Time-cou ses o plasma IL-6 and HMGB-1 eflec ini ial se e i y o clinical
p esen a ion bu do no p edic poo neu ologic ou come ollowing
suba achnoid hemo hage
Heikki Kiiski
a,
⁎, Jaakko Långsjö
a
, Jy ki Tenhunen
a,b
, Ma ika Ala-Peija i
a
, Heini Huh ala
c
,Ma iHämäläinen
d
,
Ee a Moilanen
d
,JuhaÖhman
e
, Jukka Pel ola
a
C i ical Ca e Medicine Resea ch G oup, Depa men o In ensi e Ca e, Tampe e Uni e si y Hospi al, Tampe e, Finland
b
Depa men o Su gical Sciences, Di ision o Anes hesiology and In ensi e Ca e, Uppsala Uni e si y, Uppsala, Sweden
c
School o Heal h Sciences, Uni e si y o Tampe e, Tampe e, Finland
d
The Immunopha macology Resea ch G oup, Uni e si y o Tampe e School o Medicine and Tampe e Uni e si y Hospi al, Tampe e, Finland
e
Depa men o Neu osu ge y, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland
Depa men o Neu ology, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland
abs ac a icle in o
A icle his o y:
Recei ed 6 No embe 2016
Accep ed 28 No embe 2016
A ailable online 2 Decembe 2016
Objec i e: Pa ien s wi h aneu ysmal suba achnoid hemo hage (aSAH) expe ience high mo ali y and mo bidi y.
Neu oinflamma ion causes b ain damage expansion a e aSAH. Due o he complexi y o he inflamma o y e-
sponse mul iple bioma ke s a e needed o e alua e i s' p og ession. We s udied inflamma o y p ocess a e
aSAH by measu ing wo inflamma o y bioma ke s, in e leukin-6 (IL-6) and high-mobili y g oup box 1
(HMGB1) a simul aneous ime-poin s a e aSAH.
Me hods: In his p ospec i e popula ion-based s udy, IL-6 and HMGB1 we e measu ed in aSAH pa ien s (n = 47)
o up o fi e days. Plasma concen a ions o IL-6 and HMGB1 we e measu ed a 0, 12 and 24 h a e hospi al ad-
mission, and he ea e daily o up o fi e days o un il he pa ien was ans e ed om he in ensi e ca e uni
(ICU). The pa ien s' neu ological ou comes we e e alua ed wi h he modified Rankin Scale a six mon hs a e
aSAH.
Resul s: A high IL-6 le el du ing he fi s day a e aSAH was associa ed wi h a se e e ini ial clinical p esen a ion
(p = 0.002) and in ec ion du ing ollow-up (p = 0.031). The HMGB1 le el did no associa e wi h hese pa am-
e e s. The e was no co ela ion be ween IL-6 and HMGB1 le els a any ime poin du ing he ollow-up. The
concen a ions o IL-6 and HMGB1 we e no associa ed wi h neu ological ou come.
Conclusions: High ini ial IL-6 alues seem o eflec he in ensi y o he inflamma o y esponse bu no he b ain
damage pe se. An ea ly inflamma o y esponse migh e en be beneficial since al hough ele a ed IL-6 le els we e
obse ed in pa ien s wi h a mo e se e e ini ial clinical p esen a ion, hey we e no associa ed wi h neu ological
ou come. The lack o co ela ion be ween IL-6 and HMGB1 ques ions he ole o mac ophages in he p ocess o
he sec e ion o hese inflamma o y ma ke s a e aSAH, ins ead poin ing o he ac i a ion o al e na i e p o-
inflamma o y pa hways.
© 2016 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/).
Keywo ds:
Aneu ysmal suba achnoid hemo hage
Bioma ke s
Neu oinflamma ion
Inflamma o y esponse
Il-6
HMGB1
1. In oduc ion
Despi e ecen ad ances in he managemen o aneu ysmal sub-
a achnoid hemo hage (aSAH), i emains a de as a ing disease wi h a
mo ali y app oaching 50% and ewe han 60% o he su i o s achie -
ing unc ional independence [1]. The b ain inju y de eloping a e aSAH
occu s in mul iple phases. The e is e idence sugges ing ha a e he
p ima y insul , an addi ional b ain inju y is e oked by ea ly b ain inju y
(EBI) and delayed ce eb al ischemia (DCI). The e a e epo s ha he
de elopmen o DCI doubles he isk o poo ou come in aSAH [2,3].
