Beha io al pain scales, i al signs, and pupilome y o pain assessmen in
he c i ically ill pa ien : A c oss sec ional s udy
☆
Yolanda L´
opez-De-Audícana-Jimenez-De-Abe as u i
a,b,c,*,1
, Ana Vallejo-De-La-Cue a
b,c,2
,
Naia a Pa aza-Diez
d,e,3
a
Uni e si y o he Basque Coun y UPV/EHU, Vi o ia-Gas eiz School o Nu sing, Jos´
e A xo egi, Vi o ia-Gas eiz 01009, Spain
b
Bioa aba Heal h Resea ch Ins i u e, Jose A xo egi, Vi o ia-Gas eiz 01009, Spain
c
Osakide za Basque Heal h Se ice, A aba Uni e si y Hospi al, Jose A xo egi, Vi o ia-Gas eiz 01009, Spain
d
Epidemiology and Public Heal h G oup, Bioa aba Heal h Resea ch Ins i u e, Vi o ia-Gas eiz, Spain
e
Resea ch Ne wo k on Ch onic Diseases, P ima y Ca e, and Heal h P omo ion RICAPPS, Mad id, Spain
ARTICLE INFO
Keywo ds:
C i ical illness
Nocicep ion
Pain Measu emen
Re lex, Pupilla y
ABSTRACT
Backg ound: De ec ing pain in seda ed c i ically ill pa ien s equi es u mos a en ion.
Aim: To assess he pain in mechanically en ila ed c i ically ill pa ien s wi h he Beha io al Pain Scale (BPS),
Beha io al Indica o s Pain Scale (ESCID), he pupilla y dila ion esponse (PDR), and i al signs.
Design: C oss-sec ional s udy
Me hods: The s udy was conduc ed be ween Ma ch and Decembe 2019, in ol ing pa ien s wi h a baseline BPS o
3, ESCID o 0, and RASS be ween −1 and −4. Pa ien s wi h mobili y limi a ions o al e ed pupilla y e lexes we e
excluded. We measu ed be o e and a e non-pain ul s imula ion (NP) ollowed by 10–20–30–40 mA s imuli and
endo acheal aspi a e (ETA). The p ima y ou come was he pain measu ed wi h BPS and ESCID scales and PDR
wi h AlgiScan®pupilome e de ined as BPS≥4, ESCID≥1, and PDR≥11,5 %. We pe o med a desc ip i e s udy
and analyzed he ag eemen be ween pain de ec ion me hods.
Resul s: Thi y-one pa ien s we e included, and 183 measu emen s we e eco ded. The scales showed minimal
changes. App oxima ely 30 % o pa ien s epo ed pain a a 30 mA s imulus, inc easing o o e 70 % a e ETA.
The PDR anged om 2 % o 6-33% on he ETA, e en in pain- ee pa ien s, wi h pain incidence be ween 70 %
and 100 % o he 40 mA and ETA s imuli. Vi al signs did no show ele an changes. The PDR had o e 90 %
ag eemen wi h scales o no pain. Fo highe -in ensi y s imuli, ag eemen anged om 60 % o 80 %.
Disag eemen occu ed when he e was no pain by scales (BPS<4; ESCID<1) and pain wi h PDR (PDR≥11.5).
Conclusions: Pain beha io al sco es and i al signs we e low in c i ically ill pa ien s. PDR de ec ed a nocicep i e
pain esponse in no-pain pa ien s.
1. In oduc ion
Pain is a equen symp om in medical and su gical c i ical ca e uni s
and is s ill emembe ed a discha ge [1]. Mul iple causes o pain make
c i ically ill pa ien s pa icula ly ulne able [2]. In e na ional guide-
lines emphasize he need o adequa e pain assessmen , moni o ing, and
analgesia adjus men o imp o e pa ien com o , and adjus ed use o
seda i e d ugs [3,4].
Valida ed beha io al scales, such as he Beha io al Pain Scale (BPS)
and Pain Beha io Scale (ESCID), a e ecommended o assessing pain in
non-communica i e pa ien s. Howe e , medica ion and he se e i y o
he unde lying disease may diminish he pa ien ’s beha io al esponse
o pain, pa icula ly in seda ed and mechanically en ila ed pa ien s [5,
6].
☆
T ial egis a ion Phase 1 o he p ojec PUPIPAIN ClinicalT ials.go Iden i ie : NCT04078113
* Co esponding au ho a : Uni e si y o he Basque Coun y UPV/EHU,Vi o ia-Gas eiz School o Nu sing, Jos´
e A xo egi, Vi o ia-Gas eiz 01009, Spain.
E-mail add esses: [email p o ec ed],[email p o ec ed] (Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i), delacue a_79@
ho mail.com (A. Vallejo-De-La-Cue a), [email p o ec ed] (N. Pa aza-Diez).
