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Techniques to improve neurological outcome after cardiac surgeryKok, Linde

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Nederlandse samenvatting (Dutch Summary)

Het doel van dit proefschrift was het onderzoeken en verbeteren van

therapeutische interventies, die momenteel gebruikt worden in de

cardiopulmonale bypass-geassisteerde chirurgische procedures, met als

uiteindelijke doelstelling om postoperatieve uitkomst te verbeteren.

Deel A van dit proefschrift onderzoekt de resultaten uit de weefseloxygenatie in

coronair arterie bypass grafting (CABG) studie, kortweg de TO-CABG studie.

In deze studie zijn patiënten gerandomizeerd for electieve CABG procedures,

met of zonder het gebruik van de cardiopulmonale bypass (CPB), dus on-pump

of off-pump. Nabij-infrarode spectroscopie (NIRS) werd gebruikt om cerebrale,

renale en perifere weefseloxygenatie te evalueren. Verder zijn bloed en urine

samples gestandaardizeerd afgenomen, en cognitieve functie testen zijn

uitgevoerd voorafgaand aan en na afloop van de chirurgische procedure.

Hoofdstuk 2 is het eerst gepubliceerde artikel wat voortkomt uit de TO-CABG

studie. In dit artikel is onderzocht wat het effect van on-pump en off-pump

CABG is op de non-invasieve intra-operatieve registratie van cerebrale

weefseloxygenatie, in relatie tot de ontwikkeling van postoperatieve cognitieve

dysfunctie (POCD). We observeerden dat significante cerebrale deoxygenatie

zelden voorkwam in onze patiëntpopulatie, en de indicentie van desaturaties,

zelfs met andere drempelwaarden, was niet verschillend tussen patiënten

gerandomizeerd voor on-pump en off-pump cardiale chirurgie. Daarentegen, we

vonden wel een significante reductie in de incidentie van cognitieve dysfunctie

3 maanden na off-pump CABG. Door het onderzoeken van de effecten van CPB

in cardiale procedures op neurologische uitkomst kunnen nieuwe inzichten

ontstaan aangaande preventie van neurologische complicaties en het verbeteren

van postoperatieve uitkomst.

In hoofdstuk 3 worden de effecten van CPB op neuronale schade biomarkers in

het bloed onderzocht en hoe deze relateren aan postoperatieve cognitieve

dysfunctie op de lange termijn en postoperatieve overleving. Klassieke

neuronale schade gerelateerde biomarkers hadden geen duidelijke prognostische

waarde in onze studiepopulatie. Daarentegen, plasma vrij hemoglobine bij

sternum sluiten en hs-troponine T gemeten op 1 dag na chirurgie waren

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significant geassocieerd met cognitieve dysfunctie op de lange termijn.

Daarnaast vonden we significant hogere waarden van brein vetzuurbindend

eiwit (BFABP) in de pre-operatieve bloed samples van patiënten met

symptomen van POCD gemeten op 15 maanden na chirurgie. Onze resultaten

laten zien dat cognitieve dysfunctie, gemeten op 3 maanden na CABG, dus

buiten de acute fase, een waardevolle prognostische factor is in het voorspellen

van voortgaande cognitieve stoornissen een jaar later. Daarnaast was er een

duidelijke associatie tussen POCD gemeten op 3 maanden na chirurgie en all-

cause postoperatieve mortaliteit. Meer onderzoek is noodzakelijk om de waarde

van alternatieve neuronale schade gerelateerde biomarkers te bepalen. Onze

data suggereren dat POCD als een interessante optie kan fungeren als surrogaat

marker voor postoperatieve mortaliteit.