Ea ly b ain inju y e e s o he acu e e ec s o blood in he suba ach-
noid space and he ansien global ischemia caused by acu e ele a ion
in he in ac anial p essu e. Delayed ce eb al ischemia is a mul i ac o ial
phenomenon in ol ing angiog aphic asospasm, mic oci cula o y
asocons ic ion, mic o ascula h ombosis, co ical sp eading depola -
iza ion and blood-b ain ba ie dys unc ion. I is also hough ha
p ocesses ac i a ed du ing EBI con ibu e o he de elopmen o DCI
[2,4,5].
Va ious bioma ke s ha e been examined in aSAH pa ien s bu hus
a , he e a e no clinically eliable bioma ke s o p edic ing DCI o
eNeu ologicalSci 6 (2017) 55–62
⁎Co esponding au ho : Depa men o In ensi e Ca e, Tampe e Uni e si y Hospi al, PL
2000, Tampe e, Finland.
E-mail add ess: heikki.kiiski@fimne .fi(H. Kiiski).
h p://dx.doi.o g/10.1016/j.ensci.2016.11.010
2405-6502/© 2016 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/).
Con en s lis s a ailable a ScienceDi ec
eNeu ologicalSci
jou nal homepage: h p://ees.else ie .com/ensci/
p ognosis [6]. Recen findings om ou g oup suppo he hypo hesis
ha UCH-L1 could be use ul in p edic ing pa ien ou come a e aSAH
al hough no associa ion be ween UCH-L1and DCI was ound[7]. Ne e -
heless, he e is accumula ing e idence ha inflamma ion con ibu es
o hede elopmen o DCI [2,8–10]. Knowledge abou he neu al con ol
mechanisms o inflamma ion is accumula ing apidly [11]. A numbe o
cy okines and p oinflamma o y ma ke s ha e been associa ed wi h a
poo ou come in aSAH [6]. In e leukin-6 (IL-6) and high-mobili y
g oup box 1 (HMGB1) a e wo impo an inflamma o y bioma ke s;
hei pe iphe al blood concen a ions ha e been associa ed wi h a
poo ou come in aSAH [12–14].
I has been pos ula ed ha he inflamma o y esponse displays bi-
phasic ea u es in EBI and DCI [2,15]. The biphasic esponse e e s o
he double-edged e ec s o he inflamma o y esponse which can be
de imen al a some phase o he disease bu alle ia ing a ano he .
The biphasic p ope ies o mul iple molecula pa hways ha e been p o-
posed o con ibu e o he seconda y b ain inju y also in o he ypes o
acu e s okes [16,17]. The pu a i e biphasic e ec s o he inflamma o y
esponse highligh he need o a be e unde s anding o he mecha-
nisms and imescale o he esponse in aSAH. The de elopmen o eli-
able bioma ke s ac ing as su oga es o he esponse could help o
achie e his goal.
The aim o he p esen s udy was o analyze he ole o wo bio-
ma ke s in a g oup o pa ien s wi h ecen aSAH. We e alua ed whe he
he e was any co ela ion be ween IL-6 and HMGB1 le els. By compa -
ing he concen a ions o hese wo inflamma o y bioma ke s a he
same ime poin s, we wan ed o de e mine whe he he changes in
hei concen a ions could o e mo e specific in o ma ion abou he in-
flamma o y pa hways and possible mechanisms leading o he neu al
inju y de eloping a e aSAH. In addi ion, we assessed hei associa ion
wi h neu ological ou come and selec ed clinical condi ions.
2. Me hods
Following he app o al o he ins i u ional e hics commi ee, we
conduc ed a p ospec i e, obse a ional, single-cen e clinical s udy in
Tampe e Uni e si y Hospi al (Tampe e, Finland). The hospi al is one
o fi e e ia y e e al cen e s in Finland se ing a popula ion o ap-
p oxima ely 1 million inhabi an s and hus p o iding ca e o all pa-
ien s su e ing om suba achnoid hemo hage in he a ea.