1
ORCID iD: h ps://o cid.o g/0000-0001-5703-2706
2
ORCID iD:h ps://o cid.o g/0000-0003-4094-6506
3
ORCID iD:h ps://o cid.o g/0000-0002-5902-0351
Con en s lis s a ailable a ScienceDi ec
Clinical Neu ology and Neu osu ge y
jou nal homepage: www.else ie .com/loca e/clineu o
h ps://doi.o g/10.1016/j.clineu o.2024.108644
Recei ed 27 Sep embe 2024; Recei ed in e ised o m 16 No embe 2024; Accep ed 16 No embe 2024
Clinical Neu ology and Neu osu ge y 247 (2024) 108644
A ailable online 18 No embe 2024
0303-8467/© 2024 The Au ho (s). Published by Else ie B.V. This is an open access a icle unde he CC BY-NC-ND license (
h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/ ).
Ongoing e o s a e essen ial o enhance pain assessmen and man-
agemen p ecision ools o pa ien s wi h a limi ed abili y o exp ess pain
beha io ally. S anda dized assessmen and eco ding o pain in non-
communica i e pa ien s is insu icien . Less han hal o in ensi e ca e
p o essionals e alua e he p esence o pain [7,8]. Subjec i e e alua ion
based on clinical expe ience emains a common p ac ice o he de ec-
ion o pain in hese pa ien s [9,10]. I is impo an o no e ha i al
signs a e un eliable indica o s o assessing pain [11]. Howe e ,
heal hca e p o essionals some imes conside he a iabili y o i al signs
as a ac o in e alua ing and making he apeu ic decisions ega ding a
pa ien ’s pain si ua ion. This si ua ion highligh s he daily limi a ions
and di icul y in de ec ing pain.
Pupilla y dila ion is a sensi i e indica o o pain in seda ed pa ien s
in a su gical en i onmen [12,13]. The s udy will explo e whe he
au onomic esponses, measu ed h ough ideo pupillome y, can help
de ec pain in seda ed c i ically ill pa ien s. I will assess eac ions o
non-pain ul s imuli, calib a ed elec ical nocicep i e s imuli (10, 20, 30,
and 40 mA), and endo acheal aspi a ion (ETA) s imuli using he BPS,
ESCID, pupilla y e lex (PDR), and i al signs. Addi ionally, he s udy
analyzes he beha io o he ools in pa ien s ca ego ized by pain ac-
co ding o he BPS.
2. Me hods
2.1. S udy design
I was a c oss-sec ional s udy conduc ed be ween Ma ch 2019 and
Decembe 2019. Pa ien ec ui men and in e en ion p o ocol mea-
su emen s we e ca ied ou du ing he i s week o ICU admission.
2.2. Pa ien s
Pa ien s we e selec ed in he o de o admission o he uni . Pa ien s
wi h he ollowing c i e ia we e included: o e eigh een yea s o age, on
mechanical en ila ion, wi h a baseline BPS o h ee and a RASS be-
ween one and ou , and unable o communica e e bally. Exclusion
c i e ia included pa ien s wi h limi ed beha io al exp ession o pain (in
ea men wi h muscle elaxan s and, neu omuscula diseases), pa ien s
wi h diso de s o he pupilla y esponse (oph halmological pa hologies,
in ol emen o he hi d c anial ne e, Glasgow less han six, in ac a-
nial hype ension), and pa ien s in ea men wi h epineph ine, cloni-
dine, dexmede omidine, amadol, ke amine, ad enaline, Ca
an agonis s, o an ieme ics.
2.3. P o ocol and measu emen s
All pa ien s we e gi en a p o ocol o s imuli, s a ing wi h a non-
pain ul s imula ion (NP) ollowed by 10, 20, 30, and 40 mA s imuli
(Fig. 1). The non-pain ul s imulus used was he ubbing o a gauze pad
on he o ea m. A e hem, a po en ially pain ul p ocedu e, such as
endo acheal suc ioning (ETA) was pe o med [1,2]. Baseline alues and
maximum pos -s imulus a ia ions in all indica o s we e eco ded. Fi e
minu es we e wai ed be ween each nocicep i e s imulus un il he pa-
ien eco e ed he baseline alues.
The pa ien ’s baseline pain was assessed be o e he p o ocol and all
pa ien s began i wi h a BPS alue o h ee.
The p o ocol was conduc ed in a con olled en i onmen . In he hou
p eceding he bs imula ion, we a oided pain ul in e en ions and
silenced o p e en and minimize dis ac ions. The analgoseda ion
egimen and he es o he medica ions emained cons an be o e,
du ing, and a e he s imuli.
Th ee esea che s measu ed beha io al scales and pe o med
pupillome y simul aneously. A collabo a ing uni membe eco ded
i al signs om he bedside moni o . All measu emen s pe o med by
he in es iga o s we e blinded o each o he . The nu se in cha ge o he
pa ien pe o med he NP and ETA s imuli.
2.4. Va iables
2.4.1. BPS and ESCID scales
The BPS scale is a alida ed scale wi h psychome ic p ope ies o
assess pain in seda ed pa ien s [14] whose sco e anges om 3 o 12
while he ESCID, a scale ecommended by he Spanish Socie y o
In ensi e Ca e Medicine and Co ona y Uni s [6], om 0 o 10. Sco es o
1–3 indica e mild o mode a e pain, 4–6 indica e medium o se e e pain,
and abo e 6 indica e se e e pain.
Ou uni ’s analgesia p o ocol included he alida ed BPS and ESCID
scales. Values o BPS g ea e han o equal o ou and ESCID g ea e
han o equal o one we e conside ed pain [6,15,16].
