseline pupil diameter
against which the intra-operative pupil diameters were
compared. An independent investigator who had no input
into the clinical management measured pupillary diame-
ter during the skin incisions and insertion of the trocars,
and at 10 min intervals thereafter the pupil diameter was
assessed and compared with the baseline. Ce remifenta-
nil was adjusted according to the stepwise protocol
detailed in Supplemental digital content; http://
links.lww.com/EJA/A534. Briefly, if the pupil diameter
increased more than 15% compared with baseline, the
remifentanil concentration was increased by 0.5 ng ml1.
If the pupil diameter increased 5 to 15% compared with
baseline, Ce remifentanil was not changed. If blood
pressure and/or heart rate were increased more than
20% compared with baseline, or heart rate increased to
90 beats min1 or blood pressure increased to 140/
90 mmHg and the percentage variation of pupil diameter
was lower than 15%, the patient received a per-protocol
bolus of antihypertensive drugs, such as esmolol, nicar-
dipine or urapidil (Supplemental digital content; http://
links.lww.com/EJA/A534). If the pupil diameter
remained within 5% of the baseline measurement, a
new evaluation of the pupil diameter was performed to
confirm this value. If the value was confirmed after
10 min, the Ce remifentanil was decreased by 0.2 ng ml1.
Standardised postoperative analgesia and care
Postoperative analgesia was standardised in both groups.
All patients received an intravenous dose of paracetamol
(1 g), ketoprofen (50 mg) (or 20 mg nefopam in case of a
contra-indication to ketoprofen) and a bolus of morphine
(0.1 mg kg1) 10 min before wound closure (Supplemen-
tal digital content; http://links.lww.com/EJA/A534).
Remifentanil was stopped at the completion of wound
closure. Laparoscopic ports were not infiltrated with local
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Haemodynamic events under pupillometry-guided analgesia 977
anaesthetics as it was not the standard-of-care at the time
of the study.
Pain was evaluated in the postanaesthetic care unit
(PACU) using a simple verbal numeric scale (SVS) that
ranged from 0 to 4 (Supplemental digital content; http://
links.lww.com/EJA/A534). For responses at least 2, intra-
venous morphine boluses (2 mg) were administered every
5 min (titration) until the SVS was less than 2/4.
Measurements
Patient characteristics, including age, sex, BMI, and pre-
operative haemodynamic parameters [systolic pressure
(systolic arterial pressure; SAP), mean, diastolic arterial
pressure and heart rate] were recorded. Pupil diameter and
SAP were measured before orotracheal intubation, after
intubation, at skin incision and during the insertion of the
trocars, and at the initiation of pneumoperitoneum, then
every 10 min throughout the procedure and when any
haemodynamic events occurred (see definition below).
Primary and secondary study endpoints
The primary endpoint was intra-operative remifentanil
consumption.
The secondary endpoints included total morphine con-
sumption (intra-operative þ PACU) and the number of
patients experiencing at least one of the following hae-
modynamic events: SAP greater than 140 mmHg or 20%
increase from baseline; heart rate above 90 bpm or 20%
increase from baseline; SAP less than 90 mmHg or 20%
decrease from baseline and heart rate less than 55 bpm or
20% decrease from baseline). Propofol consumption and
use of antihypertensive and vasoactive drugs were also
secondary endpoints.
The time to extubation, occurrence of nausea and/or
vomiting, pain scores in PACU on admission and dis-
charge and time spent in the PACU were also recorded.
Statistical analysis
The mean intra-operative remifentanil consumption
(TCI) of patients undergoing laparoscopic surgery at our
institution was 0.14  0.047 mg kg1 min1 in a previous
unpublished report. To detect a 20% (0.03 mg kg1 min1)
decrease in intra-operative remifentanil consumption, a
sample size of n¼49 patients per group would provide a
power (1  b) of 90% with a type I error rate (a) of 5%.
Therefore, a total of 100 patients were recruited.
Descriptive statistics for quantitative variables are
expressed as the means (SD) or median [IQR] when-
ever data were nonnormally distributed or as a number
(%) for qualitative variables. The normality of the distri-
bution was tested using a D’Agostino and Pearson test.
Remifentanil, morphine in the PACU, and total mor-
phine consumption were analysed using Mann–Whitney
U tests. Secondary endpoints, such as intra-operative
haemodynamic events were analysed using Fisher’s exact
Eur J Anaesthesiol 2021; 38:975–984
 978 Guerci et al.
test with relative risks (RRs) calculated from the 2  2
contingency tables, and the results are presented with
95% confidence intervals (CIs). Other secondary end-
points were analysed using an independent two-tailed t
test or the Mann–Whitney U-test depending on the
distribution of the data. For comparison of SAP and
PRD between the two groups throughout the surgery
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(as the duration of surgery was not similar for each
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patient’s case), a two-way linear mixed-effects model
(fixed: time and group; random effects: patients) using
a compound symmetry covariance matrix was used and
fitted using restricted maximum likelihood. P values less
than 0.05 were considered significant. An intention-to-
Fig. 1 Study flow chart
Enrolment
Allocated to PRO-guided group (n = 50)
• Received allocated intervention (n = 47)
• Did not receive allocated intervention (n = 3)
- Technical problem with TCI pump (n = 1)
- Protocol violation (n = 1)
- Decision for immediate laparotomy (n = 1)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Analysed (n = 48)
• Excluded from analysis (n = 0)
The ITT analysis included patients with protocol violations. ITT, intention-to-treat; TCI, target-controlled infusion.
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treat analysis was used with the exclusion of patients with
complete data loss or who did not receive any interven-
tion (technical failure). Statistical analyses were per-
formed using GraphPad Prism version 8.4.1 for MacOS
(GraphPad software, San Diego, California, USA).
Results
A total of 163 patients were assessed for eligibility. One
hundred patients were recruited, and 95 patients were
included in the final intention-to-treat analysis. Details
are provided in the flowchart (Fig. 1). Patient character-
istics, type of surgery, preoperative haemodynamic
parameters and health status were similar in both groups
Assessed for eligibility (n = 164)
Excluded (n = 64)
• Not meeting inclusion criteria (n = 11)
• Declined to participate (n = 47)
• Other reasons (n = 6)
Randomised (n = 100)
Allocation
Allocated to standard practice group (n = 50)
• Received allocated intervention (n = 47)
• Did not receive allocated intervention (n = 3)
- Technical problem with TCI pump (n = 1)
- Protocol violation (n = 1)
- Technical problem with pupillometer (n = 1)
Follow-up
Lost to follow-up (n = 1):
- Data loss (n = 1)
Discontinued intervention (n = 0)
ITT analysis
Analysed (n = 47)
• Excluded from analysis (n = 0)
 Haemodynamic events under pupillometry-guided analgesia 979

