Peripheral Blood Biomarkers in Aneurysmal Subarachnoid Hemorrhage

105 Pages·2017·3.89 MB·English

H Acta Universitatis Tamperensis 2380
E
I
K
K
I

K
I
I
S
K
I

P
e HEIKKI KIISKI
r
ip
h
e
r
a
l
B
lo
o
d

B
io
m
a
r
k
e
r
s

in Peripheral Blood Biomarkers
A
n
e
u in Aneurysmal Subarachnoid
r
y
s
m
a Hemorrhage
l
S
u
b
a
r
a
c
h
n
o
id

H
e
m
o
r
r
h
a
g
e

A
U
T

2
3
8
0
HEIKKI KIISKI
Peripheral Blood Biomarkers
in Aneurysmal Subarachnoid
Hemorrhage
ACADEMIC DISSERTATION
To be presented, with the permission of
the Faculty Council of the Faculty of Medicine and Life Sciences
of the University of Tampere,
for public discussion in the auditorium F114 of the Arvo building,
Arvo Ylpön katu 34, Tampere,
on 26 May 2018, at 12 o’clock.
UNIVERSITY OF TAMPERE
HEIKKI KIISKI
Peripheral Blood Biomarkers
in Aneurysmal Subarachnoid
Hemorrhage
Acta Universitatis Tamperensis 2380
Tampere University Press
Tampere 2018
ACADEMIC DISSERTATION
University of Tampere, Faculty of Medicine and Life Sciences
Tampere University Hospital, Department of Intensive Care
Tampere University Hospital, Department of Anaesthesia
Finland
Supervised by Reviewed by
Professor Jukka Peltola Docent Tapani Keränen
University of Tampere University of Eastern Finland
Finland Finland
Docent Jyrki Tenhunen Docent Anu Maksimow
University of Tampere University of Turku
Finland Finland
The originality of this thesis has been checked using the Turnitin OriginalityCheck service
in accordance with the quality management system of the University of Tampere.
Copyright ©2018 Tampere University Press and the author
Cover design by
Mikko Reinikka
Acta Universitatis Tamperensis 2380 Acta Electronica Universitatis Tamperensis 1888
ISBN 978-952-03-0749-3 (print) ISBN 978-952-03-0750-9 (pdf)
ISSN-L 1455-1616 ISSN 1456-954X
ISSN 1455-1616 http://tampub.uta.fi
Suomen Yliopistopaino Oy – Juvenes Print
Tampere 2018
P4a4i1n o t7u2o9te
To Ann-Mari, Elias and Oskari