The s udy coho consis ed o 61 consecu i e aSAH pa ien s admi -
ed o ou cen e om Ma ch2013 o Decembe 2013. W i en in o med
consen was ob ained om each pa ien o om hei nex o kin. The
ime o he onse o symp oms associa ed wi h aSAH was egis e ed
om he pa ien eco ds. We excluded pa ien s wi h an unknown
ime o onse o symp oms as well as pa ien s whose samples o he
IL-6 and HMGB1 assays we e no collec ed wi hin he fi s 24 h a e
he onse o symp oms. All pa ien s we e ea ed acco ding o s anda d-
ized in-house guidelines. In o al, 47 pa ien s we e conside ed eligible
and we e hus included in he s udy.
These e i y o he ini ial clinical p esen a ion was e alua ed acco d-
ing o he Wo ld Fede a ion o Neu ological Su geons (WFNS) and Hun
& Hess g ading scales. The ex en o he p ima y hemo hage on he CT
scan was g aded wi h Fishe scale. WFNS and Hun & Hess we e dicho -
omized in o non-se e e (WFNS 1–3/Hun & Hess 1–3) o se e e (WFNS
4–5 / Hun & Hess 4–5). The Fishe g ade was dicho omized in o non-
se e e (Fishe 1–2) o se e e (Fishe 3–4). The neu ological ou come
was e alua ed wi h he modified Rankin Scale (mRS) six mon hs a e
aSAH based on a s uc u ed in e iew pe o med by elephone o du -
ing an ou pa ien clinic isi . mRS was dicho omized in o a a o able
ou come (mRS 0–2) o an un a o able ou come (mRS 3–6). De ailed
ca ego iza ions o WFNS, Hun & Hess, Fishe and mRS a e p esen ed
in a Supplemen a y able. Addi ionally, we assessed he incidence o in-
ec ion, which was defined as he need o an imic obial medica ion
du ing he ollow-up pe iod.
Plasma concen a ions o IL-6 and HMGB1 we e measu ed in he
samples collec ed a 0, 12 and 24 h a e he admission, and he ea e
a e e y 24 h o up o fi e days o un il he pa ien was ans e ed
om he ICU. Be o e he s a is ical analysis, he IL-6 and HMGB1 mea-
su emen s we e di ided in o consecu i e 24 h in e als s a ing om
he onse o symp oms. I IL-6 and HMGB1 we e measu ed mo e han
once pe in e al, he mean concen a ion was used. In a subg oup o
22 pa ien s who had up o fi e days' ollow-up, we also checked i he
pa ien had been ea ed o DCI. T ea men o DCI was ini ia ed based
on he clinical e alua ion.
Blood samples we e collec ed in o EDTA-con aining ubes om an
a e ial cannula ha had been ou inely inse ed o in asi e blood
p essu e moni o ing as well as o blood sampling. A e collec ion, he
sample was immedia ely deli e ed o he labo a o y whe e i was cen-
i uged o 10 min a 2000g( oom empe a u e). A e cen i uga ion,
he plasma was collec ed and kep a - 70 °C. IL-6 and HMBG1
Fig. 1. IL6 le els measu ed wi hin he fi s 24 h a e aSAH in ela ion o he ini ial clinical p esen a ion. Pa ien s wi h mo e se e e clinical p esen a ions had significan ly highe IL-6 le els
(p = 0.002). Black ci cles ep esen ou lie s.
56 H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62
concen a ions in he plasma samples we e measu ed by ELISA wi h e-
agen s om eBioscience Inc. (San Diego, CA, USA) and IBL In e na ional
(Hambu g, Ge many), espec i ely. Assay p o ocols a e desc ibed in he
ollowing da ashee s:
h p://www.ebioscience.com/media/pd / ds/88/88-7066.pd (IL-6)
h p://www.ibl-in e na ional.com/media/ca alog/p oduc /S/T/
ST51011_IFU_EU_en_HMGB1_ELISA_V2011-01_sym4.pd (HMGB1)
The abso bance was measu ed wi h Vic o 3 Mul ilabel Coun e
(Pe kin Elme , Finland) and he esul s we e calcula ed agains a
s anda d cu e using he smoo hed spline me hod wi h Mul iCalcTM
(Pe kin Elme , Finland).