2.4.2. Vi al signs
Vi al signs, hemodynamic pa ame e s (hea a e-HR, an in asi e
sys olic blood p essu e-SBP, dias olic blood p essu e-DBP, and medium
blood p essu e-MBP), espi a o y pa ame e s ( espi a o y a e-RR and
pulse oxime y sa u a ion-02 Sa ) we e eco ded wi h con inuous mul-
imodally moni o s.
Va ia ions highe han 10 % we e conside ed indica i e o pain.
2.4.3. Pupil dila ion esponse
The pupilla y dila ion e lex is a physiological au onomic esponse o
s imuli. In his s udy, PDR was quan i ied as he pe cen age change om
he ini ial size o he pupil, measu ed objec i ely using ideo pupill-
ome y. Fo his pu pose, he AlgiScan®po able ideo pupillome e (ID
Company, Ma seille, F ance) was used.
The s udy employed bo h Dila ion Re lex Mode (DRP) o con inuous
measu emen s du ing he NP and ETA s imulus, and Te anus Mode o
assessing esponses o calib a ed elec ical s imuli (10–40 mA). These
calib a ed nocicep i e s imuli we e applied h ough an elec ode placed
on a clean, uninju ed a ea o skin o e he ulna ne e a he w is .
Measu emen s we e made a he op imal impedance le el, as indica ed
by he pupilome e and we e aken wi h a 5 minu es wai ime be ween
each.
Pupillome y was conduc ed on one andomly selec ed eye, while he
o he was closed. We used a p o ec i e silicone sc een on he s udy eye.
Measu emen s we e made once he pupil had s abilized in da kness.
A PDR alue g ea e han 11.5 % was conside ed pain, as indica ed
by p e ious s udies [17].
2.5. S a is ical analysis
This s udy is pa o PUPIPAIN p ojec (ClinicalT ials.go Iden i ie :
NCT04078113), o which a sample size o a leas 50 pain- esponse
40mA
10mA
20mA
30mA
NP
ETA
NP ETA
Fig. 1. S udy p o ocol design. NP: Non pain ul es imulus; mA: Miliampe es; ETA: Endo acheal aspi a ion; 5 minu es was main ained be ween s imula ions.
Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i e al. Clinical Neu ology and Neu osu ge y 247 (2024) 108644
2
measu es acco ding o BPS was es ablished [17].
Pa ien s’demog aphic cha ac e is ics we e desc ibed using medians
and in e qua ile ange o equency analysis as app op ia e. We con-
duc ed a desc ip i e and g aphical s udy o he sco es o BPS, ESCID,
PDR, and i al signs. The pain sco e o he di e en ools acco ding o
he BPS pain classi ica ion was calcula ed. The ag eemen be ween he
BPS and he o he pain assessmen ools was also e alua ed using he
kappa index. The analyses we e epea ed o s udy he pain o he
di e en ools acco ding o PDR.
S a is ical analysis was pe o med wi h IBP SPSS S a is ics, e sion
23 o Windows. A s a is ical signi icance le el o p=0.05 was consid-
e ed in he s udy.
The da a om he s udy a e a ailable in a p i a e eposi o y o
Basque Heal h Sys em as equi ed by Spanish law [Real Dec e o 1090/
2015].
2.6. E hical conside a ions
The Clinical Resea ch E hics Commi ee o Basque Coun y app o ed
his s udy (CEIC-X; in e nal code: PI2017100). All pa ien s we e he-
modynamically s able, ecei ing con inuous in a enous analgesics and
seda i es. Rela i es o legal ep esen a i es we e in o med and p o ided
w i en consen o pa icipa ion.
3. Resul s
3.1. Demog aphic and clinical cha ac e is ics o pa icipan s
Thi y-one pa ien s we e included, and 183 measu emen s we e
eco ded. Fig. 2 shows he lowcha o he ec ui ed pa ien s and he
gene al cha ac e is ics o he pa ien s a e p esen ed in Table 1. The
mean age o he 31 included pa ien s was 62.9 (17.1) yea s. They had a
Cha lson como bidi y index o 3.59 (0.55), an APACHE II sco e o 21
(16.5–23.5), and 7.4 % died du ing ICU admission [18]. All pa ien s
ecei ed an analgesic ea men egimen and had a mode a e le el o
seda ion wi h a BIS o 63 (19.46) and an RASS o −3.39 (0.76).
3.2. Va ia ion in scales, i al signs and PDR sco es, and incidence o pain
a e s imula ions
Fig. 3 g aphically illus a es he ools’beha io in esponse o he
s imuli. We ha e included he esul s in supplemen a y Table SDC 1 o
u he de ails.
ASSESSED FOR ELIGIBILITY
(n= 50)
ENROLLED
(n= 32)
Excluded pacien s (n=18):
1. Family e usal (n=6)
2. No mee�ng inclusion c i e ia (RASS>-1) (n=6)
3. No amily e e ences (n=4)
4. Technical p oblem (n=2)
Pa�en excluded o sa e y (n=1)
FINAL SAMPLE
(n= 31)
GLOBAL MEASUREMENTS
(n= 183)
Measu emen s no ca ied ou (n=3):
1. P o ocol adjus men (n=2)
2. Incomple e p o ocol (n=1)
Fig. 2. Flowcha o ec ui ed pa ien s.