We weten uit eerdere studies dat postoperatieve mortaliteit nauw gerelateerd is

aan acute nierschade. Daarom hebben we geëvalueerd of renale

weefseloxygenatie het ontstaan van postoperatieve nierfunctiestoornissen in

volwassen patiënten kan voorspellen, in vergelijking met de renale

schademarkers neutrofiele gelatinase-geassocieerd lipocalin (NGAL), en nier

schade molecuul-1 (KIM-1) in hoofdstuk 4. In onze analyse was nierweefsel

specifieke deoxygenatie geassocieerd met toegenomen postoperatieve serum

creatinine waardes in patienten die off-pump CABG ondergaan. Dit bevestigde

onze hypothese dat nierweefsel specifieke deoxygenatie een voorspellende

waarde kan hebben voor ongunstige renale uitkomsten. Daarentegen vonden we

in on-pump chirurgie een omgekeerde associatie tussen nierweefsel specifieke

deoxygenatie en nierfunctie, aangezien deoxygenatie paradoxaal geassocieerd

was met betere renale uitkomst in een multivariate regressie analyse.

Vervolgens hebben we verlies van autoregulatie geanalyseerd, aangezien dit

mogelijk een logische verklaring zou zijn voor deze paradoxale associatie. We

evealueerden de relatie tussen intra-operatieve mean arterial pressure en renale

weefseloxygenatie. We vonden een sterk positieve correlatie tussen MAP en

renale weefseloxygenatie in de laatste fase van on-pump CABG, terwijl een

dergelijk verband absent was in off-pump procedures. Waarschijnlijk is de

positieve correlatie een indicatie voor verlies van autoregulatie van renale

bloedstroom in deze populatie. Onze resultaten laten zien dat intra-operatief

verlies van renale autoregulatie de tegenovergestselde relatie tussen intra-

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operatieve renale weefsel deoxygenatie en postoperatieve nierfunctiestoornissen

in on-pump CABG zou kunnen verklaren.

Om meer inzicht te krijgen in de mechanistische effecten van major systemische

chirurgische stimuli op neurologische processen, hebben we de

neuroinflammatoire response onderzocht in een chirurgisch laparatomie model

in de muis. We verwachtten dat microglia sterker en langduriger geactiveerd

zouden zijn in oude dieren, in vergelijking met volwassen dieren. Dus

onderzochten we in hoofdstuk 5 reactieve en priming aspecten van

neuroinflammatie na systemische inflammatie in een laparotomie chirurgisch

model zonder inductie van sepsis. Dit hoofdstuk toont dat oude muizen hogere

pro-inflammatoire cytokines tot expressie brengen, zowel na operatie als in

controle dieren, in vergelijking met volwassen muizen. Daarnaast vonden we in

oude muizen lagere brain-derived neurotrophic factor (Bdnf) eiwit expressie en

mRNA. De activatie van pro-inflammatoire cytokines in oude muizen was

toegenomen op 4 uur postoperatief, in vergelijking met controle, maar er was

een significante afname waarneembaar op 24 uur na procedure, net zoals dit in

volwassen muizen het geval was. Hieruit concluderen we dat een chirurgische

impuls, zoals een laparotomie, geen langdurige en overdadige

neuroinflammatoire respons uitlokt in oude muizen.

Deel B begint vanuit een therapeutisch oogpunt met de voordelen van

hypothermie in targeted temperature management (TTM). Hoofdstuk 6 is een

overzicht van de mechanismen waardoor TTM zijn beschermende werking

uitoefent tegen ischemie/reperfusie (I/R) schade in het brein. TTM reduceert

glutamaat afgifte en oxidatiee stress and inhibeert de afgifte van pro-

inflammatoire factoren. Vervolgens heeft TTM een remmende werking op

mitochondrieel geïnduceerde apoptosis, neuronale excitotoxiciteit, en

neuroinflammatie. Recente literatuur wijst uit dat TTM de unfolded protein

response (UPR) remt, door verminderde activatie van de PERK-eIF2α-ATF4

pathway. Daarnaast worden SUMOylatie en de productie van cold shock eiwit

RBM3 gestimuleerd. Nader onderzoek naar TTM is noodzakelijk om de

toepassing ervan te verfijnen en de mogelijkheden van farmacologische

nabootsing of stimulering van de cellulaire effecten van TTM te exploreren. Het

verbeteren van de toepassing van TTM kan de ziektelast van patiënten met

hartstilstand, beroerte of post-cardiaal chirurgische complicaties doen afnemen.