Table 1 Patient characteristics, preoperative haemodynamic parameters and type of surgery

Variable PRD-guided group (n U 48) Control group (n U 47) P value

F/M sex (n/n) 47/1 44/3 0.297
Age (years) 49 [39 to 59] 46 [38 to 56] 0.713
Weight (kg) 67  12 67  11 0.935
BMI (kg m2) 25.2  4.2 24.7  4.1 0.549
Medical history
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Hypertension 12 (25) 8 (17) 0.452

Diabetes 1 (2) 2 (4) 0.617
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ASA class 0.453

ASA 1 19 (40) 24 (51)
ASA 2 25 (52) 21 (45)
ASA 3 4 (8) 2 (4)
SAP (mmHg) 128 [116 to 140] 126 [112 to 136] 0.470
DAP (mmHg) 75 [69 to 86] 75 [67 to 83] 0.612
MAP (mmHg) 94 [85 to 102] 91 [81 to 101] 0.383
Heart rate (BPM) 79 [68 to 86] 73 [67 to 81] 0.225
Gynaecology 43 (90) 42 (89)
Visceral surgery 5 (10) 5 (11)
Chronic medications
ACE inhibitors or ARBs 8 (17) 6 (13) 0.773
Calcium channel blockers 1 (2) 1 (2) 1.000
ß-blockers 4 (8) 4 (8) 1.000
Aspirin 1 (2) 1 (2) 1.000

Data are median [IQR], mean ( SD) or number (%). ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, American Society of
Anaesthesiologists; BPM, beats per minute; BMI, body mass index; DAP, diastolic arterial pressure; SAP, systolic arterial pressure.