TABLE OF CONTENTS
1 Introduction .................................................................................................................... 15
2 Review of the Literature ................................................................................................ 17
2.1 Incidence of aneurysmal subarachnoid hemorrhage ....................................... 17
2.2 Risk factors of aneurysmal subarachnoid hemorrhage ................................... 18
2.3 Clinical presentation and diagnosis ................................................................... 19
2.4 Preoperative and operative management ......................................................... 20
2.4.1 Medical management before operative treatment ......................... 20
2.4.2 Surgical and endovascular treatment............................................... 20
2.5 Neurocritical care (and complications) ............................................................. 21
2.5.1 Rebleeding ......................................................................................... 22
2.5.2 Acute hydrocephalus ........................................................................ 22
2.5.3 Seizures .............................................................................................. 23
2.5.4 Cardiopulmonary complications ..................................................... 24
2.5.5 Delayed cerebral ischemia ................................................................ 24
2.6 Predictors of prognosis ...................................................................................... 26
2.6.1 Hunt & Hess scale ............................................................................ 27
2.6.2 World Federation of Neurological Surgeons (WFNS)
scale .................................................................................................... 28
2.6.3 Fisher scale ........................................................................................ 29
2.7 Determining the functional outcome ............................................................... 31
2.7.1 Modified Rankin Scale (mRS).......................................................... 31
2.8 Biomarkers with possible prognostic potential after aSAH ........................... 32
2.8.1 Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) .................... 33
2.8.2 Interleukin-6 (IL-6)........................................................................... 33
2.8.3 High-mobility group box 1 (HMGB1) ........................................... 34
2.8.4 Soluble urokinase-type plasminogen activator receptor
(suPAR) ............................................................................................. 35
2.8.5 Neuron-specific enolase (NSE) ....................................................... 35
2.8.6 S100 calcium-binding protein B (S100B) ....................................... 36
2.8.7 Matrix metalloproteinase-9 (MMP-9) ............................................. 37
3 Aims of the Study........................................................................................................... 38
4 Materials and Methods................................................................................................... 39
4.1 Enzyme-linked immunosorbent assay (ELISA) measurements ..................... 40
4.1.1 Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)
evaluation study .................................................................................40
4.1.2 Interleukin-6 (IL-6) and high-mobility group box 1
(HMGB1) evaluation study ..............................................................41
4.1.3 Soluble urokinase-type plasminogen activator receptor
(suPAR) evaluation study..................................................................41
4.1.4 Neuron specific enolase (NSE), matrix metalloproteinase-
9 (MMP-9) and S100 calcium-binding protein B (S100B)
evaluation study .................................................................................42
4.2 Statistics ................................................................................................................42
4.2.1 UCH-L1 evaluation study .................................................................42
4.2.2 IL-6 and HMGB1 evaluation study .................................................43
4.2.3 suPAR evaluation study ....................................................................43
4.2.4 NSE, MMP-9 and S100B evaluation study .....................................43
5 Results ..............................................................................................................................44
5.1.1 Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)
evaluation study .................................................................................46
5.1.2 Interleukin-6 (IL-6) and high-mobility group box 1
(HMGB1) evaluation study ..............................................................50
5.1.3 Soluble urokinase-type plasminogen activator receptor
(suPAR) evaluation study..................................................................53
5.1.4 Neuron specific enolase (NSE), matrix metalloproteinase-
9 (MMP-9) and S100 calcium-binding protein B (S100B)
evaluation study .................................................................................55
6 Discussion........................................................................................................................60
6.1 Methodological considerations ..........................................................................61
6.1.1 Sample size and demographics .........................................................61
6.1.2 The timing of blood samples and follow-up period .......................62
6.1.3 Enzyme-Linked Immunosorbent Assay ..........................................62
6.2 Neuroglial (UCH-L1, NSE, S100B) and extracellular matrix (MMP-
9) biomarkers .......................................................................................................63
6.3 Inflammatory biomarkers (IL-6, HMGB1, suPAR) .........................................65
6.4 Future implications .............................................................................................66
7 Summary and Conclusions .............................................................................................68
8 Acknowledgements .........................................................................................................70
9 References ........................................................................................................................72
10 Original Communications ..............................................................................................81
LIST OF ORIGINAL COMMUNICATIONS
Kiiski H, Tenhunen J, Ala-Peijari M, Huhtala H, Hämäläinen M, Långsjö J, Moilanen
E, Narkilahti S, Öhman J, Peltola J. Increased plasma UCH-L1 after
aneurysmal subarachnoid hemorrhage is associated with unfavorable
neurological outcome. J Neurol Sci. 2016, 361:144-9
Kiiski H, Långsjö J, Tenhunen J, Ala-Peijari M, Huhtala H, Hämäläinen M, Moilanen
E, Öhman J, Peltola J. Time-courses of plasma IL-6 and HMGB-1
reflect the initial severity of clinical presentation but do not predict poor
neurologic outcome following subarachnoid hemorrhage.
eNeurologicalSci. 2017, 6, pp. 55-62
Kiiski H, Jalkanen V, Ala-Peijari M, Hämäläinen M, Moilanen E, Peltola J, Tenhunen
J. Plasma Soluble Urokinase-Type Plasminogen Activator Receptor Is
Not Associated with Neurological Outcome in Patients with
Aneurysmal Subarachnoid Hemorrhage. Front. Neurol. 2017, 8:144
Kiiski H, Långsjö J, Tenhunen J, Ala-Peijari M, Huhtala H, Hämäläinen M, Moilanen
E, Peltola J. S100B, NSE and MMP-9 fail to predict neurologic
outcome while elevated S100B associates with milder initial clinical
presentation after aneurysmal subarachnoid hemorrhage. (J Neurol Sci.
2018, In Press)
ABBREVIATIONS
aSAH aneurysmal subarachnoid hemorrhage
BBB blood-brain barrier
CPP cerebral perfusion pressure
CT computed tomography
CSF cerebrospinal fluid
CTA computed tomography angiography
CRP C-reactive protein
DCI delayed cerebral ischemia
DSA digital subtraction angiography
EBI early brain injury
ECG electrocardiogram
ELISA enzyme-linked immunosorbent assay
EVD external ventricular drainage
Fisher Fisher grading scale
GCS Glasgow coma scale
GOS Glasgow outcome scale
H&H Hunt & Hess aSAH scale
HMGB1 high-mobility group box 1
ICU intensive care unit
IL-6 interleukin-6
MAP mean arterial pressure
MMP-9 matrix metalloproteinase-9