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De effecten van TTM op de lange-termijn postoperatieve overleving in een

groot cohort van patiënten die cardiale chirurgie hebben ondergaan, is

onderzocht in hoofdstuk 7. We identificeerden dat milde hypothermie (32-

35oC) in CABG procedures en milde tot matige hypothermie (30-35

oC) in

klepchirurgie als richttemperatuur geassocieerd zijn met lange-termijn

postoperatieve overleving. Wat interessant is, is dat we een grote variantie

vonden in de mate van adaptatie van de patiënts kerntemperatuur aan de

geforceerde koeling door de CPB. Patiënten kunnen een hoge of lage mate van

temperatuurcompliantie met geforceerde koeling vertonen. Zowel in CABG als

klepchirurgie is lage compliantie met geforceerde koeling geassocieerd met een

significant betere postoperatieve overleving, onafhankelijk van

richttemperatuur. We hebben dus de ideale richttemperatuur vastgesteld in de

twee meest voorkomende types van cardiale chirurgie, en identificeerden een

nieuwe temperatuur-gerelateerde patiënt factor die geassocieerd is met

postoperatieve overleving.

De effecten van milde en diepe hypothermie op de neuroinflammatoire response

in een model voor de CPB in de rat staan beschreven in hoofdstuk 8.

Neuroinflammatie in ratten die CPB of sham procedure ondergingen onder

hypotherme condities bij 18oC of 33

oC werd onderzocht middels PET-scans op

dag 1, 3 en 7 na de procedure, door standard uptake values (SUV) te vergelijken

van de tracer [11

C]-PBR28, die bindt aan geactiveerde microglia. We vonden

een significante toename van SUV in hippocampus en amygdala van ratten die

CPB bij 18oC ondergingen op 7 dagen na de procedure, terwijl op dag 1 na

procedure nog geen verschil zichtbaar was. Verder observeerden we een

toename in TrkB en RBM3 in cortex op dag 1 en in hippocampus op dag 7 in

ratten die CPB ondergingen bij 33oC. We concluderen hieruit dat diepe

hypothermie toegenomen neuroinflammatoire response veroorzaakt in

kwetsbare hersengebieden, vergeleken met milde hypothermie. Daarnaast

induceert milde hypothermie cold shock eiwit activatie in zowel cortex als

hippocampus bij ratten na CPB, in vergelijking met diepe hypothermie.

Samenvattend zou dit kunnen betekenen dat neuroinflammatie wordt getemperd

in milde hypothermie, mogelijkerwijs door activatie van beschermende

mechanismen door cold shock eiwit inductie.

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Acknowledgements

In the past few years I've become acquainted with many kind, intelligent, and

wonderful people. Starting with my fellow MD/PhD-ers, Vera and Jojanneke,

thank you for becoming good friends. You’ve introduced me in the laboratory,

animal science, and brain research. We have shared so many shiny, glorious,

and devastating experiences. I reckon you will become excellent doctors. The

same applies to you, Edwin. You have become my CDP buddy, especially in

untimely hours. I've become fond of your good humour, friendly conversation,

and beautiful scientific images. Thrombocytes will never be the same again.

Marziyeh, you have been a wonderful office neighbour. I admire your class,

your hairdresser, and your Iranian style. I enjoyed our trips out of the UMCG

and shared the cultural shock at the numerous Ladies Nights we visited. You are

The Boss! Talking about bosses, thank you Dalibor, Seb, and Arash. Thank you

for holding open so many doors for me, while not mansplaining me, and letting

me believe I was one of the guys. As certainly I am not, I think I made a good

shot by performing between 2 and 300 push-ups. You still owe me. Thanks for

sharing the nerdiness, such as Game of Thrones, South Park, Pokemon Go, and

Friendly vegetables. Marloes, you joined in last, but not least. Good luck with

your kitten and I hope you will enjoy Groningen as much as I did!

All of you, good luck with your projects!

I wouldn't have published this thesis if it wasn't for you, Rob. After applying for

a job as a student-assistant in the development team of the new curriculum for

G2020, you casually asked me if I had any interest at all in working at your lab.