Table 1
Gene al cha ac e is ics o he pa ien s (n=31).
Cha ac e is ics Values
Age (y ) mean (SD) 62,35 (17,08)
Sex a io Men, Women, n (%) 19/12 (61.3/
38.7)
Body mass index (kg/m
2
), median (25–75 h pe cen ile) 27 (24−30)
Acu e Physiology And Ch onic Heal h E alua ion II, median
(25–75 h) pe cen ile)
21 (16.5–23.5)
Cha lson como bili y Index, mean (SD) 3.59 (0.55)
ICU mo ali y, n (%) 4 (14.8)
A e -ICU mo ali y, n (%) 2 (7.4)
Glasgow, median (25–75 h pe cen ile) 15 (15−15)
Bispec al index (BIS), mean (SD) 63 (19.46)
RASS, mean (SD) −3.39 (0.76)
Admission Values
Acu e espi a o y ailu e n (%) 8 (25.8)
Pos ope a i e n (%) 10 (32.2)
Sepsis n (%) 9 (29.1)
Mul iple auma n (%) 4 (12.9)
Seda i e, analgesic and asoac i e d ugs du ing he
p ocedu e
Values
P opo ol, n (%) 9 (29.03)
Dose, (mg/kg/h) mean (SD) 1.49 (0.88)
Midazolam, n (%) 16 (51.6)
Dose (mg/kg/h), mean (SD) 0.09 (0.05)
Fen anyl, n (%) 20 (64.5)
Dose (µg/kg/h), mean (SD) 1.14 (0.74)
Remi en anil, n (%) 8 (25.8)
Dose (µg/kg/h), mean (SD) 7.05 (4.12)
Mo phine, n (%) 3 (9.6)
Dose (mg/kg/h), mean (SD) 1.00 (0.44)
No epineph ine, n (%) 22 (71)
Dose (µg/kg/min), mean (SD 0.2 (0.13)
Dobu amine, n (%) 3 (9.7)
Dose (µg/kg/min), mean (SD) 4.10 (0.97)
Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i e al. Clinical Neu ology and Neu osu ge y 247 (2024) 108644
3
No signi ican changes we e no ed in median sco es o BPS and
ESCID a e 10–40 mA s imuli, achie ing sco es o 3 and 0, espec i ely.
Less han 10 % o he pa ien s showed pain (BPS≥4 o ESCID≥1) o he
lowe -in ensi y s imuli, bu his inc eased wi h in ensi y: nea ly 30 % o
30 mA, o e 40 % o 40 mA, and o e 70 % o ETA.
Simila ly, i al signs show a a ia ion o no mo e han 3 %, wi h less
han 25 % o pa ien s expe iencing pain (Va .≥10 %) e en a he highes
in ensi ies.
PDR showed a 2 % and 3 % a ia ion o no-pain (NP) and 10 mA
s imuli. This inc eased om 6 % o 34 % wi h highe in ensi ies (20 mA
o ETA). Less han 7 % showed pain (PDR≥11,5 %) wi h NP o 10 mA;
howe e , 30 % epo ed pain wi h 20–30 mA s imuli, 70 % wi h 40 mA,
0
5
10
15
20
25
30
35
40
0
10
20
30
40
50
60
70
80
90
100
NP 10mA 20mA 30mA 40mA ETA
sco e o he di e en ools ep esen ed by lines
s abybde nese pe niaph iws nei ap%
BPS ESCID PDR
BPS sco e ESCID sco e PDR sco e
0
5
10
15
20
25
30
35
40
0
10
20
30
40
50
60
70
80
90
100
NP 10mA 20mA 30mA 40mA ETA
sco e o he di e en ools ep esen ed by lines
% pa ien s wi h pain ep esen ed by ba s
SBP DBP MBP
HR RF O2 Sa
HR sco e RF sco e SBP sco e
DBP sco e MBP sco e O2 Sa sco e
Fig. 3. Pain ou come wi h di e en ools and sco es. BPS: Beha io al Pain Scale; DBP: Dias olic blood p essu e; ESCID: Beha io al Indica o s o Pain Scale; ETA:
Endo acheal aspi a ion; HR: Hea a e; IQR: In e qua ile ange; MBP: Mean a e ial blood p essu e; N: pa ien numbe ; NP: Non-pain ul; PDR: Pupilla y dila ion
e lex; RF: Respi a o y a e; SBP: Sys olic blood p essu e; O2 SAT: Oxygen sa u a ion.
Table 2
Tool sco es acco ding o BPS. Medians and in e qua ile ange.