S a is ical analyses we e pe o med wi h R ( e sion 3.3.0 o Mac OS
X). Fishe 's exac es was used o he ca ego ical a iables and Mann-
Whi ney U es o con inuous a iables. Linea eg ession was used o
he ime in e al analysis. Spea man's co ela ion was used o es ima e
whe he IL-6 and HMGB1 le els co ela ed
3. Resul s
The pa ien s wi h a se e e ini ial clinical p esen a ion o aSAH
(WFNS 4–5/Hun & Hess 4–5) had a highe plasma IL-6 concen a ion
du ing he fi s 24 h ollowing aSAH han he pa ien s wi h a non-
se e e (WFNS 1–3, p = 0.002/Hun & Hess 1–3, p = 0.019) p esen a-
ion (Fig. 1,Table 1). In addi ion, he adminis a ion o an imic obial
medica ion was associa ed wi h ele a ed plasma IL-6 le els (Fig. 2,
Table 1, p = 0.031). Finally, plasma IL-6 concen a ions ended o be
highe in pa ien s wi h se e e aSAH acco ding o Fishe scale (Fig. 3,
p = 0.051). The plasma HMGB1 concen a ion du ing he fi s 24 h
a e aSAH was no associa ed wi h he se e i y o aSAH (Table 2).
IL-6 and HMGB1 concen a ions measu ed du ing he fi s 24 h we e
no associa ed wi h neu ological ou come. The desc ip i e s a is ics o
IL-6 and HMGB1 concen a ions measu ed du ing he fi s 24 h a e
aSAH a e p esen ed in Tables 1 and 2. The linea eg ession analysis e-
ealed no associa ion be ween neu ological ou come and IL-6 o
HMGB1 concen a ions du ing he fi e-day ollow-up (Fig. 4).
Plasma IL-6 and HMGB1 concen a ions did no co ela e wi h each
o he a any o he ime poin s du ing he fi e-day ollow-up (Fig. 5,
Table 3). In he subg oup o hose pa ien s ollowed o up o fi e
days, IL-6 o HMGB1 concen a ions du ing he fi s 24 h did no p edic
he de elopmen o DCI. In addi ion, he p esen a ion o DCI did no as-
socia e wi h IL-6 o HMGB1 concen a ions measu ed on day fi e
(Table 4).
4. Discussion
In he p esen s udy, we examined he p ognos ic po en ial and in-
e dependence o wo inflamma o y bioma ke s IL-6 and HMGB1 a e
aSAH.
Ou s udy sugges s ha a high plasma IL-6 concen a ion du ing he
fi s 24 h a e aSAH is s ongly associa ed wi h a se e e clinical p esen-
a ion as well as wi h he de elopmen o in ec ion du ing he fi e-day
ollow-up pe iod. Howe e , nei he IL-6 no HMGB1 le els we e associ-
a ed wi h neu ological ou come in pa ien s su e ing om aSAH. Thus,
ou s udy ailed o suppo he findings o some p e ious s udies i.e.
ha he e would be an associa ion be ween inc eased concen a ions
o hese bioma ke s and poo neu ological ou come. Zhu e al. claimed
ha he ea ly plasma HMGB1 concen a ion was associa ed wi h one-
yea mo ali y and poo neu ological ou come as de e mined by he
Glasgow Ou come Scale. These in es iga o s applied s ic e exclusion
c i e ia, o example, pa ien s wi h sys emic diseases such as hype en-
sion, diabe es and ch onic hea o lung disease we e excluded om he
s udy [13]. Höllig e al. desc ibed an associa ion be ween ea ly se um
and ce eb ospinal fluid IL-6 concen a ion wi h poo neu ological
Table 1
IL-6 concen a ion du ing he fi s 24 h a e aSAH (n = 47).
IL-6 (pg/ml) Mean SD Median IQR p-Value
mRS 0.334
0–2 (n = 16) 9.92 6.51 8.93 4.84–13.28
3–6 (n = 31) 13.96 12.20 8.85 6.30–18.35
WFNS 0.002
1–3 (n = 28) 8.19 4.77 7.45 4.93–9.93
4–5 (n = 19) 19.07 13.58 16.30 8.88–24.05
Hun & Hess 0.019
1–3 (n = 35) 11.21 11.04 7.70 5.13–10.63
4–5 (n = 12) 16.93 9.33 16.18 9.90–21.10
Fishe 0.051
1–2 (n = 14) 11.27 14.03 6.53 4.44–9.30
3–4 (n = 33) 13.15 9.14 10.00 7.15–17.70
In ec ion 0.031
Yes (n = 14) 14.84 8.63 11.40 9.34–19.38
No (n = 33) 11.63 11.46 7.50 5.00–12.35
Mann-Whi ney U es was used.