(Table 1). Overall, 20 (21%) patients had chronic hyper-
tension, and all discontinued their medication on the
morning of surgery.
Intra-operative remifentanil and propofol consumption
Intraoperative data are described in Table 2. Median
[IQR] remifentanil consumption was lower in the PRD-
guided group than in the control group: 0.09 [0.07 to 0.11]
vs. 0.14 [0.12 to 0.16] mg kg1 min1, respectively. The
use of PRD resulted in a 35% reduction in remifentanil
consumption: median difference, 0.048 mg kg1 min1
(95% CI, 0.035 to 0.060), P less than 0.0001. Propofol
consumption was similar in both groups (P ¼ 0.76). The
duration of anaesthesia was longer in the control group
compared with the PRD-guided group: 107  19 vs.
144  45 min, P less than 0.001.
Haemodynamic events during anaesthesia and surgery
The changes in SAP and the percentage variation in pupil
diameter during the first 150 min of the surgical proce-
dure are depicted in Fig. 2. Patients in the PRD-guided
group exhibited a higher SAP from the induction of
Table 2 Intraoperative anaesthetics consumption and vasoactive drug requirements
Variable PRD-guided group (n U 48)
Remifentanil (mg kg1 min1)
Propofol (mg kg1 h1)
Vasoactive drugs Dose
Ephedrine (mg) 9 [7.5 to 15]
Nicardipine (mg) 0.5 [0.5 to 1]
Esmolol (mg) 68 [39 to 70]
Urapidil (mg) 12.5 [12.5 to 12.5]
anaesthesia and throughout surgery than patients in
the control group (Fig. 2a, P ¼ 0.002 by a random-effects
model for the between-group comparison across the
entire study intervention). The PRDs were similar in
both groups (Fig. 2b, P ¼ 0.123) and remained below the
accepted threshold of 13 to 15% of variation associated
with a response to noxious stimulus.16–18
The percentages of patients exhibiting hypertension and
tachycardia events were greater in the PRD-guided group
than in the control group [(60.4 vs. 32.6%; RR, 1.85 (95%
CI, 1.24 to 2.84), P ¼ 0.004 and 31.6 vs. 4.3%; RR, 2.09
(95% CI, 1.45 to 2.84), P < 0.001, respectively; Fig. 3].
Most of the hypertensive episodes (93%) were associated
with pupil diameter variations less than 15% compared
with baseline and a BIS or PSI ranging from 30 to 60 or 25
to 50, respectively. However, the incidence of hypoten-
sive events was similar in both groups [77.1 vs. 89.4%;
RR, 0.68 (95% CI, 0.48 to 1.11), P ¼ 0.17]. Consequently,
the proportion of patients who required the administra-
tion of a vasoconstrictive agent (ephedrine) was similar in
both groups, and more antihypertensive medications
Control group (n U 47) P value
0.09 [0.07 to 0.11] 0.14 [0.12 to 0.16] <0.0001
7.5 [6.5 to 8.3] 7.8 [6.4 to 8.6] 0.76
n (%) Dose n (%)
25 (52) 9 [8.5 to 16.5] 21 (44.7) 0.54
12 (25) 1 [0 to 3] 3 (6.4) 0.022
6 (12.5) – 0 (0)
2 (4) – 0 (0)

One patient may experience several similar or different haemodynamic events. Data are median [IQR], mean ( SD) or number (%). Fischer’s exact test was used to
compare the proportion of patients who required vasoactive drugs. PRD, pupillary reflex dilation.

Eur J Anaesthesiol 2021; 38:975–984

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 980 Guerci et al.

Fig. 2 Systolic arterial blood pressure and percentage variation in pupil diameter in the pupillary reflex dilation-guided and control groups during the
intervention period

(a) 175 PRD-guided group

Control group

150
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Systolic arterial blood pressure (mmHg)

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100

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PRD-guided group
Control group
30
Percentage change in pupil diameter (%)

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Patients
PRD-guided group 48 48 48 48 48 48 47 46 46 43 38 33 29 26 24 17 15 12 10

Control group 47 47 47 47 47 47 47 46 46 42 41 36 36 32 30 24 18 13 7

Predicted remifentanil effect site concentration (Ce) and propofol target-controlled infusions were decreased to the baseline levels of 2 ng ml1 and
2 mg ml1, respectively, after intubation. A two-way linear mixed-effects model (fixed: time and group; random effects: subjects) using a compound
symmetry covariance matrix was used and fitted using restricted maximum likelihood. (a) P ¼ 0.002 by a random-effects model for the between-group
comparison across the entire study intervention. (b) The PRDs were similar in both groups (P ¼ 0.123). PRDS, pupillary reflex dilations.