NP 10 mA 20 mA 30 mA 40 mA ETA
ESCID       
BPS<4 BPS≥4 0 (0−0)
–
0 (0−0)
–
0 (0−0)
2 (1-x)
0 (0−0)
2 (1–2.25)
0 (0−0)
2 (1−3)
0 (0−0)
4 (2.25–4.75)
PDR       
BPS<4 BPS≥4 2 (1−5)
–
3 (0−7)
–
6 (3.5–11.5)
14.5 (12-xx)
7 (3.5–10.5)
19.5 (6.2–44.2)
15 (8−18)
20 (12.5–44.5)
33 (18−53)
37.5 (25–50.7)
HR       
BPS<4 BPS≥4 0 (−1.4–1.1)
–
1 (−1−2)
–
0 (−1.7–1.8)
−1,2 (−1.2-xx)
0 (−0.5–3.6)
0.5 (−1.2–3)
1.2 (−1.2–2.1)
0 (0−3)
1.6 (0–7.5)
1.6 (−1.5–8.3)
RF       
BPS<4 BPS≥4 0 (0−0)
–
0 (0−0)
–
0 (0−0)
−2.6 (−5.2-xx)
0 (0−0)
0 (0−0)
0 (0−0)
0 (0–12.9)
0 (0–8.3)
0 (0–15.1)
SBP       
BPS<4 BPS≥4 0 (−1.1–1.7)
–
0 (−0.7–4.4)
–
0 (−0.8–1.7)
−1.3 (−3.7-xx)
0.8 (−0.3–2.8)
0.3 (0–4.6)
0.8 (−1.6–3.1)
0 (−1.3–5.2)
1.4 (−0.8–7.)
3 (−0.5–7.7)
DBP       
BPS<4 BPS≥4−1.3(−3.8–1.7)
–
1.4 (−1.6–2.6)
–
0 (−1.7–1.8)
0.8 (−1.7-xx)
1.5 (−0.7–3.3)
1.3 (−0.4–5.1)
4.4 (−2.7–5.5)
0 (−2.7–4.4)
1.2 (−7.3–5)
1.6 (−3.6–10.4)
MBP       
BPS<4 BPS≥4 0 (−2.6–2.7)
–
1.1 (−1.3–2.3)
–
0 (−0.5–2)
−0.5 (−2.5-xx)
0 (−1.7–3.5)
0.92 (−0.2–6)
1.1 (−2.7–3.5)
0 (−2.1–3.7)
2.4 (−2.6–8.1)
1.2 (−1.3–6.9)
O2 Sa       
BPS<4 BPS≥4 0 (0−0)
–
0 (0−0)
–
0 (0−0)
0 (0−0)
0 (0−0)
0 (−1.02–0)
0 (0−0)
0 (0−0)
0 (0−0)
0 (−1−0)
DBP: Dias olic blood p essu e; ESCID: Beha io al Indica o s o Pain Scale; ETA: Endo acheal aspi a ion; HR: Hea a e; IQR: In e qua ile ange; MBP: Mean a e ial
blood p essu e; NP: Non-pain ul; PDR: Pupilla y dila ion e lex; RF: Respi a o y a e; SBP: Sys olic blood p essu e; O2 SAT: Oxygen sa u a ion; –: No da a.
Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i e al. Clinical Neu ology and Neu osu ge y 247 (2024) 108644
4
and 100 % wi h ETA.
3.3. Va ia ion in scales, i al signs, and PDR sco es ca ego ized by BPS as
pain, no pain pa ien
Table 2 p esen s he ool sco es o pa ien s p e iously classi ied wi h
and wi hou pain acco ding o BPS.
In he non-pain s imuli, he ESCID sco ed 0 o all pain- ee pa ien s,
while he PDR eco ded 2 %, and i al signs showed no mo e han 1 %
a ia ion. The PDR inc eased wi h s imulus in ensi y, ising om 2 % o
6–33 % in he ETA.
In pain pa ien s, acco ding o he BPS, he ESCID showed sco es o 2
in he 20–40 mA s imuli and 4 in he ETA. PDR sco es inc eased wi h
s imulus in ensi y om 14.5 % a 20 mA o 37.5 % in he ETA, and all
i al signs showed a ia ions o mo e han 1 % excep espi a o y a e,
which did no change.
All he ools had a lowe sco e in cases whe e he BPS did no iden i y
pain compa ed o hose whe e i did.
3.4. Ag eemen be ween BPS scale wi h i al signs and PDR as pain
assessmen ools
Table 3 shows he ag eemen le els o classi ying pa ien s’pain
using he BPS scale compa ed o o he a ailable pain assessmen ools.
The ESCID beha io al scale had a mo e han 90 % conco dance wi h
he BPS o all in ensi y s imuli. The kappa index was abo e 0.815.
Disc epancies we e ound in he ETA, wi h alse posi i es and nega i es
occu ing wi h he ESCID.
Vi al signs had g ea e han 90 % ag eemen wi h he BPS a he NP
and 10 mA s imulus, bu his d opped o 40 % a highe in ensi y le els.
The kappa index ob ained o each s imulus was no highe han 0.1. The
disc epancies we e obse ed wi h BPS≥4 and i al sign a ia ions
<10 %.
The PDR had o e 90 % ag eemen wi h he BPS in he NP and 10 mA
s imuli. Fo highe -in ensi y s imuli, ag eemen anged om 60 % o
80 %. The Kappa index o each s imula ion anged om 0.3 o 0.5.
Disag eemen s occu ed mainly in cases when he BPS indica ed no pain
(BPS<4) bu he PDR indica ed pain (PDR≥11.5).
3.5. Va ia ion in he scales, and i al signs sco es in pa ien s ca ego ized
by PDR as pain, no pain pa ien
Table SDC 2 in he supplemen a y ma e ial p esen s he esul s o
pain assessmen s classi ied by he PDR ool.