Fig. 2. IL6 le els measu ed wi hin he fi s 24 h a e aSAH in ela ion o clinically suspec ed in ec ion du ing ICU ollow-up. Ea ly IL-6 le els a e significan ly highe in pa ien s wi h
in ec ion du ing ollow-up (p = 0.031). Black ci cles ep esen ou lie s.
57H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62
ou comea discha ge, bu no a six mon hs a e aSAH. They conside ed
his lack o co ela ion a six mon hs o be caused pa ly by he high
d op-ou a e (27%) a e discha ge [14]. Kao e al. obse ed an associa-
ion be ween ea ly IL-6 concen a ion measu ed om he aneu ysmal
o ifice and pe iphe al eins wi h a poo neu ological ou come a one
mon h a e aSAH. They included only pa ien s who had unde gone
endo ascula coiling while pa ien s wi h su gically liga ed aneu ysm
we e excluded om he s udy [12]. The disc epan findings be ween
hese p e ious s udies and he p esen s udy may be pa ly explained
by he di e ences in he s udy p o ocols, he pa ien selec ion and he
di e en ime-poin s used o measu e neu ological ou come. As s a ed
by Höllig e al. [14], i is also essen ial o app ecia e ha an ele a ed
IL-6 concen a ion is a non-specificfinding which can eflec he inflam-
ma o y esponse o a ious pa hologies occu ing a e aSAH. Fo exam-
ple, pneumonia is common a e aSAH since pa ien s wi h dep essed
le el o consciousness a e suscep ible o aspi a ion o gas ic con en s
un il he ai way is secu ed. In asi e mechanical en ila ion p edisposes
pa ien s o en ila o -associa ed pneumonia and need o
en iculos omy c ea es a possibili y o en iculi is. All o hese in ec-
ions may lead o inc eased le els o inflamma o y bioma ke s.
The sec e ion o IL-6 and HMGB1 as a pa o he inflamma o y e-
sponse is a complex p ocess. One well known mechanism in ol es he
elease o hese bioma ke s o a he , media o s, om monocy es and
mac ophages [18–20]. In his s udy, an ele a ed IL-6 concen a ion
was associa ed wi h he clinical se e i y a e aSAH. Fu he mo e, a
nea ly s a is ically significan end o ele a ions in IL-6 was obse ed
in pa ien s wi h mo e se e e aSAH on he p ima y CT. On he o he
hand, he HMGB1 le el was no associa ed wi h ei he clinical se e i y
o he CT findings. Fu he mo e, he IL-6 and HMGB1 concen a ions
did no co ela e wi h each o he a any ime poin du ing he fi e-day
ollow-up. Based on hese findings, i would be emp ing o specula e
ha he sec e ion o IL-6 a e aSAH is media ed h ough a pa hway un-
ela ed o hei sec e ion by monocy es and mac ophages.
Inflamma ion has been associa ed wi h DCI [2,9] and poo ou come
a e aSAH [12,14]. In ou s udy, high concen a ions o IL-6 immedia ely
a e aSAH we e associa ed wi h se e e ini ial clinical p esen a ion and
head CT findings. On he o he hand, linea eg ession did no e eal any
mass inc ease in plasma IL-6 concen a ions du ing ollow-up and he e
was no di e ence be ween IL-6 concen a ions in pa ien s wi h a o -
able and non- a o able neu ological ou comes. Mo eo e , IL-6 le els
we e no associa ed wi h he de elopmen o DCI. Thus, ou findings
aise ques ions abou he biphasic p ope ies o IL-6 in inflamma o y e-
sponse a e aSAH, sugges ing ha he ea ly inflamma o y esponse
migh no be de imen al o he pa ien 's ou come. Plasma HMGB1, as
a la e phase cy okine, was no associa ed wi h he ini ial se e i y o
aSAH o wi h he neu ological ou come. In addi ion o sec e ion om
mac ophages du ing inflamma o y esponse, HGMB1 is also eleased
om cells i hey die by nec osis bu no when hey unde go apop osis
[21]. Apop osis has been associa ed wi h EBI and DCI [2,4]. The ela i ely
low concen a ions o HMGB1 sugges ha he e had no been ex ensi e
issue nec osis in ou pa ien s and suppo he hypo hesis ha cell dea h
du ing EBI and DCI occu s by apop osis.