Eur J Anaesthesiol 2021; 38:975–984

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 Haemodynamic events under pupillometry-guided analgesia 981

Fig. 3 Percentage of patients experiencing at least one haemodynamic event during the intervention period

PRD-guided group
100
Control group

*
80
Percentage of patients experiencing
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60
at least 1 event

**

40

20

e g
lin PM

lin PM
lin Hg

lin H
se m
se B

se B
se m

e
e

ba 0 m
ba 0 m

ba 90

ba 55
m R>

m R<
m <9
m 14

fro H

fro AP

fro H
fro P>

se S
se A
S

se

se
ea

ea
ea
ea

cr

cr
cr
cr

in

de
de
in

%
%

%
%
20
20

20
20
or
or

or
or
or

Fisher’s exact test, P ¼ 0.004; P < 0.001.

(regardless of the actual drug) were administered in the remifentanil consumption compared with standard prac-
PRD-guided group as per protocol (P ¼ 0.022; Table 2). tice but it had no impact on immediate postoperative
morphine consumption. Hypertension and tachycardia
If we focused on three key events (laryngoscopy, skin
were more frequent in the PRD-guided group without
incision with insertion of the trocars and initiation of
a clinically significant increase in pupil diameter and were
pneumoperitoneum), systolic arterial pressure was signif-
treated via the administration of more antihypertensive
icantly greater in the PRD-guided group compared with
drugs. Overall, these results suggest that PRD-guided
the control group (Table 3). The percentage variation in
antinociception reduces intra-operative opioid adminis-
pupil diameter was greater in the PRD-guided group
tration, provides a better understanding of the origins of
during laryngoscopy and skin incision than the control
haemodynamic alterations observed during laparoscopic
group but the increase remained below 15%. Changes in
surgery and leads to a more tailored and physiological
pupil diameter were similar in both groups during
administration of intra-operative opioids.
peritoneal insufflation.
The current dogma of intra-operative nociception man-
Immediate postoperative care agement with opioids has been challenged over the
Postoperative data are described in Table 4. Median years.19,20 Opioids are used traditionally to correct
[IQR] morphine requirements in the PACU and total intra-operative hypertension and ensure haemodynamic
morphine consumption (intra-operative and PACU) were stability during anaesthesia. Provided that PRD is a
similar in the two groups. SVS pain scores were not genuine reflection of nociception, the present study
significantly different between the two groups at any shows that haemodynamic events during laparoscopy
major time point (Table 4). may be related to causes other than excess nociception.
If PRD is a genuine reflection of nociception, then these
The incidence of postoperative nausea and vomiting and
events may be treated appropriately with antihyperten-
length of stay in the recovery room were similar in both
sive agents rather than analgesic drugs.
groups (Table 4).

Discussion Opioid consumption

The present study used pupillometry to guide intra- Several nociception monitors have been evaluated to
operative antinociception during elective laparoscopic guide intra-operative opioid administration.10,21–26 In
surgery, which allowed us to reduce intra-operative three randomised controlled trials, compared with

Eur J Anaesthesiol 2021; 38:975–984

Copyright © European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.
 982 Guerci et al.

Table 3 Haemodynamic events, variation in pupillary reflex dilation and effect site remifentanil concentrations during laryngoscopy, skin
incision and initiation of pneumoperitoneum

Variable PRD-guided group (n U 48) Control group (n U 47) P value

Laryngoscopy
Total number of modifications in Ce Remi 32 1 N/A
Ce Remi (ng ml1) 2.5 [2.5 to 3.0] 4 [3.5 to 5.0] <0.0001
Change in pupil diameter (%) 10 [6 to 13] 5 [3 to 8] <0.0001
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SAP (mmHg) 96 [87 to 107] 91 [82 to 97] 0.015

Hypertension 29 (60.4) 14 (32.6) 0.004
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Hypotension 37 (77.1) 42 (89.4) 0.170

Tachycardia 15 (31.6) 2 (4.3) <0.001
Bradycardia 6 (12.5) 1 (2.1) 0.111
Intubation-to-incision time (min) 23 [20–30] 22 [19–28] 0.610
Incision
Ce Remi (ng ml1) 2.8 [2.5 to 3.0] 4 [3.5 to 4.5] <0.0001
Change in in pupil diameter (%) 10 [6 to 13] 4 [4 to 5] <0.0001
SAP (mmHg) 99 [91 to 111] 94 [86 to 99] <0.013
Hypertension 2 1 >0.99
Hypotension 8 17 0.038
Tachycardia 2 2 >0.99
Bradycardia 7 8 0.785
During pneumoperitoneal insufflation
Ce Remi (ng ml1) 2.7 [2.5 to 3.0] 4 [3.5 to 4.0] <0.0001
Change in pupil diameter (%) 2 [0 to 7] 0 [2 to 4] 0.462
SAP (mmHg) 119 [98 to 141] 105 [94 to 120] 0.0145
Hypertension 12 2 0.007
Hypotension 6 8 0.573
Tachycardia 3 2 >0.99
Bradycardia 4 7 0.199