The BPS and ESCID showed sco es o h ee and ze o in pa ien s who
did no show pain acco ding o he PDR, e en wi h he 30 and 40 mA
s imuli. In con as , pa ien s expe iencing pain (PDR ≥11.5 %) sco ed
ou and h ee on hese scales. All pa ien s epo ed pain du ing ETA.
Fo i al signs, pa ien s wi hou pain showed a ia ions om
−3–1.5 %, while hose wi h PDR ≥11.5 % had a ia ions anging om
Table 3
Ag eemen be ween BPS and di e en pain assessmen ools.
NP 10 mA 20 mA 30 mA 40 mA ETA
ESCID Ag eemen N (%) 31 (100) 30 (96.8) 31 (100) 30 (96.7) 27 (96.4) 29 (93.6)
Disag eemen N (%)
BPS<4; ESCID≥1
BPS≥4; ESCID<1
–
–
–
1 (3.2)
1 (3.2)
–
–
–
–
1 (3.2)
–
1 (3.2)
1 (3.6)
1 (3.6)
–
2(6,4)
1 (3.2)
1 (3.2)
Kappa (p) – – 1.00** 0.924** 0.929** 0.815**
PDR Ag eemen N (%) 29 (93.5) 29 (93.5) 24 (77.5) 25 (80.7) 18 (64.3) 24 (77.4)
Disag eemen N (%)
BPS<4; PDR≥11.5
BPS≥4; PDR<11.5
2 (6.5)
2 (6.5)
–
2 (6.5)
2 (6.5)
–
7 (22.6)
7 (22.6)
–
6 (19.4)
3 (9.7)
3 (9.7)
10 (35.7)
8 (28.6)
2 (7.1)
7 (22.6)
7 (22.6)
–
Kappa (p) – – 0.29* 0.56* 0.301 
HR Ag eemen N (%) 31 (100) 29 (93.5) 26 (83.9) 18 (58.1) 16 (57.1) 13 (42.0)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
–
–
–
2 (6.5)
2 (6.5)
–
5 (16.1)
−3 (9.7)
2 (6.5)
13 (41.9)
−3 (9.7)
10 (32.3)
12 (42.9)
1 (3.6)
11 (39.3)
18 (58.0)
1 (3.2)
17 (54.8)
Kappa (p) – – −0.084 −0.175 0.092 0.082
RF Ag eemen N (%) 28 (90.3) 28 (90.3) 27 (87.1) 22 (70.9) 16 (57.1) 13 (42.0)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
2 (6.5)
3 (9.7)
–
2 (6.5)
3 (9.7)
–
3 (9.7)
2 (6.5)
2 (6.5)
9 (29.1)
–
9 (29.0)
12 (42.9)
2 (7.1)
10 (35.7)
18 (58.0)
1 (3.2)
17 (54.8)
Kappa (p) – – −0.069 0.131 0.102 0.082
SBP Ag eemen N (%) 29 (93.5) 31 (100) 29 (93.5) 20 (64.5) 16 (57.1) 12 (38.7)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
2 (6.5)
2 (6.5)
–
–
–
–
2 (6.5)
–
2 (6.5)
11 (35.5)
1 (3.2)
10 (32.3)
12 (42.9)
–
12 (42.9)
19 (31.3)
2 (6.5)
17 (54.8)
Kappa (p) – – – −0.062 0.082 0.003
DBP Ag eemen N (%) 28 (90.3) 30 (96.8) 26 (83.9) 22 (70.9) 14 (50.0) 14 (45.2)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
2 (6.5)
3 (9.7)
–
1 (3.2)
1 (3.2)
–
5 816.1)
3 (9.7)
2 (6.5)
9 (29.1)
–
9 (29.0)
14 (50.0)
3 (10.7)
11 (39.3)
17 (54.8)
1 (3.2)
16 (51.6)
Kappa (p) – – −0.084 0.131 −0.048 0.108
MBP Ag eemen N (%) 29 (93.5) 31 (100) 27 (87.1) 21 (67.7) 17 (60.7) 12 (38.7)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
1 (3.2)
2 (6.5)
–
–
–
–
3 (9.7)
2 (6.5)
2 (6.5)
10 (32.3)
–
10 (32.3)
11 (39.3)
–
11 (39.3)
19 (31.3)
1 (3.2)
18 (58.1)
Kappa (p) – – −0.069 – 0.163 0.058
O2 Sa Ag eemen N (%) 31 (100) 31 (100) 29 (93.5) 21 (67.7) 15 (53.6) 7 (22.6)
Disag eemen N (%)
BPS<4; Va >10 %
BPS≥4; Va <10 %
–
–
–
–
–
–
2 (6.5)
–
2 (6.5)
10 (32.3)
–
10 (32.3)
13 (46.4)
–
13 (46.4)
24 (77.4)
–
24 (77.4)
Kappa (p) – – – – – –
DBP: Dias olic blood p essu e; ESCID: Beha io al Indica o s o Pain Scale; ETA: Endo acheal aspi a ion; HR: Hea a e; IQR: In e qua ile ange; MBP: Mean a e ial
blood p essu e; N: pa ien numbe ; NP: Non-pain ul; PDR: Pupilla y dila ion e lex; RF: Respi a o y a e; SBP: Sys olic blood p essu e; O2 SAT: Oxygen sa u a ion; –: No
da a. Pain sco es: ESCID ≥1, PDR ≥11,5 %, Vi al signs a ia ion be o e and a e s imuli ≥10 %. ** p<0.001; *p<0.05
Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i e al. Clinical Neu ology and Neu osu ge y 247 (2024) 108644
5

−2.5–3.5 %.