This s udy has some limi a ions. The sample size is ela i ely small o
make i possible o d aw defini e conclusions abou he p ognos ic po-
en ial o he s udied bioma ke s. Howe e , he s udy is well powe ed
o ule ou he possibili y ha he e would be a significan co ela ion
be ween IL-6 and HMGB1 le els du ing he fi e-day ollow-up. We
measu ed IL-6 and HMGB1 in pe iphe al blood so he specific mecha-
nisms in ol ed in hei sec e ion emain elusi e. S ill, he lack o co e-
la ion be ween he s udied bioma ke s aises in e es ing ques ions o
Fig. 3. IL6 le els measu ed wi hin he fi s 24 h a e aSAH in ela ion o he se e i y o aSAH in p ima y CT. The e is a end owa ds highe IL-6 le els in pa ien s wi h mo e se e e CT
findings bu s a is ical significance is no eached by a na ow ma gin (p = 0.051). Black ci cles ep esen ou lie s.
Table 2
HMGB1 concen a ion du ing he fi s 24 h a e aSAH (n = 47).
HMGB1 (ng/ml) Mean SD Median IQR p-Value
mRS 0.486
0–2 (n = 16) 7.87 4.13 6.85 5.59–8.67
3–6 (n = 31) 6.85 2.94 6.27 4.55–8.61
WFNS 0.502
1–3 (n = 28) 6.83 2.78 6.04 5.39–7.72
4–5 (n = 19) 7.73 4.13 6.95 5.04–8.73
Hun & Hess 0.097
1–3 (n = 35) 6.61 2.70 5.83 4.55–7.87
4–5 (n = 12) 8.87 4.62 8.04 6.34–10.10
Fishe 0.771
1–2 (n = 14) 6.95 2.34 6.85 5.52–8.78
3–4 (n = 33) 7.30 3.76 6.27 4.61–8.59
In ec ion 0.693
Yes (n = 14) 6.84 3.11 6.33 4.38–8.32
No (n = 33) 7.35 3.53 6.62 5.44–8.62
Mann-Whi ney U es was used.
58 H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62
Fig. 4. IL-6and HMGB1 le els o pa ien s (n = 22) wi h he ICU ollow-up las ing o fi e days (n = 22). Ci cles ep esen indi idual pa ien alues. Values a e g ouped in o a o able and
non- a o able neu ological ou come. Linea eg ession shows no significan change be ween baseline alues o IL-6 (mRS 0–2: p- alue 0.084, be a −1.048/mRS 3–6: p- alue 0.515, be a
−0.879) o HMGB1 (mRS 0–2: p- alue 0.454, be a 0.183/mRS 3–6: p- alue 0.776, be a 0.106) du ing he ollow-up. Ou lie s a e no shown.
59H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62

u u e s udies in es iga ing mo e specific cellula and molecula mech-
anisms o inflamma o y esponse du ing aSAH. He e, we defined in ec-
ion as he use o an imic obial medica ion du ing ollow-up. Al hough,
ex eme cau ion is adop ed in ou uni wi h espec o he use o an imi-
c obial medica ion in o de o a oid unnecessa y ea men , i is s ill
possible ha in a small numbe o pa ien s, an ibio ic he apy had
Fig. 5. Sca e plo s displaying he co ela ion o indi idual pa ien alues o IL-6 agains hose o HGMB1 a di e en ime poin s du ing he ICU ollow-up. Ou lie s a e no shown.
60 H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62
been ini ia ed o p ophylaxis o simply based on s ong clinical suspi-
cion o in ec ion.