I have never regretted saying yes immediately. Your casual positivism,

intelligible global view and honest feedback have inspired me to become the

person I am now. Even though you laughed at me in my face when I told you I

intend to become a general practitioner. Whether it concerns the hamster

genome, the relation of volcanoes to longevity, or a vision about interstellar

pathways towards new societies, you have proven a terrific mapmaker. I will

miss our vast strides through the hallways of the UMCG towards the

department of Anaesthesiology.

Which brings us to Tony and Thomas. Dear Tony, I have always admired the

way you remain positive and comforting throughout the hassle of everyday life

at such a large and busy department. You have seen me make my first steps in

science. Thank you for the opportunity to participate in the TO-CABG study.

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You instigated my desire to travel to Cambridge at the beginning of my PhD,

where I ended up having a wonderful scientific experience. Dear Thomas, I

appreciate your attempts to frame a clinical perspective for me from an

anaesthesiological point of view. Thank you for your patience and your critical

feedback. I would never have been able to accomplish this work without you.

Thanks to the members of the assessment committee, for your help and support.

Thank you Bart, I learned a great deal from you regarding neuroinflammation.

Thank you Fred, you are a digital magician. Thank you Anne and Hubert, for

your creative ideas and constructive feedback.

I’d like to thank all my co-authors for your valuable suggestions and

improvements on the manuscripts included in this thesis. It would have been

impossible to present these here without you!

Martin, you have been my big support in the experiments at the CDP. Without

you, I would not be standing here. Thank you for sharing your decades of

experience in animal science with me. I always enjoyed your friendly manner,

as well as your typical Groningse koppigheid. There are still Easter eggs left

lying around the CDP, which I honestly think nobody will ever find.

A warm thanks also to Catriene, Minke, Linda, Linda, Ronald, Aalzen, Michel,

Annemieke, Bianca, Andre, Ar and all other animal carers who were involved

in my projects at the CDP.

For all dear colleagues, thank you. Sunita, Ardy, Alexandra, Wessel, Marja,

Leo, Hendrik, Marry, Maaike, Femke, and Azuwerus. Thank you for doing the

things you are good at! I would not have accomplished this without your help.

All students who’ve helped me during my PhD, thank you for your hard work

and enthusiasm.

Thanks to Hjalmar, you have been a terrific mentor and teacher by example. I

think you will become a great professor in either Rheumatology, Critical Care

Medicine, Internal Medicine, Pharmacology or any other field. Also thanks to

you, Susanne. You are an excellent researcher and mother. I’ve greatly admired

the ease with which you move through life, combining science - requiring

irregularity, with motherhood - requiring regularity. I think you will become a

great professor in Neurosciences.

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Of the department of Nuclear Medicine, I would like to thank Janine. Although

you had a busy agenda, you were always willing to help out. Even if it made

you run out of obligatory coursework. Jürgen, you have literally pulled my cart

so many times to and from the department. Rolf, you helped me a great deal

with the radio-active calculations. Special thanks to Petra, Jeanet and Chantal,

for your radiant appearances and radiant products for my experiments. May the

Cyclotron cycle on and on and on.

During my stay in Cambridge, I became acquainted with even more wonderful

and intelligible people. First, thank you Giovanna, for having me over, even

though you had limited space at your lab. My experiences at the Clifford Albutt

building were novel, fruitful and exhilarating. I admire your honesty and vision.

Special thanks to Nick and Diego, for your knowledge and for making my stay

the opposite of a cold shock. Also, thanks to Heather, Olly, Hannah, Sanad,

Dhruv, and Ibrahim, for the good times and the poker games.

Special thanks to Barbara Slothouber, Cisca Wijmenga, Barbara van Leeuwen,

and Marlies Zandwijk. All strong women among whom are my greatest

examples.