3.6. Ag eemen be ween PDR wi h scales and i al signs as pain
assessmen ools
Table SDC 3 ou lines he conco dance be ween he PDR and o he
pain assessmen ools.
The BPS and ESCID had mo e han 90 % conco dance wi h he PDR
o he NP and 10 mA s imuli. Ag eemen dec eased wi h s imulus in-
ensi y and emained abo e 77 % o AET. The kappa index wi h he
scales anged om 0.2 o 0.6, wi h signi ican disc epancies no ed o
s imuli abo e 20 mA in pa ien s wi h PDR≥11.5 %.
Vi al signs had 80–90 % ag eemen wi h PDR wi h NP and 10 mA
s imuli, dec easing o 60–30 % wi h highe s imuli. The kappa indices
we e a ound 0.1, wi h he mos signi ican disc epancies obse ed in
pa ien s wi h PDR≥11.5 %.
4. Discussion
This s udy aimed o desc ibe he beha io o clinical assessmen ools
o pain and au onomic esponses as he i al signs and pupilla y eac-
i i y o nocicep i e s imuli. Acco ding o in e na ional ecommenda-
ions, he adequa e assessmen and ea men o pain is a p io i y a ea o
a en ion in seda ed pa ien s. I ecommends he use o indi ec pain
assessmen me hods such as beha io al scales [4,9,14]. Howe e ,
assessing pain in c i ically en ila ed pa ien s using beha io al scales
in ol es complexi ies ha need ca e ul conside a ion [5,6]. Applying
beha io al scales o e alua e pain should be mo e common han i is.
The implemen a ion o scales is low, po en ially exace ba ed by he
mis aken belie ha immobile, seda ed pa ien s a e unlikely o expe i-
ence pain [3]. The po en ial subjec i i y o scales makes i di icul o
each a consensus on pain diagnosis among p o essionals [7]. The e is a
clinical conce n ha pa ien s may be unde diagnosed.
Resea ch indica es ha in c i ically ill pa ien s seda ed and on me-
chanical en ila ion, beha io al scale sco es, and i al signs showed
minimal changes in esponse o nocicep i e s imuli, wi h no signi ican
a ia ions e en in pa ien s expe iencing pain. These esul s aligned wi h
p e ious mul icen e s udies, in which ool a ia ions we e also minimal
[6,16]. Howe e , he e was a high incidence o pain du ing ATE, wi h
alues highe han ou poin s on he BPS scale in 70 % o he pa ien s.
Pupilla y size a ia ion showed changes om he lowes in ensi y
s imulus. I showed inc easing a ia ions wi h inc easing s imulus in-
ensi y and eached alues abo e 37 % in pa ien s wi h pain, acco ding
o BPS. A nocicep i e esponse was no ed a a pain a e, PDR≥11,5 %,
om a 20 mA s imulus. These indings co obo a ed hose ob ained in
s udies pe o med in deeply anes he ized su gical pa ien s, which also
e idenced a p og essi e inc ease in PDR wi h he in ensi y o calib a ed
elec ical s imuli in a su gical app oach [19] and highe PDR alues in
a eas wi hou senso y blockage [13,20]. Al hough cau ious in i s in e -
p e a ion, i is essen ial o no e ha pain has been epo ed in 100 % o
he s udied pa ien s, acco ding o PDR.
Howe e , i should also be no ed ha , in his s udy, he PDR a e
AET eached sco es o 33 % in pa ien s who did no show pain acco ding
o he scale. This nocicep i e esponse was close o ha eached by
pa ien s who did show pain acco ding o BPS and ESCID. Paulus [16]
and Sabou din [19] iden i ied an inc ease in he PDR wi h inc easing
s imulus in ensi y in c i ically ill pa ien s wi h RASS-5. They also iden-
i ied highe sco es in pa ien s who demons a ed pain. S ill, he au ho s
did no p esen da a om he analysis o he pupilla y esponse by
pain/no pain g oups acco ding o he BPS scale in hei wo ks. No
s udies ha e been ound ha ha e helped us discuss his si ua ion.
The alidi y o he indica o s o de ec pain e sus BPS was a iable.
A high deg ee o ag eemen o beha io al scales o iden i y pain was
con i med [6]. The ag eemen o beha io al scales wi h i al signs was
weake , and he e was no co ela ion be ween beha io al scales o PDR,
especially in pa ien s wi h pain. Vi al signs a e o en used o sugges
po en ial pain, especially in pa ien s wi h beha io al limi a ions. Cu -
en e idence does no suppo using i al signs o his pu pose [9,14,
21]. Pa ien s aking d ugs ha slow he hea a e, pa ien s on ca dio-
onics, asop esso s, opioids, o hose expe iencing signi ican physio-
logic s ess may no show changes in i al signs ela ed o pain ul
s imuli. Despi e his, gi en he exis ing clinical need o objec i e ools
o iden i y pain, sys ems a e being de eloped o in eg a e some i al
signs as indica o s o pain [22,23].