High ini ial IL-6 concen a ions in pa ien s wi h a se e e clinical p e-
sen a ion a e aSAH seem o eflec he in ensi y o he “inflamma o y
eflex”[11] a he han he neu onal inju y i sel . Thus, he exp ession
o IL-6 di e s om ha o UCH-L1, which in ou p e ious s udy was
shown o co ela e wi h he neu onal inju y caused by aSAH [7].Acco d-
ing o ecen e idence, inflamma ion seems o be a significan con ib-
u ing ac o o DCI. I is plausible ha inflamma ion can exe bo h
de imen al o beneficial e ec s depending on he phase o he second-
a y inju y p ocess in aSAH [2]. The pu a i e biphasic e ec s o he
inflamma o y esponse highligh he need o cla i ying he specificin-
flamma o y pa hways and imescales in which hey a e ac i a ed a e
aSAH. This knowledge would be o pa amoun impo ance o a ge ing
an i-inflamma o y he apies o app op ia e pa ien s a alid ime
poin s.Ass a edbyHöllige al.[14],a“sil e -bulle ”o “b ain oponin”
migh no exis due o he ex eme complexi y o physiological p ocess-
es in ol ed in aSAH. Ou findings highligh he complexi y o inflamma-
o y esponse and pa hophysiology o DCI in aSAH . The e o e, u u e
s udies should es mul iple bioma ke s o p e e ably panels o di e se
bioma ke s measu ed a he same ime-poin s in o de o gain a be e
unde s anding o pa hophysiology unde pinning he inflamma o y e-
sponse in aSAH.
5. Conclusion
High ini ial IL-6 alues seem o eflec he in ensi y o he inflamma-
o y esponse associa ed wi h ini ial clinical p esen a ion bu no he
e en ual b ain damage pe se. An ea ly inflamma o y esponse migh
e en be beneficial since al hough ele a ed IL-6 le els we e obse ed
in pa ien s wi h a mo e se e e ini ial clinical p esen a ion, hey we e
no associa ed wi h neu ological ou come. The lack o co ela ion
be ween IL-6 and HMGB1 aises ques ions abou he ole o mac o-
phages in he p ocess o he sec e ion o hese inflamma o y ma ke s
a e aSAH, ins ead poin ing o he ac i a ion o al e na i e p o-
inflamma o y pa hways.
Funding s a emen
The s udy was financially suppo ed by Academy o Finland (G an
numbe 138402) and he Compe i i e S a e Resea ch Financing o he
Expe Responsibili y a ea o Tampe e Uni e si y Hospi al.
E hics app o al
The s udy was conduc ed wi h he app o al o he Tampe e Uni e -
si y Hospi al E hics Commi ee.
Conflic o in e es
None.
Acknowledgemen s
Ms. Meiju Kukkonen and Te hi Salonen a e acknowledged o hei
excellen echnical assis ance.
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h p://dx.
doi.o g/10.1016/j.ensci.2016.11.010.
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Table 3
Spea man's co ela ion coe ficien s o le els o IL-6 agains HMGB1 du ing ICU ollow-up.
Timepoin Numbe o pa ien s in ollow-up Spea man's co ela ion
Day 1 47 0.171
Day 2 44 0.114
Day 3 38 −0.034
Day 4 22 −0.306
Day 5 22 0.212
Table 4
Desc ip i e s a is ics o IL-6 and HMGB1 le els in pa ien s su e ing DCI (n = 16) and
hose wi hou DCI (n = 6) in a subg oup o pa ien s (n = 22) wi h a leas fi e days'
ICU ollow-up.
Mean SD Median IQR p-Value
IL-6 (pg/ml)
Day 1 DCI 12.07 8.87 8.93 6.33–12.79 0.155
NO DCI 21.73 17.56 18.35 10.94–21.75
Day 5 DCI 14.48 13.08 11.65 6.43–17.50 0.914
NO DCI 11.48 3.94 10.70 9.50–11.30
HMGB-1 (ng/ml)
Day 1 DCI 6.03 2.46 5.48 4.17–7.59 0.197
NO DCI 7.67 3.42 7.14 6.49–8.95
Day 5 DCI 6.92 3.04 6.33 5.20–9.29 0.507
NO DCI 6.07 2.70 5.50 4.83–7.56
Mann-Whi ney U es was used.
61H. Kiiski e al. / eNeu ologicalSci 6 (2017) 55–62
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