Data are n (%) or median [IQR]. Haemodynamic parameters were compared with the baseline values obtained before induction of anaesthesia. Hypertension (SAP
>140 mmHg or increase in SAP >20%), hypotension (SAP <90 mmHg or decrease in SAP >20%); tachycardia (HR >90 min1 or increase >20%), bradycardia (HR
55 min1 or decrease >20%). Ce Remi, effect site remifentanil; HR, heart rate; PRD, pupillary reflex dilation; SAP, systolic arterial pressure.

standard practice, the intra-operative remifentanil con-
sumption was consistently reduced by 25 to 50% when its
administration was guided by a nociception moni-
tor.10,21,25 Although intra-operative remifentanil con-
sumption was higher in the present study, a similar
decrease in remifentanil consumption (35.7%) was
observed in the PRD-guided group.
While using pupillometry with PRD analysis to guide
opioid administration, two critical points should be con-
sidered: the choice of a clinically relevant threshold
(percentage variation in pupil diameter) that is consid-
ered to represent inadequate antinociception; and the
magnitude and timing of the decrease in remifentanil
concentrations. Sabourdin et al.21 selected a PRD thresh-
old of 30%, but Isnardon et al.,27 using a standardised
noxious stimulus that was similar to ours, reported a PRD
increase of up to 20% in response to the noxious stimulus
applied on the unblocked leg compared with the leg
treated with a nerve block. Therefore, a threshold of
15% was considered relevant in our study.16–18

Table 4 Immediate postoperative care

Variable PRD-guided group (nU48) Control group (nU47) P value

Time to extubation (min) 7.5 [5 to 10] 7.5 [5 to 10] 0.90
Morphine consumption in PACU (mg kg1) 0 [0 to 0.13] 0.03 [0 to 0.1] 0.56
Total morphine consumption (mg kg1) 0.13 [0.1 to 0.5] 0.15 [0.11 to 0.4] 0.18
Nausea/vomiting 4 (8.3) 3 (6.4) >0.99
Verbal rating scale at PACU admission 0.42
No pain 26 (54) 22 (47)
Slight pain 8 (17) 5 (11)
Moderate pain 5 (10) 10 (21)
Severe pain 8 (17) 10 (21)
Unbearable pain 1 (2) 0 (0)
Verbal rating scale at PACU discharge 0.052
No pain 17 (35.4) 20 (42.6)
Slight pain 29 (60.4) 19 (40.4)
Moderate pain 2 (4.2) 8 (17.0)
Severe pain 0 (0) 0 (0)
Unbearable pain 0 (0) 0 (0)
PACU length of stay (min) 110 [90 to 125] 105 [80 to 130] 0.44

Data are median [IQR] or number (%). PACU, postanaesthesia care unit.