In he case o he PDR, ag eemen wi h he pain scales was good o
low-in ensi y s imuli. Howe e , he deg ee o ag eemen dec eased a e
high-in ensi y s imuli, e ealing some pa ien s who appea ed calm bu
had ele a ed nocicep i e esponses (PDR ≥11.5 %). Gi en he impos-
sibili y o pa ien s o e balize pain and e idence o i s p esence, i could
only e idence ele a ed nocicep ion in pa ien s wi hou signs o pain.
Howe e , his ac may lead us o conside unde -diagnosed pain pa-
ien s. We ha e no ye ound p e ious s udies o compa e he esul s.
Ou indings could ha e signi ican clinical implica ions, pa icula ly
o c i ically ill pa ien s on mechanical en ila ion wi h limi ed mobili y
and an inabili y o communica e hei pain. The incidence o pos -
in e en ion pain in he uni s emains e y high and an objec i e ool
o moni o pain and guide indi idualized ea men s emains needed.
Pupilla y e lex dila ion would be a eliable physiological indica o o
noxious s imula ion independen o o he physiological a iables. Some
s udies p opose he pupillome y as an ins umen o assess au onomic
esponses o s imuli o adjus he pa ien ’s need o analgesia a oiding
si ua ions o o e - o unde -analgesia in he su gical ield [13,20,24]. Li
[25] ad anced ha pupilla y size a ia ion could be an op imal indi-
ca o o pain in c i ically ill pa ien s unable o demons a e a beha io al
esponse o pain. PDR has ob ained sensi i i y and speci ici y o
de ec ing pain close o 80 % in c i ically ill-seda ed pa ien s [15−17,
26]. This s udy in oduces a new line o esea ch.
Wi h all, his s udy would ha e se e al limi a ions. Fi s ly, he pa-
ien s’beha io al esponse o pain was low. I would ha e a ec ed he
eco ding he BPS and he classi ica ion o pain acco ding o he scale.
On he o he hand, pupilla y eac i i y is an au onomous e lex in
s ess ul si ua ions and no only in pain. E en hough all pa ien s s udied
showed a PDR a e he s imuli, he p esence o opioids, would dec ease
i s ampli ude [27]. Due o his, s esso s imuli we e limi ed, and opioid
doses emained cons an du ing he p o ocol o minimize po en ial bias
in he measu emen s. Fu he s udies a e needed o alida e hese
indings and e alua e he echnique’s applicabili y in clinical p ac ice
o mechanically en ila ed pa ien s.
5. Conclusions
The PDR eco ded highe modi ica ion alues a e s imuli in his
s udy han he o he ools, wi h s ong ag eemen be ween he scales.
The PDR de ec ed ele a ed nocicep i e esponses in pa ien s who did no
show beha io al pain esponses.
E hics app o al and consen o pa icipa e
The Clinical Resea ch E hics Commi ee o Basque Coun y app o ed
his s udy. CEIC-E; in e nal code: PI2017100. In o med consen was
ob ained om all indi idual pa icipan s included in he s udy o hei
legally au ho ized ep esen a i es. The s udy was co e ed by P o es-
sional Ci il Liabili y insu ance in any ad e se e en s.
Funding
This wo k was suppo ed by AID in Resea ch P ojec s om he
Basque Go e nmen Depa men o Heal h wi h ile numbe
2018111017.
Y. L´
opez-De-Audícana-Jimenez-De-Abe as u i e al. Clinical Neu ology and Neu osu ge y 247 (2024) 108644
6
CRediT au ho ship con ibu ion s a emen
Naia a Pa aza-Diez: W i ing –o iginal d a , So wa e, Me hod-
ology, Fo mal analysis. Ana Vallejo-De-La-Cue a: W i ing –o iginal
d a , In es iga ion, Funding acquisi ion, Concep ualiza ion. Yolanda
L´
opez-De-Audícana-Jimenez-De-Abe as u i: W i ing –o iginal d a ,
Supe ision, Me hodology, In es iga ion, Funding acquisi ion, Da a
cu a ion, Concep ualiza ion.
Decla a ion o Compe ing In e es
The au ho s decla e ha hey ha e no known compe ing inancial
in e es s o pe sonal ela ionships ha could ha e appea ed o in luence
he wo k epo ed in his pape .
Acknowledgmen s
To hose who o med pa o he esea ch eam collabo a ing in he
ec ui men and da a collec ion phase o he PUPIPAIN p ojec o hei
a ailabili y, dedica ion and ime, as well as o he, head o in es iga ion
se ice o Heal h Resea ch Ins i u e, BIOARABA, and he heads o se -
ice and he nu se s a o he In ensi e Ca e Uni s o he A aba Uni-
e si y Hospi al, o he suppo and acili a ing a i ude shown
h oughou he p ojec .
Con lic s o in e es
The au ho s ha e no con lic s o in e es o epo .
Appendix A. Suppo ing in o ma ion
Supplemen a y da a associa ed wi h his a icle can be ound in he
online e sion a doi:10.1016/j.clineu o.2024.108644.
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