During my PhD, I had so much support from all these great people. Thank you

Afra, for your optimism, and your strong leading and teaching abilities. Thanks

to Niels and Hajo, for the liflafs in the past and the liflafs yet to come; Yara and

Francisca, for whom I should have published in Plos One; My lady Eva of

House Stark; Sanne and Lysanne - as I hope you will be around longer than we

already know each other; Shasti, my future reumatologist, Admira, my future

surgeon and, Liselotte, my future anaesthesiologist; of course all members of

Epic Emmen, and Jeanette, the best neighbour in the world!

Hiya bro! Thank you for your nonchalant sarcasm. It made me laugh. I hope

you can appreciate the work presented with some pride for your big sis. Also, I

am grateful for having you as my paranymph.

Mum and Ded, Arend en Ineke, thank you for believing in me. It was your

endless optimism and genuine encouragement that brought me to Groningen,

the UMCG, and across the globe. Due to your honesty, I was capable of being

true to myself.

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Frank, thank you for always being around, even though you might have been

physically elsewhere sometimes. You brought me Netflix, HBO Go, Spotify,

Sonos, Misfit, Fitbit, Skype, Samsung Galaxy S6, nrc-next.nl, the Twitters, and

a beautiful shiny ring. You made me a lot more digital and a lot happier since

we met. I am a proud and lucky woman having you standing next to me.

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Resume

Linde Kok was born on the 15th of November 1989 in Deventer, The

Netherlands. She grew up in the village of Heino, close to the city of Zwolle,

where she completed her secondary education. Kok earned her Bachelor’s

degree in Medicine at the Rijksuniversiteit Groningen in 2011, together with an

Honours certificate for completion of the Junior Scientific Masterclass program.

She continued her Medical education with the scientific clerkship of the Master

program, by participating in the TO-CABG study with Prof. dr. A.R. Absalom

and Prof. dr. T.W.L. Scheeren at the department of Anesthesiology, University

Medical Center Groningen. Simultaniously, she started with the Master

Honours program - Leadership and Interdisciplinarity, which was completed in

2013.

After becoming a student-member of the development team of the new

Bachelor curriculum for Medicine, under the directions of Prof. dr. R.H.

Henning, she applied for an MD/PhD in 2013 as a close collaboration between

the departments of Anesthesiology and Clinical Pharmacy and Pharmacology.

This resulted in a graduation in Medicine in December 2014, followed by two

years of research at the department of Clinical Pharmacy and Pharmacology.

During her PhD, Kok investigated the application of hypothermia in association

with long-term survival after cardiopulmonary bypass-assisted cardiac surgery.

In addition, she investigated the cerebral cold shock response in rats cooled with

the cardiopulmonary bypass, at the department of Clinical Neurosciences,

University of Cambridge, UK, led by Prof. dr. G.R. Mallucci. In December

2016, she finished her PhD, resulting in this thesis. Currently, she is working as

a resident (not in training) Cardiology at the Haaglanden MC in The Hague.

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Recommended literature

Het verslag van Brodeck - Philippe Claudel

De eenzaamheid van de priemgetallen - Paolo Giordano

I am pilgrim - Terry Hayes

Onder professoren - W.F. Hermans

De gevleugelde - Arthur Japin

The girl who saved the king of Sweden - Jonas Jonasson

To kill a mockingbird - Harper Lee

One hundred years of solitude - G. García Márquez

Love in the time of cholera - G. García Márquez

The Tsar of Love and Techno - Anthony Marra

A Game of Thrones - G.R.R. Martin

A Clash of Kings - G.R.R. Martin

A Storm of Swords - G.R.R. Martin

PAAZ - Myrthe vd Meer

Big Sur and the Oranges of Hieronymus Bosch - Henry Miller

The Bone Clocks - David Mitchell

Slade House - David Mitchell

Norwegian wood - Haruki Murakami

Us - David Nichols

Calamiteitenleer voor gevorderden - Marisha Pessl

The Interpretation of Murder - Jed Rubenfeld

The House of God - Samuel Shem

Suezkade - Jan Siebelink

The Rosie Project - Graeme Simsion

Wat denkt u, dokter? - Rutger Verhoeff

De zomer hou je ook niet tegen - Dimitri Verhulst

Candide - Voltaire

Mrs. Dalloway - Virginia Woolf

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