Eur J Anaesthesiol 2021; 38:975–984

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The magnitude and timing of the decrease in Ce remi-
fentanil are different between different studies, varying
from steps of 0.5 ng ml1 every 60 s in some studies to
0.2 ng ml1 every 5 min in our study. Remifentanil
changes were performed after two reliable and consistent
measures in the present study. The adaptation of the
intra-operative opioid dose was consequently slower,
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which may explain the higher remifentanil consump-
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tion.10,21
Whether nociception monitoring to guide intra-operative
opioid use has benefits for postoperative opioid consump-
tion and postoperative pain are debatable.10,13,21,24 High
intra-operative remifentanil often results in increased
postoperative morphine requirements secondary to the
development of opioid-induced hyperalgesia.9 No differ-
ence in immediate postoperative morphine consumption
or pain scores between the groups was observed in our
study, which is consistent with previous studies.10,11,13
Angst28 reported that an increase in postoperative mor-
phine consumption occurred only for remifentanil doses
ranging between 0.20 and 0.40 mg kg1 min1, which are
greater than the doses in our control group.
Haemodynamic events
In a meta-analysis of randomised controlled trials, Grue-
newald et al.24 reported no clear benefits of nociception
monitors on the incidence of intra-operative haemody-
namic events. The number of hypotensive events were
similar in the two groups in the present study. Similarly,
Defresne et al.12 observed hypotension in 45 and 54% of
patients in the control and nociception-guided groups
using the Surgical Pleth Index (SPI, GE Healthcare,
Chicago, Illinois, USA), respectively. However, Meijer
et al.10 observed less hypotension in the nociception-
guided group using the nociception level index (NOL,
Medasense Biometrics Ltd., Ramat Gan, Israel). A sig-
nificantly higher number of hypertensive events were
documented in our PRD-guided group. As no increase in
pupil diameter above the predefined threshold of 15%
occurred during several of these hypertensive events,
precluding inadequate antinociception if PRD is a genu-
ine reflection of nociception, the number of administra-
tions of antihypertensive drugs increased. Similarly,
Sabourdin et al.21 reported increased use of nicardipine
in the PRD-guided group. Whether transient hyperten-
sive events have a significant impact on outcomes is
not known.
CO2 insufflation to create pneumoperitoneum during
laparoscopy results in haemodynamic changes.5,8,29,30
Our study adjusted ventilation to maintain end-tidal
carbon dioxide between 4.6 and 5.3 kPa in both groups.
Consequently, changes in blood pressure induced by
potential hypercarbia were unlikely and should be similar
in both groups. However, increases in intra-abdominal
pressure induce hormone release,5 and plasma concen-
trations of cortisol, catecholamines, vasopressin, and
Copyright © European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.
Haemodynamic events under pupillometry-guided analgesia 983
renin increase.5 Analysis of the PRD during laparoscopy
in our study confirmed episodes of hypertension unre-
lated to an excessive PRD response and the latter may
help to differentiate haemodynamic changes because of
inadequate antinociception from changes secondary to
other causes.
Although the monitoring of antinociception remains con-
troversial, regardless of the type of monitor used, moni-
toring may improve our understanding of the causes of
haemodynamic responses during laparoscopy. The short-
term and long-term benefits of these monitors for patients
remain to be determined. In our study, pupillometry
distinguished between noxious-related and nonnox-
ious-related intra-operative events and resulted in
reduced intra-operative outcomes.
Limitations
First, our study included mostly young, healthy patients,
which precludes the extrapolation of our results to old
and frail patients. Second, PRD was measured every
10 min, and pupillometry does not allow continuous
monitoring. Therefore, short episodes of pupil dilation
may have been missed. Also, arterial blood pressure was
not continuously measured. Third, the down titration
protocol for remifentanil was gradual and slow. The
difference in remifentanil consumption would likely
have been more marked with larger and hence quicker
reductions of the remifentanil target concentration.
Fourth, a tetanic stimulation of 100 Hz at 60 mA for 5 s
was used to produce an intense noxious stimulus; this
may not represent the genuine level of nociception at
laryngoscopy or skin incision. Fifth, the influence of the
blood carbon dioxide content on pupil diameter has not
been elucidated, but some data suggest that hypercarbia
may cause myosis.31 Finally, hyperalgesia and chronic
pain were not assessed, and further studies are necessary
to confirm any possible benefits.
Conclusion
PRD analysis may help to differentiate the cause of the
haemodynamic variations during laparoscopic surgery
and result in reduced intra-operative remifentanil con-
sumption secondary to a tailored management of anti-
nociception. However, an increased number of intra-
operative hypertensive episodes were observed. The
reduction in remifentanil consumption did not affect
postoperative morphine consumption or pain scores. Fur-
ther studies are required to extend these findings to
surgery other than laparoscopy.
Acknowledgements relating to this article
Assistance with the study: we thank our patients and all nurse
anaesthetists who made this trial possible. We are grateful to the
APICIL Foundation, which consistently supports clinical research
to improve pain management.
Eur J Anaesthesiol 2021; 38:975–984
 984 Guerci et al.
Financial support and sponsorship: this work was supported by the
Department of Anaesthesiology and Critical Care Medicine, Uni-
versity Hospital of Nancy, Nancy France. This study was also
supported by a grant from the APICIL Foundation to buy a
video pupillometer.
Conflict of interest: none.
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Presentation: preliminary data were presented at the national SFAR
meeting (French Society of Anaesthesiology and Critical Care
XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 01/23/2024
Medicine).
The authors would like to thank Dr L
ea Petry for her involvement
in the study.
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